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Hum Vaccin Immunother. 2014 April; 10(4): 1036–1046.
Published online 2014 February 10. doi:  10.4161/hv.27999
PMCID: PMC4896561

Listeria monocytogenes

A promising vehicle for neonatal vaccination


Vaccination as a medical intervention has proven capable of greatly reducing the suffering from childhood infectious disease. However, newborns and infants in particular are age groups for whom adequate vaccine-mediated protection is still largely lacking. With the challenges that the neonatal immune system faces and the required highest level of stringency for safety, designing vaccines for early life in general and the newborn in particular poses great difficulty. Nevertheless, recent advances in our understanding of neonatal immunity and its responses to vaccines and adjuvants suggest that neonatal vaccination is a task fully within reach. Among the most promising developments in neonatal vaccination is the use of Listeria monocytogenes (Lm) as a delivery platform. In this review, we will outline key properties of Lm that make it such an ideal neonatal and early life vaccine vehicle, and also discuss potential constraints of Lm as a vaccine delivery platform.

Keywords: Listeria monocytogenes, neonate, birth, vaccination, safety, attenuation, adjuvant, antigen delivery


It has been over 200 y since the breakthrough of vaccination as a life-saving tool.1 Yet despite great contribution by vaccines to the reduction of mortality and morbidity, the number of lives claimed by infectious diseases among newborns and infants under 6 mo of age still amount to more than 2 million every year.2 This is partly due to the fact that there are presently only 3 vaccines licensed for at-birth administration;3 for many other diseases that strike early, there still exists no vaccine.

Newborns have a higher risk of suffering from infection than any other age group.4 This is believed to be attributable to inherent limitations of the newborn’s immune system as compared with adults.5 However, a number of studies have now shown that given the appropriate stimulus, the neonate is indeed capable of generating an adult-like immune response,6-8 suggesting the possibility that newborns can respond to vaccination in a manner similar to their adult counterparts.4

Listeria monocytogenes (Lm) is a facultatively anaerobic, non-spore-forming, and gram-positive microbe. With a tolerance for low temperatures, high salt concentrations, and alkaline environments, Lm is able to survive and replicate in various niches, including food products–contamination of which is a common source of severe Listeria infection in humans.9Lm also possesses a host of devices that facilitate its pathogenesis, enabling it to effectively enter into and move within target cells, avoid autophagy, and spread cell-to-cell.9Lm has a relatively low infection rate in the general population (ranging from 0.1 to 11.3 per million people) despite its ubiquity.10 In addition, Lm displays non-uniformity in its age distribution, causing infection mostly in newborns or the elderly, with a disproportionately high mortality rate of 20–60% in those groups. Natural infection by Lm normally presents asymptomatically in the healthy host; clinical symptomatic infection by Lm on the other hand, known as “listeriosis,” may exist as a non-invasive form that develops as a febrile gastroenteritis, or an invasive form characterized by the systemic spread of Lm targeting mainly the placenta, liver and spleen, and the central nervous system.10 Clinical features of listeriosis in children most commonly include meningitis or septicemia, although a number of other complications may also occur.10

The serious impact that Lm has as a pathogen in newborns could preclude its consideration as a neonatal vaccine system. However, some of the very same aspects that make Lm such a formidable pathogen also make it a powerful vaccine delivery platform. Recent years have not only seen the establishment of Lm as a practical and versatile approach to vaccination in adults, but also the generation of very promising results as a neonatal vaccine vehicle. Following the success of increasing Lm’s safety profile while maintaining its potent immune stimulatory characteristics, we propose that Lm holds great potential as a vaccine vehicle for the human newborn.

What is Currently Known About Lm-Based Vaccination?

The concept of Lm-based delivery of antigens first emerged at the University of Pennsylvania when Dr Yvonne Paterson demonstrated the ability of a recombinant Lm strain expressing and secreting the influenza virus nucleoprotein (NP) to efficiently access both major histocompatibility complex (MHC) class I and II pathways.11 Moreover, the Lm-NP vector induced an antigen-specific and T cell-dependent anti-tumor response that not only protected immunized mice against lethal challenge by NP-expressing tumors, but also caused the regression of established tumors.12,13 This suggested that Lm as a delivery platform effectively induces both prophylactic as well as therapeutic immunity.

Anti-tumor Lm-based immunotherapy

The development of Lm as a vaccine delivery platform against neoplastic disease has given rise to a notable repertoire of recombinant Lm strains capable of expressing and secreting a variety of tumor-associated antigens, a number of which have entered clinical-stage testing against a wide range of cancers; several of these Lm-based vectors have advanced to Phase II trials.14,15 One such strain expresses the E7 antigen of human papillomavirus (HPV) as a fusion protein with listeriolysin O (LLO), and is used against HPV-associated cancers such as cervical, head and neck, or anal cancer.16 Another Lm strain expresses human mesothelin and is being explored as an immunotherapeutic agent to treat pancreatic cancer.17 In preclinical studies using a murine prostate tumor model, it has furthermore been shown that the combination of Lm-based PSA (prostate specific antigen) immunotherapy and radiation therapy was more effective for the treatment of established tumors than either of the 2 treatment modalities used alone, with the combinatorial treatment demonstrating a multifold increase in PSA-specific cytotoxic T lymphocytes (CTLs) as well as a significant increase in CTL infiltration of tumor tissues.18 The immunotherapeutic efficacy of Lm-based vectors has been further improved when combined with anti-PD-1 antibodies.19 In a metastatic model of hepatic colorectal cancer, an AH1 peptide-expressing Lm strain elicited potent cytotoxic tumor-specific CD8+ T cell responses that could cure mice of hepatic metastasis and subsequently protect from tumor re-challenge.20 Recently, an Lm strain expressing and secreting a fusion of multiple peptides of the hepatocellular carcinoma (HCC)-related tumor-associated antigen was shown to slow the development of HCC in both prophylactic and therapeutic settings, demonstrating also the induction of strong cytotoxic T cell immunity against each epitope in the fusion peptide; this supports what we know regarding Lm’s ability to overcome self-tolerance to an endogenous antigen.21 While Lm is indeed capable of delivering a wide selection of proteins into the cells it infects, the versatility of Lm as a bacterial carrier system is further seen in its ability to also transport DNA into mammalian target cells, with the successful delivery of pro-drug converting enzymes by Lm into tumor cells having been reported.22

Lm-based immunotherapy has also been shown to severely reduce the suppressive activity of myeloid-derived suppressor cells as well as regulatory T cells in the tumor microenvironment (TME), thereby lessening the impairment of T cell function; this modulation of immunosuppression in the TME is an inherent property of all Lm-based vaccines.23 With a proven capability to target tumors both effectively and safely, as well as the surprising success observed when combined with various forms of cancer therapy (e.g., bacterial-based immunotherapy with chemotherapy), Lm-based immunotherapy has made significant contributions in the fight against cancer.

Anti-infective Lm-based vaccination

As a vaccine vehicle against infectious disease, immunization with recombinant Lm has been shown to protect against immunosuppressive strains of lymphocytic choriomeningitis virus (LCMV).24 An Lm strain expressing the human immunodeficiency virus (HIV) Gag protein was capable of inducing antigen-specific CD4+ T cells with a Th1 interferon-gamma (IFN-α)-producing phenotype, and immunized mice displayed accelerated clearance of viral challenge with a Gag-expressing vaccinia virus construct.25,26 Lm-based vaccination has also succeeded in inducing robust and functional HIV-specific cellular immune responses in mice regardless of underlying chronic infection status (e.g., helminth infections).27 Against the parasite Leishmania major, immunization of mice with recombinant Lm delivering an L. major antigen has been shown to generate in vivo CD4+ T cells with a Th1 phenotype that exerted protective antiparasitic function.28 Lastly, a recombinant Lm vaccine stably expressing the IglC protein of Francisella tularensis was found to induce protective immunity against lethal F. tularensis challenge in mice; this success was shown to be due to the powerful cellular CD4+ and CD8+ T cell immune responses against IglC.29 Moreover, mice immunized with this strain showed protection even against lethal intranasal challenge by F. tularensis LVS, i.e., mimicking the natural route of infection for humans (airborne).29

Lm-based vaccination in the neonate

Cognizant of the safety concerns regarding neonatal vaccination, one of the first studies exploring Lm as a neonatal vaccine sought to evaluate the safety and immunogenicity of a hyperattenuated Lm strain expressing the HIV Gag protein, as well as the protection it could afford against challenge by a Gag-expressing recombinant of vaccinia virus.30 This Lm strain given to neonatal mice was found to be safe, and with the administration of a booster dose, also able to initiate a protective CD8+ cytolytic T cell response. The emergence of yet more promising results came several years later, when neonatal mice that were immunized at birth with only one dose of the attenuated strain ΔactA-Lm achieved protective immunity from severe Listeria infection.31 The same study not only demonstrated the induction of a T cell response in neonatal mice similar in kinetics to that displayed by their adult counterparts, but also identified the generation of robust and sustained Th1 CD4+ and CD8+ Lm-specific T cell memory responses, along with strong antigen-specific primary and memory CD8+ T cell responses.31

It was subsequently shown that Lm-immunized neonatal mice required only a single dose to reach maximal antigen-specific CD8+ T cell expansion, whereas adult mice required a booster dose; antigen-specific CD4+ T cell expansion on the other hand, required a boost to reach its peak, in both neonates and adults.32 With the ability to generate substantial protection and immune memory with only a single dose, Lm thus circumvents the requirement for boosting that subunit or inactivated vaccines often face.32 Specifically, a single administration of an attenuated Lm vaccine in mice during the first week of life was shown to induce protection from lethal challenge as early as 1 wk following immunization, lasting the lifetime of the mouse without the need for additional booster doses.33 In addition, mice immunized as neonates or adults displayed no difference in the functional avidity, sensitivity and T cell receptor Vβ(TCR-Vβ) repertoire of their antigen-specific T cells; receiving immunization as a neonate also did not compromise on protection or preclude booster responses with the same Lm vector at a later point in time.32 “Original antigenic sin” (a phenomenon where the specific immune response mounted against the initial antigen prevails even during subsequent infection by dissimilar variants of the antigen34) appears unlikely to impact the use of live Lm for neonatal vaccination, given that the introduction of new antigens in neonates via Lm vectors has been shown to allow for induction of protective cell-mediated immunity to the newly-introduced, while maintaining responsiveness to the original antigens.32,35 Furthermore, immune memory responses to specific multiple antigens in a live Lm-vectored vaccine were all found to last the lifetime of the mouse whether they were immunized as newborns or adults.33 Attenuated Lm has also been shown to clear from the host within 1 wk of administration in both neonates and adults, and would therefore be unlikely to alter the normal cytokine milieu for prolonged periods of time.33

Taken together, these data indicate that neonatal vaccination with Lm achieves at least similar—if not better—immune responses as compared with Lm immunization in adults, strengthening the notion of Lm being highly suitable as a neonatal vaccine delivery platform. The known pathogenicity of Lm, however, has meant that safety remains an issue of major concern.

Vaccine Safety and Strategies of Attenuation

Lm as a pathogen is well endowed with a range of virulence factors that enable it to cause disease. Many of these virulence factors have been targeted in ways that allow for attenuation while retaining immunogenicity. Understanding the functions of these virulence factors as well as their roles in pathogenesis is a central theme in the design of vaccines. Here, we briefly review the pathogenesis of Lm and current attenuation strategies (Table 1) aimed at providing optimal vaccine safety for this live vaccine vector.

Table thumbnail
Table 1. Current strategies to the attenuation of Lm-based vaccines

Lm pathogenesis

Lm infection begins with oral ingestion of the bacteria.36,37 In the human gastrointestinal tract, Lm moves across the mucosal barrier by first adhering to the mucosal lining via the bacterial protein Ami;38 this is followed by entry into intestinal target cells either through phagocytosis or through the action of listerial internalin A (InlA).39 Transcytosis across the intestinal epithelium follows, after which Lm is released into the lamina propria by exocytosis and disseminates systemically.40

Lm primarily targets the liver, with the help of bacterial adhesin FbpA.41 FbpA binds to human fibronectin expressed on the surface of hepatocytes.41 Another listerial internalin, InlB, next binds to the host hepatocyte growth factor receptor (a tyrosine kinase receptor, Met) or complement component C1q receptor,42 in turn mediating efficient entry into hepatocytes (as well as fibroblasts and epithelioid cells).43 However, invasion efficiency is much higher in phagocytes, especially macrophages and monocytes.9 Macrophages and dendritic cells (DCs) represent the main carriers of the bacterium in infected tissue.44 The uptake of Lm by phagocytes occurs via the binding of scavenger receptors on host cells to lipoteichoic acid (a component of the listerial cell wall),45 or the binding of certain listerial cell surface components to host cell complement receptors, e.g., InlB.42 In order for Lm to avoid destruction inside the phagocyte, it has to escape from the phagocytic vacuole.46 Apart from several host factors involved in this process,46 the 3 bacterial factors most clearly responsible for enabling the escape of Lm into the cytosol are LLO and 2 phospholipase C enzymes, PlcA and PlcB. LLO is a secreted cholesterol-dependent cytolysin (CDC) toxin. In mice, LLO is essential for bacterial escape from primary vacuoles as well as secondary double-membrane vacuoles formed during cell-to-cell spread.47,48 In humans, the bacterial factors critical for phagosomal vacuolar escape are instead, the 2 phospholipases, PlcA and PlcB.9 PlcA is required for lysis of the phagosome formed during initial entry into the host cell,49 and PlcB is required for efficient escape from the secondary vacuole;50 the 2 phospholipases work synergistically with LLO in allowing Lm to escape into the cytoplasm.51,52 Once in the cytoplasm, Lm is able to replicate intracellularly by usurping nutrients provided by the host. Lm next induces polymerization of host actin filaments to move in the cytoplasm and spread from cell to cell;53,54 the only determinant that Lm requires for its actin-based motility is the bacterial surface protein ActA.55,56 The genes encoding Lm’s most prominent virulence-associated proteins (LLO, ActA, PlcA and PlcB) are located adjacently in a 9.6 kb virulence gene cluster,57 chiefly regulated by a pleiotropic virulence regulator, PrfA (a protein encoded by prfA).36,58

Current strategies of attenuation

The selective and irreversible deletion of classical virulence factors is perhaps the most direct means of attenuating Lm.59,60 An Lm strain lacking prfA recently demonstrated a high level of safety in a Phase II clinical trial in patients with recurrent cervical cancer.61 Another Lm strain generated via the deletion of both actA and inlB exhibited diminished toxicity in vivo, primarily from impediment of the direct InlB-mediated infection of non-phagocytic cells as well as the reduction of ActA-mediated cell-to-cell spread from adjacent phagocytic cells; there was no compromise on Lm’s ability to infect phagocytic cells, which meant that immunogenicity was retained.62 In addition, actA deletion accompanied by deletion of plcB generated a strain that could be administered orally to adult volunteers without any adverse health sequelae.63

Auxotrophy has also been explored as a means of attenuation, where the Lm mutants generated require exogenous factors for in vivo and in vitro growth.59 The inactivation of 2 genes, dal and dat, has resulted in Lm strains that grow only when supplemented with d-alanine (a cell wall component in virtually all bacteria64,65).66 Consequently, these strains are unable to grow in the cytoplasm of eukaryotic host cells, Lm’s natural habitat during infection. Nevertheless, immunogenicity has remained as evidenced by the induction of T-lymphocyte responses and protective immunity against lethal challenge by wild-type Lm.66 A shuttle vector was designed containing a copy of the Lm dal gene, which could complement the growth of the Lm dal dat mutant both in vivo and in vitro.67 However, anticipated concerns over the recombination of plasmid with bacterial chromosomes led to the dalLm-containing plasmid being replaced with a plasmid containing an Lm actA promoter-regulated resolvase gene and the dal gene from Bacillus subtilis (dalBs) flanked by 2 res1 sites; this allowed the highly-regulated and transient expression of the dal gene upon exposure to the host cell cytosol, without the risk of reversion to a virulent microbe via recombination.68 Furthermore, the introduction of an irreversible deletion in the actA gene has resulted in a strain that is dal dat ΔactA attenuated and complementable by the dalBs-based antibiotic-free plasmid.69

Other approaches to attenuation have included deletions in aro genes, a family of genes belonging to the common branch of the biosynthesis pathway leading to aromatic compounds affecting oxidative respiration.70 Lm aro mutants displayed drastically reduced rates of cytosolic replication and cell-to-cell spread, yet retained immunogenicity.70 Mutation in the glcV gene of Lm was found to preclude the binding of certain listerial phages and produce profound attenuation by mechanisms that have yet to be elucidated, although it is speculated that glcV mutation leads to alterations in the listerial phage receptor and therefore interferes with normal host-pathogen interactions required for virulence.71 Such a strain, when administered orally to mice, induced robust and long-lasting protective immunity despite the near absence of vital organ infectivity.72 By removing genes required for nucleotide excision repair (uvrAB) and thus rendering Lm highly sensitive to photochemical inactivation, a Killed But Metabolically Active (KBMA) strain of Lm was designed that is unable to replicate yet still having sufficient metabolic activity for delivering antigens to the immune system.73 It was later on demonstrated that constitutive activation of prfA leads to the enhanced ability of KBMA Lm to induce protective cellular immunity.74 Deletion of the frvA gene resulted in an Lm strain incapable of iron homeostasis and strongly attenuated in virulence, yet retaining the ability for intracellular growth in antigen-presenting cells. Furthermore, immunization with the ΔfrvA mutant was found to offer complete protection from listerial infection.75 A self-destructing mutant of Lm achieved via the expression of a Listeria-specific phage lysin has also been described; however, safety concerns over the integration of the relevant Lm plasmid DNA into the host cell genome have prevented further development.76

Finally, forcing the expression of flagellin (flaA) or PrgJ (from the Type III secretion system of Salmonella typhimurium) by Lm in the host cell cytosol has been employed to specifically target the Caspase-1 activation pathway, bringing about the preferential clearance of bacteria via activation of the NLRC4 inflammasome.77 Although this strategy was indeed confirmed to bring about a high degree of attenuation in Lm,78 its impact on immunogenicity is not clear–with one group demonstrating the induction of protective immunity in mice against lethal challenge with Lm,77 and another showing instead, a poor induction of protective immunity.78 This conflicting data may be due to the different methods used in these 2 studies to increase flagellin expression, as well as the difference in bacterial species from which flagellin was taken.

Among the array of attenuation strategies that exist for Lm-based vectors, perhaps the method that would best achieve safety for use in the neonate is the irreversible deletion of Lm virulence genes. The major genes that have been shown to be important for the virulence of this pathogen include actA, plcA, plcB, hly, prfA, inlA and inlB.59 Of these, the deletion of actA, which is responsible for cell-to-cell spread of Lm, causes at least a thousand-fold attenuation while still retaining immunogenicity.79 The deletion of hly or prfA completely eliminates the ability of Lm to grow intracellularly, reducing immunogenicity to a level that hinders its use as a vaccine platform.59 The presence of other deletions in an actA mutant strain (e.g., Lm dal dat ΔactA; Lm ΔactA/ΔInlB) has been demonstrated to further enhance the overall attenuation to Lm. With actA deletion having already been proven safe yet effective in newborn mice, coupled with the additional credibility ascribed to it by its utility in multiple Lm vectors (Table 1), such a strategy, when employed with efforts to further reduce the risk for reversion to wild-type Lm (e.g., dal dat deletion), currently represents the most favorable option for Lm-based neonatal vaccination.

Proof-of-concept for safety of neonatal immunization using live-attenuated vaccines has been established with the BCG and oral polio vaccines.3 Moreover, while it impossible to predict at this stage if current strategies of Lm attenuation would definitely be safe for the human newborn, the currently available data summarized above strongly suggest this to be the case.30,31,33

Live L. monocytogenes as an Immune Modulator and Vaccine Adjuvant

Vaccine adjuvants are agents that serve to activate the innate immune system, directing the quantity and quality of the adaptive immune response following an antigen-specific stimulus.80 The inclusion of adjuvants has been key to the efficacy of most vaccines given early in life, which are often subunit vaccines that lack inherent adjuvant activity required for the generation of a favorable immune response.81 The increasing attention that Lm has been receiving as a vaccine vector is in part due to its adjuvant activity, i.e., its ability to elicit a strong innate immune response. The potent and predictable immune modulatory activity of Lm allows for the induction of robust Th1-type cell-mediated immunity by Lm-based vaccines. The capacity to function as a powerful adjuvant relates to the specific signaling pathways that Lm activates.

Lm-activated signaling pathways

Lm infection of antigen presenting cells (APCs) results in the activation of at least 3 distinct bacterial recognition pathways82: 1) a TLR/MyD88-dependent pathway that induces the expression of inflammatory as well as suppressive/regulatory cytokines (such as TNF-α, IL-12 and IL-10), autophagy and production of reactive oxygen species (ROS);83-85 2) a STING/IRF3-dependent pathway that leads to expression of interferon (IFN)-β and co-regulated genes;86 and 3) an AIM-2/Caspase-1-dependent inflammasome pathway that results in proteolytic activation and secretion of IL-1β and IL-18, in addition to pyroptotic cell death.87 Importantly, activation of STING/IRF3- or AIM-2/Caspase-1-dependent pathways require that Lm be alive and escape into the cytosol.88,89

Immune response to Lm

Activation of the 3 pathways mentioned above by Lm initiates the innate immune response in monocytes and macrophages.36,82 The release of IL-6 by infected cells leads to recruitment of neutrophils to the site of infection, which in turn destroy extracellular bacteria, digest apoptotic cells and secrete chemokines that recruit monocytes/macrophages.59 Infected macrophages also produce IL-12, inducing the synthesis of IFN-γ by NK cells and bystander CD8+ T cells; IFN-γ subsequently activates macrophages to become listericidal through the production of ROS and reactive nitrogen species (RNS).90,91 Lm is also known for its ability to induce type I IFNs (e.g., IFN-α and IFN-β), which although typically associated with anti-viral immune responses and essential for the clearance of many intracellular pathogens, have also been suggested to be detrimental to the host during the immune response to Lm.92,93 Lm infection also activates autophagy, where the formation of a double membrane vacuole around cytosolic Lm leads to subsequent degradation of the bacterium via the lysosomal pathway.94 In DCs, Lm induces the release of IL-2; IL-6; IL-12; and TNF-α, as well as the subsequent upregulation of other proteins (e.g., CD40, PD-L1) that promote the maturation and activation of high-affinity T cells.59,95

The adaptive immune response against Lm infection serves 2 main functions: the specific lysis of infected cells and the rapid secretion of IFN-γ in response to innate production of IL-12 and IL-18.96,97 IFN-γ is a crucial contributor to the cell-mediated immune response via macrophage activation; the increasing of antigen presentation via the MHC class I and II pathways; and the inhibition of Th2 cell expansion.91 During infection, Lm secretes a limited number of proteins into the cytosol of the host cell, which when rapidly degraded by the proteasome, generate peptide fragments that enter the MHC class I antigen processing pathway.59,98 Lm infection also generates a robust MHC class II-restricted CD4+ T cell response and drives CD4+ T cells toward a Th1 phenotype;25,59,99 occurring simultaneously is the expansion of CD8+ T cell responses.59,100 A strong and lasting Th1 cell-mediated response dominated by CD8+ T cells and made optimal by CD4+ T cells is what drives protective immunity to Lm infection101,102 and ensures complete and final clearance of the microbe, with humoral responses playing only a minimal role.91

Lm-activated signaling pathways in the neonate

The particularly high risk of severe outcome from Lm infection in the newborn suggests that possible differences exist between the immune signaling pathways activated by Lm in neonates vs. the adult.103,104 The importance of the MyD88-dependent pathway for host resistance is clearly seen from the extreme vulnerability displayed by MyD88-deficient mice to Lm infection.105,106 Even though the ability for innate recognition of pathogens via the TLR/MyD88 pathway early in life does not appear to be different compared with adults,107 there are stark contrasts between the downstream effector responses generated in the human newborn as compared with the young adult103,104 (discussed in the following section). The TLR/MyD88-dependent response of human neonatal monocytes specifically to Lm infection has yet to be explored.104

While IRF3-dependent production of type I IFN via the STING/IRF3-dependent pathway in human newborns is reduced compared with adults,103 the production of IFN-β in humans in response to Lm appears not IRF3-dependent but instead, p38 MAPK-dependent.108 The role of the STING/IRF-3 pathway in human neonatal Lm infection is thus still unclear.104

Finally, although the developmental patterns of the various inflammasome pathways in humans in response to Lm have not been unravelled, it is known that activation of the inflammasome is one way through which aluminum hydroxide (alum, the most common vaccine adjuvant) exerts its function.109 Given that innate immune responses induced by alum decrease over the first 2 y of life,110 age-dependent differences in at least some inflammasome activities are likely to exist.104 This has, however, not been investigated in relation to Lm.104

Immune response to Lm in the neonate

Splenocytes from infected neonates of a murine neonatal listeriosis model have been shown to exhibit much lower expression levels of Th1-supporting cytokines (IL-12p70 and IFN-γ), even when presented with Th1-driving stimuli.104,111 IL-10 is also produced at elevated levels by neonatal mice upon infection with Lm.112 In addition, CD71+ erythroid cells in neonatal mice and human cord blood have been shown to exert immunosuppressive effects; in mice, they appear to be crucial in rendering the neonate more susceptible to Lm infection.113 In humans, the response to Lm has not been studied as a function of age.104 As a proxy, it is known that the generation of proinflammatory cytokines (e.g., TNF-αand IL-1β) by TLR activation in the neonate can differ according to stimuli, and reaches adult levels of production between 1–2 y of age.114,115 There is also a progressive decline in the production of IL-10, IL-6 and IL-23 during this timeframe, from levels initially higher than those found in adults.114,115 Type I IFN production induced by TLR agonists reaches adult levels within only a few weeks of life, despite being significantly lower at birth.114,115 Th1-supporting innate cytokines (IL-12p70 and IFN-γ) likewise eventually reach adult levels of production.114,115 In addition, neonates display significantly reduced TLR-mediated production of cytokines that induce the production of ROS or RNS.116,117

Neonatal CD4+ T cell responses in mice appear to have a Th2 bias at birth.118 Although murine primary neonatal CD4+ Th1 cells and Th2 cells develop in tandem, only Th1 cells were found to undergo apoptosis when re-exposed to antigen.119 Additionally, the production of less IL-12p70 and more IL-10 by neonatal innate cells upon stimulation (as compared with their adult counterparts) would likely lead to suboptimal activation of neonatal CD4+ Th1 and CD8+ T cells.103,104,114,115 However, in spite of the established differences between the human newborn and adult adaptive immune responses,4 given the appropriate stimuli, the human newborn is very much capable of displaying strong and protective Th1-type responses even prior to birth.104,120

L. monocytogenes as an Antigen Delivery Vehicle

While the limitations of the immune system in early life have been speculated to be due to a functional impairment of neonatal T cells, studies in recent years have suggested that functional alterations in neonatal APCs also play a part. APCs are known to be key players during the innate immune response and serve as the link to the adaptive immune response. In the context of vaccination, the effectiveness of the role APCs play depends broadly on 2 factors: the delivery of antigens to APCs and the ability of APCs to subsequently process and present the antigens.

Antigen / Protein load processing for Lm vaccine vectors

Lm is an excellent candidate for a neonatal antigen delivery vehicle given its ability to deliver antigen (in the form of DNA, or expressed and secreted as proteins) directly and efficiently into APCs.121,122 This capacity has led to Lm being among the most commonly employed bacterial vectors for efficacious antigen delivery.123 In most Lm vaccine strains, the antigen of interest is expressed from an episomal origin, delivered in the form of a multicopy plasmid and expressed under the control of an Lm promoter.123 The retention of such plasmids by Lm in vivo is achieved by prfA complementation from the plasmid in a prfA-negative mutant background.11,124,125 In the absence of prfA complementation, phagolysosome escape is not possible, thereby leading to loss of intracellular growth and antigen presentation.62 The expression system used in Lm-vectored transgene expression is derived from 2 different plasmids, with one portion containing the p15 origin of replication (providing a low copy number in Escherichia coli), and the other with its original copy control gene deleted (resulting in an upregulation of plasmid copy number).126,127 Besides plasmid-based strategies, chromosomal integration techniques have also been utilized to generate recombinant vaccine strains that express antigen from a chromosomal origin, e.g., a phage-based system that integrates genes at specific locations in the bacterial genome with the help of a site-specific integrase,67 or homologous recombination using allelic exchange.69 Between the 2, however, plasmid-based strategies might offer a greater advantage than chromosomal integration, in that the former allows for higher expression levels than a single copy chromosomal gene.123 Furthermore, the development of antibiotic marker-free plasmid expression systems for Lm has made this bacterial vector highly suitable for use in humans.67,69

The intracellular lifestyle of Lm involves phagosomal and cytoplasmic phases, thus giving it access to both MHC class I and II pathways as well as the consequent activation of CD8+ T cells and CD4+ T cells. The LLO and ActA virulence factors of Lm have been found to contain PEST-like sequences, which have been associated with ubiquitin-mediated protein degradation.128,129 In studies involving Lm as an anti-tumor vaccine, the expression and secretion of antigens fused to LLO or ActA enhanced anti-tumor efficacies and were highly effective at inducing tumor regression with complete regression of established tumors.128 In addition, the fusion of antigens with a truncated non-hemolytic fragment of LLO has been shown to significantly enhance the antigen-specific T cell-mediated immune response.124,125 LLO is also capable of inducing various cytokines such as IL-12, IL-18 and IFN-γ, which are believed to be critically important for the expression of nonspecific resistance and the generation of acquired immunity in an infected host.130,131

DCs are perhaps the most important APCs of the immune system. This is significant because as previously mentioned, DCs are one of the phagocytic cells that Lm can infect.121 More importantly, associated with Lm-induced DC maturation is the increased efficiency of antigen processing as well as a slower turnover rate of surface-expressed MHC-peptide complexes, which leads to more effective antigen presentation to CD8+ or CD4+ T cells.132 Although Lm is known to induce death in other cell types, the ability of human DCs to resist death and undergo maturation by the upregulation of costimulatory signals despite Lm infection is indeed an important component in their role as effective APCs for listerial immunity.120

Antigen processing pathways in the neonate

Antigen processing capabilities are important for APC maturation as well as the generation of fully-activated effector T cells.133,134 In mice, neonatal DCs compared with their adult counterparts exhibit lower efficiency in the classical pathways leading to antigen processing and presentation;135 this has been shown to result in lower antigen-specific CD8+ T cells.136,137 Cross-presentation refers to the ability to process and present exogenous antigens via the MHC class I pathway;138 and neonatal DCs have been shown to be deficient in MHC class I cross-presentation of soluble antigen as well.139 However, such an age-dependent deficit in antigen presentation can be overcome if the antigen is delivered into (or produced within) the cytoplasm of neonatal DCs.7,137 In light of the neonate’s capacity for effective antigen processing and presentation, as well as the ability to generate adult-like Th1 responses when immunized in the presence of strong adjuvants,6-8 the impaired capacity of neonates to mount optimal immune responses appears less likely to be due to reduced antigen presentation, and more likely a result of lower or altered responses to stimuli leading to activation of APCs, such as adjuvants.140,141 Adjuvants can enhance antigen presentation to and antigen uptake by APCs (e.g., alum), and/or directly induce innate immune responses (e.g., the TLR4 agonist, monophosphoryl lipid A).79,142 The fact that Lm possesses both kinds of adjuvant characteristics is significant, and likely provided the basis for its success as a vaccine delivery vehicle. In other words, in addition to being an ideal vehicle for antigen delivery, Lm also possesses the adjuvant properties that appear capable and required for overcoming the apparent defects reported in neonatal antigen processing and presentation.

Limitations of L. monocytogenes as a Vaccine Vehicle

There are presently several limitations in considering Lm as a vector for neonatal vaccination. First and foremost, as a live vaccine for the neonate, the utmost level of safety has to be guaranteed if Lm were to be administered early in life. However, currently available data on the safety of Lm vectors is sufficiently convincing to suggest that further exploration of this approach is warranted. Second, Lm lacks the ability to carry out the full range of post-translational modifications observed in mammalian cells, and proteins greater than 60 kDa are not always properly folded.143 In addition, the need for secretion of protein antigens expressed by bacteria places restraints on the choice of antigens.143 Nevertheless, existing data on the processing and delivery of antigen via live Lm suggest that these theoretical limitations do not hinder Lm’s efficacy. Third and perhaps also the most important limitation of Lm as a vaccine vehicle is its poor induction of antibody responses, given that antibodies are known to be key components for many vaccines achieving protective immunity.141,144 High-affinity and diverse antibody repertoires have been shown to be inducible in neonatal mice.145,146 The mechanisms of infection and intracellular lifestyle of Lm typically result in poor induction of humoral immune responses by Lm.147 However, considering that diminished T cell help as well as immature antigen presentation have been implicated as factors contributing to the limited vaccine B cell responses in infants,144 Lm as a neonatal vaccine vehicle might well be a possible solution to such a shortcoming of the newborn–rather than a shortcoming itself–given its powerful induction of T cell responses and antigen presentation capabilities. In fact, we have shown that Lm induces antibody responses in neonatal mice surpassing those of their adult counterparts.148

Early-Life Vaccine Targets That Stand to Benefit From Live Listeria-Vectored Vaccination

Lm offers great potential against a number of infectious diseases that strike very early in life. With its major strength being the immediate induction of highly effective cell-mediated protective immunity, Lm should benefit vaccines against microbes for which the role of cell-mediated immunity in protection from infection has been clearly and most consistently identified; namely, microbes with an intracellular life cycle. These include viruses, several parasites (e.g., Leishmania, malaria), and certain bacteria (e.g., Burkholderia, Mycobacteria, Yersinia). Importantly, against many of these pathogens, Lm has, in fact, already been shown to effectively induce cell-mediated immunity in animal models.24,25,28,149,150Lm-vectored vaccines targeting microbes with an intracellular lifestyle would fill a vacant niche, given that there are currently no licensed vaccines against them (with the exception of BCG, whose effectiveness has been contentious). Furthermore, Lm-vectored vaccines also stand to address the important medical need of inducing immunity near birth, especially against microbes that are known to infect early in life (e.g., Mycobacteria, Leishmania, Burkholderia, respiratory syncytial virus, malaria). Yet given the limitations of Lm-based vaccine delivery, most notably the relatively poor induction of humoral immunity by Lm, vaccines that protect mostly on the basis of high titers of specific antibodies (e.g., those directed against toxins such as diphtheria or tetanus, or against pathogens such as hepatitis, influenza virus, or B. pertussis) may not be well served if delivered via an Lm-based vector. For many of those pathogens, however, existing vaccines already provide at least reasonable protection in most circumstances.


The burden of infectious disease leading to suffering and death early in life is immense, underscoring the urgency for an effective approach to neonatal immunization. The particular advantages that Lm has to offer as a neonatal vaccine vehicle are substantial. Attenuated strains of Lm safe for neonates have now been identified; more importantly, these attenuated strains are very efficient at inducing robust Th1-type immunity in neonates. Furthermore, with Lm’s ability to confer lasting and possibly lifelong immunity when given during the neonatal period, Lm-based vaccines not only stand to benefit the infant with protection throughout early life, but also offer a favorable solution to the logistical issues often faced in the need for administration of booster doses later in life. The merits of Lm as a neonatal vaccine platform are clear and significant, and as such, worthy of further exploration.



Listeria monocytogenes
major histocompatibility complex
human papillomavirus
listeriolysin O
prostate specific antigen
cytotoxic T lymphocyte
cluster of differentiation
hepatocellular carcinoma
deoxyribonucleic acid
tumor microenvironment
lymphocytic choriomeningitis virus
human immunodeficiency virus
T helper 1
live vaccine strain
T cell receptor
dendritic cell
killed but metabolically active
Bacillus Calmette-Guérin
antigen presenting cell
Toll-like receptor
tumor necrosis factor
reactive oxygen species
reactive nitrogen species
T helper 2

Disclosure of Potential Conflicts of Interest

A.W. is an employee and shareholder of Advaxis Inc.


1. Stern AM, Markel H. The history of vaccines and immunization: familiar patterns, new challenges. Health Aff (Millwood) 2005; 24:611 - 21;; PMID: 15886151 10.1377/hlthaff.24.3.611 [PubMed] [Cross Ref]
2. Bhutta ZA, Chopra M, Axelson H, Berman P, Boerma T, Bryce J, Bustreo F, Cavagnero E, Cometto G, Daelmans B, et al. . Countdown to 2015 decade report (2000-10): taking stock of maternal, newborn, and child survival. Lancet 2010; 375:2032 - 44;; PMID: 20569843 10.1016/S0140-6736(10)60678-2 [PubMed] [Cross Ref]
3. Demirjian A, Levy O. Neonatal vaccination: a once in a lifetime opportunity. Pediatr Infect Dis J 2009; 28:833 - 5;; PMID: 19710589 10.1097/INF.0b013e3181badba4 [PubMed] [Cross Ref]
4. Wilson CB, Kollmann TR. Induction of antigen-specific immunity in human neonates and infants. Nestle Nutr Workshop Ser Pediatr Program 2008; 61:183 - 95; PMID: 18196952 [PubMed]
5. Wilson CB, Lewis DB, English BK. T cell development in the fetus and neonate. Adv Exp Med Biol 1991; 310:17 - 27;; PMID: 1808993 10.1007/978-1-4615-3838-7_2 [PubMed] [Cross Ref]
6. Marchant A, Appay V, Van Der Sande M, Dulphy N, Liesnard C, Kidd M, Kaye S, Ojuola O, Gillespie GM, Vargas Cuero AL, et al. . Mature CD8(+) T lymphocyte response to viral infection during fetal life. J Clin Invest 2003; 111:1747 - 55;; PMID: 12782677 10.1172/JCI200317470 [PMC free article] [PubMed] [Cross Ref]
7. Dadaglio G, Sun CM, Lo-Man R, Siegrist CA, Leclerc C. Efficient in vivo priming of specific cytotoxic T cell responses by neonatal dendritic cells. J Immunol 2002; 168:2219 - 24; PMID: 11859108 [PubMed]
8. Hermann E, Truyens C, Alonso-Vega C, Even J, Rodriguez P, Berthe A, Gonzalez-Merino E, Torrico F, Carlier Y. Human fetuses are able to mount an adultlike CD8 T-cell response. Blood 2002; 100:2153 - 8; PMID: 12200380 [PubMed]
9. Cossart P. Illuminating the landscape of host-pathogen interactions with the bacterium Listeria monocytogenes.. Proc Natl Acad Sci U S A 2011; 108:19484 - 91;; PMID: 22114192 10.1073/pnas.1112371108 [PubMed] [Cross Ref]
10. Cherry J, Demmler-Harrison GJ, Kaplan SL, Steinbach WJ, Hotez P. Feigin and Cherry’s textbook of pediatric infectious diseases. 7th ed. [Philadelphia, PA]: Saunders; c2013. Chapter 95, Listeriosis; p. 1329-1334.
11. Ikonomidis G, Paterson Y, Kos FJ, Portnoy DA. Delivery of a viral antigen to the class I processing and presentation pathway by Listeria monocytogenes.. J Exp Med 1994; 180:2209 - 18;; PMID: 7964496 10.1084/jem.180.6.2209 [PMC free article] [PubMed] [Cross Ref]
12. Pan ZK, Ikonomidis G, Lazenby A, Pardoll D, Paterson Y. A recombinant Listeria monocytogenes vaccine expressing a model tumour antigen protects mice against lethal tumour cell challenge and causes regression of established tumours. Nat Med 1995; 1:471 - 7;; PMID: 7585097 10.1038/nm0595-471 [PubMed] [Cross Ref]
13. Pan ZK, Ikonomidis G, Pardoll D, Paterson Y. Regression of established tumors in mice mediated by the oral administration of a recombinant Listeria monocytogenes vaccine. Cancer Res 1995; 55:4776 - 9; PMID: 7585503 [PubMed]
14. Le DT, Dubenksy TW Jr., Brockstedt DG. Clinical development of Listeria monocytogenes-based immunotherapies. Semin Oncol 2012; 39:311 - 22;; PMID: 22595054 10.1053/j.seminoncol.2012.02.008 [PMC free article] [PubMed] [Cross Ref]
15. Rothman J, Paterson Y. Live-attenuated Listeria-based immunotherapy. Expert Rev Vaccines 2013; 12:493 - 504;; PMID: 23659298 10.1586/erv.13.34 [PubMed] [Cross Ref]
16. Maciag PC, Radulovic S, Rothman J. The first clinical use of a live-attenuated Listeria monocytogenes vaccine: a Phase I safety study of Lm-LLO-E7 in patients with advanced carcinoma of the cervix. Vaccine 2009; 27:3975 - 83;; PMID: 19389451 10.1016/j.vaccine.2009.04.041 [PubMed] [Cross Ref]
17. Le DT, Brockstedt DG, Nir-Paz R, Hampl J, Mathur S, Nemunaitis J, Sterman DH, Hassan R, Lutz E, Moyer B, et al. . A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction. Clin Cancer Res 2012; 18:858 - 68;; PMID: 22147941 10.1158/1078-0432.CCR-11-2121 [PMC free article] [PubMed] [Cross Ref]
18. Hannan R, Zhang H, Wallecha A, Singh R, Liu L, Cohen P, Alfieri A, Rothman J, Guha C. Combined immunotherapy with Listeria monocytogenes-based PSA vaccine and radiation therapy leads to a therapeutic response in a murine model of prostate cancer. Cancer Immunol Immunother 2012; 61:2227 - 38;; PMID: 22644735 10.1007/s00262-012-1257-x [PubMed] [Cross Ref]
19. Mkrtichyan M, Chong N, Eid RA, Wallecha A, Singh R, Rothman J, Khleif SN. Anti-PD-1 antibody significantly increases therapeutic efficacy of Listeria monocytogenes (Lm)-LLO immunotherapy. J Immunother Cancer 2013; 1:15; 10.1186/2051-1426-1-15 [PMC free article] [PubMed] [Cross Ref]
20. Olino K, Wada S, Edil BH, Pan X, Meckel K, Weber W, Slansky J, Tamada K, Lauer P, Brockstedt D, et al. . Tumor-associated antigen expressing Listeria monocytogenes induces effective primary and memory T-cell responses against hepatic colorectal cancer metastases. Ann Surg Oncol 2012; 19:Suppl 3 S597 - 607;; PMID: 21979110 10.1245/s10434-011-2037-0 [PMC free article] [PubMed] [Cross Ref]
21. Chen Y, Yang D, Li S, Gao Y, Jiang R, Deng L, Frankel FR, Sun B. Development of a Listeria monocytogenes-based vaccine against hepatocellular carcinoma. Oncogene 2012; 31:2140 - 52;; PMID: 21927025 10.1038/onc.2011.395 [PubMed] [Cross Ref]
22. Stritzker J, Pilgrim S, Szalay AA, Goebel W. Prodrug converting enzyme gene delivery by L. monocytogenes.. BMC Cancer 2008; 8:94;; PMID: 18402662 10.1186/1471-2407-8-94 [PMC free article] [PubMed] [Cross Ref]
23. Wallecha A, Malinina I, Molli P. Listeria monocytogenes (Lm)-LLO immunotherapies reduce the immunosuppressive activity of myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment. J Immunother Cancer 2013; 1:O18; 10.1186/2051-1426-1-S1-O18 [PubMed] [Cross Ref]
24. Shen H, Slifka MK, Matloubian M, Jensen ER, Ahmed R, Miller JF. Recombinant Listeria monocytogenes as a live vaccine vehicle for the induction of protective anti-viral cell-mediated immunity. Proc Natl Acad Sci U S A 1995; 92:3987 - 91;; PMID: 7732018 10.1073/pnas.92.9.3987 [PubMed] [Cross Ref]
25. Mata M, Paterson Y. Th1 T cell responses to HIV-1 Gag protein delivered by a Listeria monocytogenes vaccine are similar to those induced by endogenous listerial antigens. J Immunol 1999; 163:1449 - 56; PMID: 10415046 [PubMed]
26. Mata M, Yao ZJ, Zubair A, Syres K, Paterson Y. Evaluation of a recombinant Listeria monocytogenes expressing an HIV protein that protects mice against viral challenge. Vaccine 2001; 19:1435 - 45;; PMID: 11163666 10.1016/S0264-410X(00)00379-0 [PubMed] [Cross Ref]
27. Shollenberger LM, Bui C, Paterson Y, Allen K, Harn D. Successful vaccination of immune suppressed recipients using Listeria vector HIV-1 vaccines in helminth infected mice. Vaccine 2013; 31:2050 - 6;; PMID: 23470236 10.1016/j.vaccine.2013.02.037 [PubMed] [Cross Ref]
28. Soussi N, Milon G, Colle JH, Mougneau E, Glaichenhaus N, Goossens PL. Listeria monocytogenes as a short-lived delivery system for the induction of type 1 cell-mediated immunity against the p36/LACK antigen of Leishmania major.. Infect Immun 2000; 68:1498 - 506;; PMID: 10678966 10.1128/IAI.68.3.1498-1506.2000 [PMC free article] [PubMed] [Cross Ref]
29. Jia Q, Lee BY, Clemens DL, Bowen RA, Horwitz MA. Recombinant attenuated Listeria monocytogenes vaccine expressing Francisella tularensis IglC induces protection in mice against aerosolized Type A F. tularensis.. Vaccine 2009; 27:1216 - 29;; PMID: 19126421 10.1016/j.vaccine.2008.12.014 [PMC free article] [PubMed] [Cross Ref]
30. Rayevskaya M, Kushnir N, Frankel FR. Safety and immunogenicity in neonatal mice of a hyperattenuated Listeria vaccine directed against human immunodeficiency virus. J Virol 2002; 76:918 - 22;; PMID: 11752181 10.1128/JVI.76.2.918-922.2002 [PMC free article] [PubMed] [Cross Ref]
31. Kollmann TR, Reikie B, Blimkie D, Way SS, Hajjar AM, Arispe K, Shaulov A, Wilson CB. Induction of protective immunity to Listeria monocytogenes in neonates. J Immunol 2007; 178:3695 - 701; PMID: 17339467 [PMC free article] [PubMed]
32. Smolen KK, Loeffler DI, Reikie BA, Aplin L, Cai B, Fortuno ES 3rd, Kollmann TR. Neonatal immunization with Listeria monocytogenes induces T cells with an adult-like avidity, sensitivity, and TCR-Vbeta repertoire, and does not adversely impact the response to boosting. Vaccine 2009; 28:235 - 42;; PMID: 19796722 10.1016/j.vaccine.2009.09.091 [PubMed] [Cross Ref]
33. Reikie BA, Smolen KK, Fortuno ES 3rd, Loeffler DI, Cai B, Blimkie D, Kollmann TR. A single immunization near birth elicits immediate and lifelong protective immunity. Vaccine 2010; 29:83 - 90;; PMID: 21034825 10.1016/j.vaccine.2010.10.013 [PubMed] [Cross Ref]
34. Francis T. On the doctrine of original antigenic sin. Proc Am Philos Soc 1960; 104:572 - 8
35. Leong ML, Hampl J, Liu W, Mathur S, Bahjat KS, Luckett W, Dubensky TW Jr., Brockstedt DG. Impact of preexisting vector-specific immunity on vaccine potency: characterization of listeria monocytogenes-specific humoral and cellular immunity in humans and modeling studies using recombinant vaccines in mice. Infect Immun 2009; 77:3958 - 68;; PMID: 19528221 10.1128/IAI.01274-08 [PMC free article] [PubMed] [Cross Ref]
36. Remington JS, Klein JO, Wilson CB, Nizet V, Maldonado Y. Infectious diseases of the fetus and newborn. 7th ed. [Philadelphia, PA]: Saunders; 2010.
37. Farber JM, Ross WH, Harwig J. Health risk assessment of Listeria monocytogenes in Canada. Int J Food Microbiol 1996; 30:145 - 56;; PMID: 8856380 10.1016/0168-1605(96)01107-5 [PubMed] [Cross Ref]
38. Milohanic E, Jonquières R, Cossart P, Berche P, Gaillard JL. The autolysin Ami contributes to the adhesion of Listeria monocytogenes to eukaryotic cells via its cell wall anchor. Mol Microbiol 2001; 39:1212 - 24;; PMID: 11251838 10.1111/j.1365-2958.2001.02208.x [PubMed] [Cross Ref]
39. Bou Ghanem EN, Jones GS, Myers-Morales T, Patil PD, Hidayatullah AN, D’Orazio SE. InlA promotes dissemination of Listeria monocytogenes to the mesenteric lymph nodes during food borne infection of mice. PLoS Pathog 2012; 8:e1003015;; PMID: 23166492 10.1371/journal.ppat.1003015 [PMC free article] [PubMed] [Cross Ref]
40. Nikitas G, Deschamps C, Disson O, Niault T, Cossart P, Lecuit M. Transcytosis of Listeria monocytogenes across the intestinal barrier upon specific targeting of goblet cell accessible E-cadherin. J Exp Med 2011; 208:2263 - 77;; PMID: 21967767 10.1084/jem.20110560 [PMC free article] [PubMed] [Cross Ref]
41. Dramsi S, Bourdichon F, Cabanes D, Lecuit M, Fsihi H, Cossart P. FbpA, a novel multifunctional Listeria monocytogenes virulence factor. Mol Microbiol 2004; 53:639 - 49;; PMID: 15228540 10.1111/j.1365-2958.2004.04138.x [PubMed] [Cross Ref]
42. Braun L, Ghebrehiwet B, Cossart P. gC1q-R/p32, a C1q-binding protein, is a receptor for the InlB invasion protein of Listeria monocytogenes.. EMBO J 2000; 19:1458 - 66;; PMID: 10747014 10.1093/emboj/19.7.1458 [PubMed] [Cross Ref]
43. Seveau S, Pizarro-Cerda J, Cossart P. Molecular mechanisms exploited by Listeria monocytogenes during host cell invasion. Microbes Infect 2007; 9:1167 - 75;; PMID: 17761447 10.1016/j.micinf.2007.05.004 [PubMed] [Cross Ref]
44. Edelson BT. Dendritic cells in Listeria monocytogenes infection. Adv Immunol 2012; 113:33 - 49;; PMID: 22244578 10.1016/B978-0-12-394590-7.00006-3 [PubMed] [Cross Ref]
45. Dunne DW, Resnick D, Greenberg J, Krieger M, Joiner KA. The type I macrophage scavenger receptor binds to gram-positive bacteria and recognizes lipoteichoic acid. Proc Natl Acad Sci U S A 1994; 91:1863 - 7;; PMID: 8127896 10.1073/pnas.91.5.1863 [PubMed] [Cross Ref]
46. Lam GY, Czuczman MA, Higgins DE, Brumell JH. Interactions of Listeria monocytogenes with the autophagy system of host cells. Adv Immunol 2012; 113:7 - 18;; PMID: 22244576 10.1016/B978-0-12-394590-7.00008-7 [PubMed] [Cross Ref]
47. Gedde MM, Higgins DE, Tilney LG, Portnoy DA. Role of listeriolysin O in cell-to-cell spread of Listeria monocytogenes.. Infect Immun 2000; 68:999 - 1003;; PMID: 10639481 10.1128/IAI.68.2.999-1003.2000 [PMC free article] [PubMed] [Cross Ref]
48. Portnoy DA, Jacks PS, Hinrichs DJ. Role of hemolysin for the intracellular growth of Listeria monocytogenes.. J Exp Med 1988; 167:1459 - 71;; PMID: 2833557 10.1084/jem.167.4.1459 [PMC free article] [PubMed] [Cross Ref]
49. Camilli A, Tilney LG, Portnoy DA. Dual roles of plcA in Listeria monocytogenes pathogenesis. Mol Microbiol 1993; 8:143 - 57;; PMID: 8388529 10.1111/j.1365-2958.1993.tb01211.x [PMC free article] [PubMed] [Cross Ref]
50. Gründling A, Gonzalez MD, Higgins DE. Requirement of the Listeria monocytogenes broad-range phospholipase PC-PLC during infection of human epithelial cells. J Bacteriol 2003; 185:6295 - 307;; PMID: 14563864 10.1128/JB.185.21.6295-6307.2003 [PMC free article] [PubMed] [Cross Ref]
51. Smith GA, Marquis H, Jones S, Johnston NC, Portnoy DA, Goldfine H. The two distinct phospholipases C of Listeria monocytogenes have overlapping roles in escape from a vacuole and cell-to-cell spread. Infect Immun 1995; 63:4231 - 7; PMID: 7591052 [PMC free article] [PubMed]
52. Marquis H, Doshi V, Portnoy DA. The broad-range phospholipase C and a metalloprotease mediate listeriolysin O-independent escape of Listeria monocytogenes from a primary vacuole in human epithelial cells. Infect Immun 1995; 63:4531 - 4; PMID: 7591098 [PMC free article] [PubMed]
53. Mounier J, Ryter A, Coquis-Rondon M, Sansonetti PJ. Intracellular and cell-to-cell spread of Listeria monocytogenes involves interaction with F-actin in the enterocytelike cell line Caco-2. Infect Immun 1990; 58:1048 - 58; PMID: 2108086 [PMC free article] [PubMed]
54. Theriot JA, Mitchison TJ, Tilney LG, Portnoy DA. The rate of actin-based motility of intracellular Listeria monocytogenes equals the rate of actin polymerization. Nature 1992; 357:257 - 60;; PMID: 1589024 10.1038/357257a0 [PubMed] [Cross Ref]
55. Domann E, Wehland J, Rohde M, Pistor S, Hartl M, Goebel W, Leimeister-Wächter M, Wuenscher M, Chakraborty T. A novel bacterial virulence gene in Listeria monocytogenes required for host cell microfilament interaction with homology to the proline-rich region of vinculin. EMBO J 1992; 11:1981 - 90; PMID: 1582425 [PubMed]
56. Kocks C, Hellio R, Gounon P, Ohayon H, Cossart P. Polarized distribution of Listeria monocytogenes surface protein ActA at the site of directional actin assembly. J Cell Sci 1993; 105:699 - 710; PMID: 8408297 [PubMed]
57. Gouin E, Mengaud J, Cossart P. The virulence gene cluster of Listeria monocytogenes is also present in Listeria ivanovii, an animal pathogen, and Listeria seeligeri, a nonpathogenic species. Infect Immun 1994; 62:3550 - 3; PMID: 8039927 [PMC free article] [PubMed]
58. Kazmierczak MJ, Wiedmann M, Boor KJ. Contributions of Listeria monocytogenes sigmaB and PrfA to expression of virulence and stress response genes during extra- and intracellular growth. Microbiology 2006; 152:1827 - 38;; PMID: 16735745 10.1099/mic.0.28758-0 [PubMed] [Cross Ref]
59. Rothman J, Wallecha A, Maciag PC, Rivera S, Shahabi V, Paterson Y. The use of living Listeria monocytogenes as an active immunotherapy for the treatment of cancer. In: Fialho AM, Chakrabarty, eds. Emerging Cancer Therapy: Microbial approaches and Biotechnological Tools. Hoboken, NJ: John Wiley & Sons, Inc.; 2009.
60. Tangney M, Gahan CG. Listeria monocytogenes as a vector for anti-cancer therapies. Curr Gene Ther 2010; 10:46 - 55;; PMID: 20158470 10.2174/156652310790945539 [PubMed] [Cross Ref]
61. Petit RG, Basu P. ADXS11-001 immunotherapy targeting HPV-E7: updated survival and safety data from a phase 2 study in Indian women with recurrent/refractory cervical cancer. J Immunother Cancer 2013; 1:231; 10.1186/2051-1426-1-S1-P231 [Cross Ref]
62. Brockstedt DG, Giedlin MA, Leong ML, Bahjat KS, Gao Y, Luckett W, Liu W, Cook DN, Portnoy DA, Dubensky TW Jr.. Listeria-based cancer vaccines that segregate immunogenicity from toxicity. Proc Natl Acad Sci U S A 2004; 101:13832 - 7;; PMID: 15365184 10.1073/pnas.0406035101 [PubMed] [Cross Ref]
63. Angelakopoulos H, Loock K, Sisul DM, Jensen ER, Miller JF, Hohmann EL. Safety and shedding of an attenuated strain of Listeria monocytogenes with a deletion of actA/plcB in adult volunteers: a dose escalation study of oral inoculation. Infect Immun 2002; 70:3592 - 601;; PMID: 12065500 10.1128/IAI.70.7.3592-3601.2002 [PMC free article] [PubMed] [Cross Ref]
64. Snell EE, Radin NS, Ikawa M. The nature of D-alanine in lactic acid bacteria. J Biol Chem 1955; 217:803 - 18; PMID: 13271442 [PubMed]
65. Holden JT, Snell EE. The relation of D-alanine and vitamin B6 to growth of lactic acid bacteria. J Biol Chem 1949; 178:799 - 809; PMID: 18117001 [PubMed]
66. Thompson RJ, Bouwer HG, Portnoy DA, Frankel FR. Pathogenicity and immunogenicity of a Listeria monocytogenes strain that requires D-alanine for growth. Infect Immun 1998; 66:3552 - 61; PMID: 9673233 [PMC free article] [PubMed]
67. Verch T, Pan ZK, Paterson Y. Listeria monocytogenes-based antibiotic resistance gene-free antigen delivery system applicable to other bacterial vectors and DNA vaccines. Infect Immun 2004; 72:6418 - 25;; PMID: 15501772 10.1128/IAI.72.11.6418-6425.2004 [PMC free article] [PubMed] [Cross Ref]
68. Zhao X, Li Z, Gu B, Frankel FR. Pathogenicity and immunogenicity of a vaccine strain of Listeria monocytogenes that relies on a suicide plasmid to supply an essential gene product. Infect Immun 2005; 73:5789 - 98;; PMID: 16113297 10.1128/IAI.73.9.5789-5798.2005 [PMC free article] [PubMed] [Cross Ref]
69. Wallecha A, Maciag PC, Rivera S, Paterson Y, Shahabi V. Construction and characterization of an attenuated Listeria monocytogenes strain for clinical use in cancer immunotherapy. Clin Vaccine Immunol 2009; 16:96 - 103;; PMID: 19020110 10.1128/CVI.00274-08 [PMC free article] [PubMed] [Cross Ref]
70. Stritzker J, Janda J, Schoen C, Taupp M, Pilgrim S, Gentschev I, Schreier P, Geginat G, Goebel W. Growth, virulence, and immunogenicity of Listeria monocytogenes aro mutants. Infect Immun 2004; 72:5622 - 9;; PMID: 15385459 10.1128/IAI.72.10.5622-5629.2004 [PMC free article] [PubMed] [Cross Ref]
71. Spears PA, Suyemoto MM, Palermo AM, Horton JR, Hamrick TS, Havell EA, Orndorff PE. A Listeria monocytogenes mutant defective in bacteriophage attachment is attenuated in orally inoculated mice and impaired in enterocyte intracellular growth. Infect Immun 2008; 76:4046 - 54;; PMID: 18559424 10.1128/IAI.00283-08 [PMC free article] [PubMed] [Cross Ref]
72. Spears PA, Suyemoto MM, Hamrick TS, Wolf RL, Havell EA, Orndorff PE. In vitro properties of a Listeria monocytogenes bacteriophage-resistant mutant predict its efficacy as a live oral vaccine strain. Infect Immun 2011; 79:5001 - 9;; PMID: 21930759 10.1128/IAI.05700-11 [PMC free article] [PubMed] [Cross Ref]
73. Brockstedt DG, Bahjat KS, Giedlin MA, Liu W, Leong M, Luckett W, Gao Y, Schnupf P, Kapadia D, Castro G, et al. . Killed but metabolically active microbes: a new vaccine paradigm for eliciting effector T-cell responses and protective immunity. Nat Med 2005; 11:853 - 60;; PMID: 16041382 10.1038/nm1276 [PubMed] [Cross Ref]
74. Lauer P, Hanson B, Lemmens EE, Liu W, Luckett WS, Leong ML, Allen HE, Skoble J, Bahjat KS, Freitag NE, et al. . Constitutive Activation of the PrfA regulon enhances the potency of vaccines based on live-attenuated and killed but metabolically active Listeria monocytogenes strains. Infect Immun 2008; 76:3742 - 53;; PMID: 18541651 10.1128/IAI.00390-08 [PMC free article] [PubMed] [Cross Ref]
75. McLaughlin HP, Bahey-El-Din M, Casey PG, Hill C, Gahan CG. A mutant in the Listeria monocytogenes Fur-regulated virulence locus (frvA) induces cellular immunity and confers protection against listeriosis in mice. J Med Microbiol 2013; 62:185 - 90;; PMID: 23105022 10.1099/jmm.0.049114-0 [PubMed] [Cross Ref]
76. Dietrich G, Bubert A, Gentschev I, Sokolovic Z, Simm A, Catic A, Kaufmann SH, Hess J, Szalay AA, Goebel W. Delivery of antigen-encoding plasmid DNA into the cytosol of macrophages by attenuated suicide Listeria monocytogenes.. Nat Biotechnol 1998; 16:181 - 5;; PMID: 9487527 10.1038/nbt0298-181 [PubMed] [Cross Ref]
77. Warren SE, Duong H, Mao DP, Armstrong A, Rajan J, Miao EA, Aderem A. Generation of a Listeria vaccine strain by enhanced caspase-1 activation. Eur J Immunol 2011; 41:1934 - 40;; PMID: 21538346 10.1002/eji.201041214 [PMC free article] [PubMed] [Cross Ref]
78. Sauer JD, Pereyre S, Archer KA, Burke TP, Hanson B, Lauer P, Portnoy DA. Listeria monocytogenes engineered to activate the Nlrc4 inflammasome are severely attenuated and are poor inducers of protective immunity. Proc Natl Acad Sci U S A 2011; 108:12419 - 24;; PMID: 21746921 10.1073/pnas.1019041108 [PubMed] [Cross Ref]
79. Goossens PL, Milon G. Induction of protective CD8+ T lymphocytes by an attenuated Listeria monocytogenes actA mutant. Int Immunol 1992; 4:1413 - 8;; PMID: 1286064 10.1093/intimm/4.12.1413 [PubMed] [Cross Ref]
80. Mortellaro A, Ricciardi-Castagnoli P. From vaccine practice to vaccine science: the contribution of human immunology to the prevention of infectious disease. Immunol Cell Biol 2011; 89:332 - 9;; PMID: 21301476 10.1038/icb.2010.152 [PubMed] [Cross Ref]
81. Blanchard-Rohner G, Pollard AJ. Long-term protection after immunization with protein-polysaccharide conjugate vaccines in infancy. Expert Rev Vaccines 2011; 10:673 - 84;; PMID: 21604987 10.1586/erv.11.14 [PubMed] [Cross Ref]
82. Witte CE, Archer KA, Rae CS, Sauer JD, Woodward JJ, Portnoy DA. Innate immune pathways triggered by Listeria monocytogenes and their role in the induction of cell-mediated immunity. Adv Immunol 2012; 113:135 - 56;; PMID: 22244582 10.1016/B978-0-12-394590-7.00002-6 [PubMed] [Cross Ref]
83. Gilchrist M. Cutaneous Listeria infection. Br J Hosp Med (Lond) 2009; 70:659; PMID: 20081597 [PubMed]
84. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 2011; 34:637 - 50;; PMID: 21616434 10.1016/j.immuni.2011.05.006 [PubMed] [Cross Ref]
85. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nuñez G, Flavell RA. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 2005; 307:731 - 4;; PMID: 15692051 10.1126/science.1104911 [PubMed] [Cross Ref]
86. Barber GN. Innate immune DNA sensing pathways: STING, AIMII and the regulation of interferon production and inflammatory responses. Curr Opin Immunol 2011; 23:10 - 20;; PMID: 21239155 10.1016/j.coi.2010.12.015 [PMC free article] [PubMed] [Cross Ref]
87. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol 2009; 27:229 - 65;; PMID: 19302040 10.1146/annurev.immunol.021908.132715 [PubMed] [Cross Ref]
88. Leber JH, Crimmins GT, Raghavan S, Meyer-Morse NP, Cox JS, Portnoy DA. Distinct TLR- and NLR-mediated transcriptional responses to an intracellular pathogen. PLoS Pathog 2008; 4:e6;; PMID: 18193943 10.1371/journal.ppat.0040006 [PubMed] [Cross Ref]
89. McCaffrey RL, Fawcett P, O’Riordan M, Lee KD, Havell EA, Brown PO, Portnoy DA. A specific gene expression program triggered by Gram-positive bacteria in the cytosol. Proc Natl Acad Sci U S A 2004; 101:11386 - 91;; PMID: 15269347 10.1073/pnas.0403215101 [PubMed] [Cross Ref]
90. Vázquez-Boland JA, Kuhn M, Berche P, Chakraborty T, Domínguez-Bernal G, Goebel W, González-Zorn B, Wehland J, Kreft J. Listeria pathogenesis and molecular virulence determinants. Clin Microbiol Rev 2001; 14:584 - 640;; PMID: 11432815 10.1128/CMR.14.3.584-640.2001 [PMC free article] [PubMed] [Cross Ref]
91. Pamer EG. Immune responses to Listeria monocytogenes.. Nat Rev Immunol 2004; 4:812 - 23;; PMID: 15459672 10.1038/nri1461 [PubMed] [Cross Ref]
92. Nakane A, Minagawa T. The significance of alpha/beta interferons and gamma interferon produced in mice infected with Listeria monocytogenes.. Cell Immunol 1984; 88:29 - 40;; PMID: 6206958 10.1016/0008-8749(84)90049-2 [PubMed] [Cross Ref]
93. Decker T, Müller M, Stockinger S. The yin and yang of type I interferon activity in bacterial infection. Nat Rev Immunol 2005; 5:675 - 87;; PMID: 16110316 10.1038/nri1684 [PubMed] [Cross Ref]
94. Zenewicz LA, Shen H. Innate and adaptive immune responses to Listeria monocytogenes: a short overview. Microbes Infect 2007; 9:1208 - 15;; PMID: 17719259 10.1016/j.micinf.2007.05.008 [PMC free article] [PubMed] [Cross Ref]
95. Peng X, Hussain SF, Paterson Y. The ability of two Listeria monocytogenes vaccines targeting human papillomavirus-16 E7 to induce an antitumor response correlates with myeloid dendritic cell function. J Immunol 2004; 172:6030 - 8; PMID: 15128786 [PubMed]
96. Berg RE, Crossley E, Murray S, Forman J. Memory CD8+ T cells provide innate immune protection against Listeria monocytogenes in the absence of cognate antigen. J Exp Med 2003; 198:1583 - 93;; PMID: 14623912 10.1084/jem.20031051 [PMC free article] [PubMed] [Cross Ref]
97. Posfay-Barbe KM, Wald ER. Listeriosis. Semin Fetal Neonatal Med 2009; 14:228 - 33;; PMID: 19231307 10.1016/j.siny.2009.01.006 [PubMed] [Cross Ref]
98. Villanueva MS, Fischer P, Feen K, Pamer EG. Efficiency of MHC class I antigen processing: a quantitative analysis. Immunity 1994; 1:479 - 89;; PMID: 7534616 10.1016/1074-7613(94)90090-6 [PubMed] [Cross Ref]
99. Yamamoto K, Kawamura I, Tominaga T, Nomura T, Kohda C, Ito J, Mitsuyama M. Listeriolysin O, a cytolysin derived from Listeria monocytogenes, inhibits generation of ovalbumin-specific Th2 immune response by skewing maturation of antigen-specific T cells into Th1 cells. Clin Exp Immunol 2005; 142:268 - 74;; PMID: 16232213 10.1111/j.1365-2249.2005.02922.x [PubMed] [Cross Ref]
100. Skoberne M, Schenk S, Hof H, Geginat G. Cross-presentation of Listeria monocytogenes-derived CD4 T cell epitopes. J Immunol 2002; 169:1410 - 8; PMID: 12133966 [PubMed]
101. Shedlock DJ, Shen H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 2003; 300:337 - 9;; PMID: 12690201 10.1126/science.1082305 [PubMed] [Cross Ref]
102. Sun JC, Bevan MJ. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 2003; 300:339 - 42;; PMID: 12690202 10.1126/science.1083317 [PMC free article] [PubMed] [Cross Ref]
103. Kollmann TR, Levy O, Montgomery RR, Goriely S. Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity 2012; 37:771 - 83;; PMID: 23159225 10.1016/j.immuni.2012.10.014 [PMC free article] [PubMed] [Cross Ref]
104. Sherrid AM, Kollmann TR. Age-dependent differences in systemic and cell-autonomous immunity to L. monocytogenes. Clin Dev Immunol 2013; 2013:917198;; PMID: 23653659 10.1155/2013/917198 [PMC free article] [PubMed] [Cross Ref]
105. Way SS, Kollmann TR, Hajjar AM, Wilson CB. Cutting edge: protective cell-mediated immunity to Listeria monocytogenes in the absence of myeloid differentiation factor 88. J Immunol 2003; 171:533 - 7; PMID: 12847214 [PubMed]
106. Chang BA, Huang Q, Quan J, Chau V, Ladd M, Kwan E, McFadden DE, Lacaze-Masmonteil T, Miller SP, Lavoie PM. Early inflammation in the absence of overt infection in preterm neonates exposed to intensive care. Cytokine 2011; 56:621 - 6;; PMID: 21940177 10.1016/j.cyto.2011.08.028 [PMC free article] [PubMed] [Cross Ref]
107. Dasari P, Zola H, Nicholson IC. Expression of Toll-like receptors by neonatal leukocytes. Pediatr Allergy Immunol 2011; 22:221 - 8;; PMID: 21054549 10.1111/j.1399-3038.2010.01091.x [PubMed] [Cross Ref]
108. Reimer T, Schweizer M, Jungi TW. Type I IFN induction in response to Listeria monocytogenes in human macrophages: evidence for a differential activation of IFN regulatory factor 3 (IRF3). J Immunol 2007; 179:1166 - 77; PMID: 17617610 [PubMed]
109. Levy O, Goriely S, Kollmann TR. Immune response to vaccine adjuvants during the first year of life. Vaccine 2013; 31:2500 - 5;; PMID: 23085363 10.1016/j.vaccine.2012.10.016 [PMC free article] [PubMed] [Cross Ref]
110. Lisciandro JG, Prescott SL, Nadal-Sims MG, Devitt CJ, Pomat W, Siba PM, Tulic MC, Holt PG, Strickland D, van den Biggelaar AH. Ontogeny of Toll-like and NOD-like receptor-mediated innate immune responses in Papua New Guinean infants. PLoS One 2012; 7:e36793;; PMID: 22649499 10.1371/journal.pone.0036793 [PMC free article] [PubMed] [Cross Ref]
111. Byun HJ, Jung WW, Lee JB, Chung HY, Sul D, Kim SJ, Park CG, Choi I, Hwang KW, Chun T. An evaluation of the neonatal immune system using a listeria infection model. Neonatology 2007; 92:83 - 90;; PMID: 17361091 10.1159/000100806 [PubMed] [Cross Ref]
112. Genovese F, Mancuso G, Cuzzola M, Biondo C, Beninati C, Delfino D, Teti G. Role of IL-10 in a neonatal mouse listeriosis model. J Immunol 1999; 163:2777 - 82; PMID: 10453021 [PubMed]
113. Elahi S, Ertelt JM, Kinder JM, Jiang TT, Zhang X, Xin L, Chaturvedi V, Strong BS, Qualls JE, Steinbrecher KA, et al. . Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature 2013; 504:158 - 62;; PMID: 24196717 10.1038/nature12675 [PMC free article] [PubMed] [Cross Ref]
114. Kollmann TR, Crabtree J, Rein-Weston A, Blimkie D, Thommai F, Wang XY, Lavoie PM, Furlong J, Fortuno ES 3rd, Hajjar AM, et al. . Neonatal innate TLR-mediated responses are distinct from those of adults. J Immunol 2009; 183:7150 - 60;; PMID: 19917677 10.4049/jimmunol.0901481 [PMC free article] [PubMed] [Cross Ref]
115. Corbett NP, Blimkie D, Ho KC, Cai B, Sutherland DP, Kallos A, Crabtree J, Rein-Weston A, Lavoie PM, Turvey SE, et al. . Ontogeny of Toll-like receptor mediated cytokine responses of human blood mononuclear cells. PLoS One 2010; 5:e15041;; PMID: 21152080 10.1371/journal.pone.0015041 [PMC free article] [PubMed] [Cross Ref]
116. Lavoie PM, Huang Q, Jolette E, Whalen M, Nuyt AM, Audibert F, Speert DP, Lacaze-Masmonteil T, Soudeyns H, Kollmann TR. Profound lack of interleukin (IL)-12/IL-23p40 in neonates born early in gestation is associated with an increased risk of sepsis. J Infect Dis 2010; 202:1754 - 63;; PMID: 20977341 10.1086/657143 [PMC free article] [PubMed] [Cross Ref]
117. Khansari N, Shakiba Y, Mahmoudi M. Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. Recent Pat Inflamm Allergy Drug Discov 2009; 3:73 - 80;; PMID: 19149749 10.2174/187221309787158371 [PubMed] [Cross Ref]
118. Adkins B. Peripheral CD4+ lymphocytes derived from fetal versus adult thymic precursors differ phenotypically and functionally. J Immunol 2003; 171:5157 - 64; PMID: 14607915 [PubMed]
119. Li L, Lee HH, Bell JJ, Gregg RK, Ellis JS, Gessner A, Zaghouani H. IL-4 utilizes an alternative receptor to drive apoptosis of Th1 cells and skews neonatal immunity toward Th2. Immunity 2004; 20:429 - 40;; PMID: 15084272 10.1016/S1074-7613(04)00072-X [PubMed] [Cross Ref]
120. Dauby N, Goetghebuer T, Kollmann TR, Levy J, Marchant A. Uninfected but not unaffected: chronic maternal infections during pregnancy, fetal immunity, and susceptibility to postnatal infections. Lancet Infect Dis 2012; 12:330 - 40;; PMID: 22364680 10.1016/S1473-3099(11)70341-3 [PubMed] [Cross Ref]
121. Kolb-Mäurer A, Gentschev I, Fries HW, Fiedler F, Bröcker EB, Kämpgen E, Goebel W. Listeria monocytogenes-infected human dendritic cells: uptake and host cell response. Infect Immun 2000; 68:3680 - 8;; PMID: 10816528 10.1128/IAI.68.6.3680-3688.2000 [PMC free article] [PubMed] [Cross Ref]
122. Paterson Y, Maciag PC. Listeria-based vaccines for cancer treatment. Curr Opin Mol Ther 2005; 7:454 - 60; PMID: 16248280 [PubMed]
123. Shahabi V, Maciag PC, Rivera S, Wallecha A. Live, attenuated strains of Listeria and Salmonella as vaccine vectors in cancer treatment. Bioeng Bugs 2010; 1:235 - 43;; PMID: 21327055 10.4161/bbug.1.4.11243 [PMC free article] [PubMed] [Cross Ref]
124. Gunn GR, Zubair A, Peters C, Pan ZK, Wu TC, Paterson Y. Two Listeria monocytogenes vaccine vectors that express different molecular forms of human papilloma virus-16 (HPV-16) E7 induce qualitatively different T cell immunity that correlates with their ability to induce regression of established tumors immortalized by HPV-16. J Immunol 2001; 167:6471 - 9; PMID: 11714814 [PubMed]
125. Singh R, Dominiecki ME, Jaffee EM, Paterson Y. Fusion to Listeriolysin O and delivery by Listeria monocytogenes enhances the immunogenicity of HER-2/neu and reveals subdominant epitopes in the FVB/N mouse. J Immunol 2005; 175:3663 - 73; PMID: 16148111 [PubMed]
126. Brantl S, Behnke D, Alonso JC. Molecular analysis of the replication region of the conjugative Streptococcus agalactiae plasmid pIP501 in Bacillus subtilis. Comparison with plasmids pAM beta 1 and pSM19035. Nucleic Acids Res 1990; 18:4783 - 90;; PMID: 2118624 10.1093/nar/18.16.4783 [PMC free article] [PubMed] [Cross Ref]
127. Behnke D, Gilmore MS, Ferretti JJ. Plasmid pGB301, a new multiple resistance streptococcal cloning vehicle and its use in cloning of a gentamicin/kanamycin resistance determinant. Mol Gen Genet 1981; 182:414 - 21;; PMID: 6272061 10.1007/BF00293929 [PubMed] [Cross Ref]
128. Sewell DA, Shahabi V, Gunn GR 3rd, Pan ZK, Dominiecki ME, Paterson Y. Recombinant Listeria vaccines containing PEST sequences are potent immune adjuvants for the tumor-associated antigen human papillomavirus-16 E7. Cancer Res 2004; 64:8821 - 5;; PMID: 15604239 10.1158/0008-5472.CAN-04-1958 [PubMed] [Cross Ref]
129. Schnupf P, Portnoy DA, Decatur AL. Phosphorylation, ubiquitination and degradation of listeriolysin O in mammalian cells: role of the PEST-like sequence. Cell Microbiol 2006; 8:353 - 64;; PMID: 16441444 10.1111/j.1462-5822.2005.00631.x [PubMed] [Cross Ref]
130. Kimoto T, Kawamura I, Kohda C, Nomura T, Tsuchiya K, Ito Y, Watanabe I, Kaku T, Setianingrum E, Mitsuyama M. Differences in gamma interferon production induced by listeriolysin O and ivanolysin O result in different levels of protective immunity in mice infected with Listeria monocytogenes and Listeria ivanovii.. Infect Immun 2003; 71:2447 - 54;; PMID: 12704115 10.1128/IAI.71.5.2447-2454.2003 [PMC free article] [PubMed] [Cross Ref]
131. Nomura T, Kawamura I, Tsuchiya K, Kohda C, Baba H, Ito Y, Kimoto T, Watanabe I, Mitsuyama M. Essential role of interleukin-12 (IL-12) and IL-18 for gamma interferon production induced by listeriolysin O in mouse spleen cells. Infect Immun 2002; 70:1049 - 55;; PMID: 11854182 10.1128/IAI.70.3.1049-1055.2002 [PMC free article] [PubMed] [Cross Ref]
132. Cella M, Engering A, Pinet V, Pieters J, Lanzavecchia A. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature 1997; 388:782 - 7;; PMID: 9285591 10.1038/42030 [PubMed] [Cross Ref]
133. Wallet MA, Sen P, Tisch R. Immunoregulation of dendritic cells. Clin Med Res 2005; 3:166 - 75;; PMID: 16160071 10.3121/cmr.3.3.166 [PubMed] [Cross Ref]
134. Velilla PA, Rugeles MT, Chougnet CA. Defective antigen-presenting cell function in human neonates. Clin Immunol 2006; 121:251 - 9;; PMID: 17010668 10.1016/j.clim.2006.08.010 [PMC free article] [PubMed] [Cross Ref]
135. Dakic A, Shao QX, D’Amico A, O’Keeffe M, Chen WF, Shortman K, Wu L. Development of the dendritic cell system during mouse ontogeny. J Immunol 2004; 172:1018 - 27; PMID: 14707075 [PubMed]
136. Siegrist CA. Neonatal and early life vaccinology. Vaccine 2001; 19:3331 - 46;; PMID: 11348697 10.1016/S0264-410X(01)00028-7 [PubMed] [Cross Ref]
137. Siegrist CA, Saddallah F, Tougne C, Martinez X, Kovarik J, Lambert PH. Induction of neonatal TH1 and CTL responses by live viral vaccines: a role for replication patterns within antigen presenting cells?. Vaccine 1998; 16:1473 - 8;; PMID: 9711791 10.1016/S0264-410X(98)00111-X [PubMed] [Cross Ref]
138. Belz GT, Carbone FR, Heath WR. Cross-presentation of antigens by dendritic cells. Crit Rev Immunol 2002; 22:439 - 48; PMID: 12803320 [PubMed]
139. Kollmann TR, Way SS, Harowicz HL, Hajjar AM, Wilson CB. Deficient MHC class I cross-presentation of soluble antigen by murine neonatal dendritic cells. Blood 2004; 103:4240 - 2;; PMID: 14982880 10.1182/blood-2003-11-3805 [PubMed] [Cross Ref]
140. Gold MC, Robinson TL, Cook MS, Byrd LK, Ehlinger HD, Lewinsohn DM, Lewinsohn DA. Human neonatal dendritic cells are competent in MHC class I antigen processing and presentation. PLoS One 2007; 2:e957;; PMID: 17895997 10.1371/journal.pone.0000957 [PMC free article] [PubMed] [Cross Ref]
141. Adkins B, Leclerc C, Marshall-Clarke S. Neonatal adaptive immunity comes of age. Nat Rev Immunol 2004; 4:553 - 64;; PMID: 15229474 10.1038/nri1394 [PubMed] [Cross Ref]
142. Brunner R, Jensen-Jarolim E, Pali-Schöll I. The ABC of clinical and experimental adjuvants--a brief overview. Immunol Lett 2010; 128:29 - 35;; PMID: 19895847 10.1016/j.imlet.2009.10.005 [PMC free article] [PubMed] [Cross Ref]
143. Paterson Y, Guirnalda PD, Wood LM. Listeria and Salmonella bacterial vectors of tumor-associated antigens for cancer immunotherapy. Semin Immunol 2010; 22:183 - 9;; PMID: 20299242 10.1016/j.smim.2010.02.002 [PMC free article] [PubMed] [Cross Ref]
144. PrabhuDas M, Adkins B, Gans H, King C, Levy O, Ramilo O, Siegrist CA. Challenges in infant immunity: implications for responses to infection and vaccines. Nat Immunol 2011; 12:189 - 94;; PMID: 21321588 10.1038/ni0311-189 [PubMed] [Cross Ref]
145. Schallert N, Pihlgren M, Kovarik J, Roduit C, Tougne C, Bozzotti P, Del Giudice G, Siegrist CA, Lambert PH. Generation of adult-like antibody avidity profiles after early-life immunization with protein vaccines. Eur J Immunol 2002; 32:752 - 60;; PMID: 11870619 10.1002/1521-4141(200203)32:3<752::AID-IMMU752>3.0.CO;2-5 [PubMed] [Cross Ref]
146. Giorgetti CA, Press JL. Somatic mutation in the neonatal mouse. J Immunol 1998; 161:6093 - 104; PMID: 9834093 [PubMed]
147. Bhunia AK. Antibodies to Listeria monocytogenes.. Crit Rev Microbiol 1997; 23:77 - 107;; PMID: 9226109 10.3109/10408419709115131 [PubMed] [Cross Ref]
148. Loeffler DI, Smolen K, Aplin L, Cai B, Kollmann TR. Fine-tuning the safety and immunogenicity of Listeria monocytogenes-based neonatal vaccine platforms. Vaccine 2009; 27:919 - 27;; PMID: 19059297 10.1016/j.vaccine.2008.11.047 [PubMed] [Cross Ref]
149. Yin Y, Tian D, Jia Y, Gao Y, Fu H, Niu Z, Sun L, Jiao X. Attenuated Listeria monocytogenes, a Mycobacterium tuberculosis ESAT-6 antigen expression and delivery vector for inducing an immune response. Res Microbiol 2012; 163:540 - 9;; PMID: 22835946 10.1016/j.resmic.2012.07.008 [PubMed] [Cross Ref]
150. Qi Z, Han X, Zhang Y, Wang J, Cao YM. Listeria monocytogenes inoculation protects mice against blood-stage Plasmodium yoelii infection. Tohoku J Exp Med 2013; 229:87 - 96;; PMID: 23303295 10.1620/tjem.229.87 [PubMed] [Cross Ref]

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