The post-translational attachment of ubiquitin or ubiquitin-like modifiers (ULMs) to proteins regulates many cellular processes including the generation of innate and adaptive immune responses to pathogens. Vice versa, pathogens counteract immune defense by inhibiting or redirecting the ubiquitination machinery of the host. A common immune evasion strategy is for viruses to target host immunoproteins for proteasomal or lysosomal degradation by employing viral or host ubiquitin ligases. By degrading key host adaptor and signaling molecules, viruses thus disable multiple immune response pathways including the production of and response to interferons as well as other innate host defense mechanisms. Recent work further revealed that viruses inhibit the ligation of ubiquitin or ULMs or remove ubiquitin from host cell proteins. Thus, viruses succeed in either stabilizing negative regulators of innate immune signaling or thwart host cell proteins that are activated by ubiquitin or ULM-modification.
Innate immunity is a primordial system that has a primary role in lung antimicrobial defenses. Recent advances in understanding the recognition systems by which cells of the innate immune system recognize and respond to microbial products have revolutionized the understanding of host defenses in the lungs and other tissues. The innate immune system includes lung leukocytes and also epithelial cells lining the alveolar surface and the conducting airways. The innate immune system drives adaptive immunity in the lungs and has important interactions with other systems, including apoptosis pathways and signaling pathways induced by mechanical stretch. Human diversity in innate immune responses could explain some of the variability seen in the responses of patients to bacterial, fungal, and viral infections in the lungs. New strategies to modify innate immune responses could be useful in limiting the adverse consequences of some inflammatory reactions in the lungs.
endotoxin; innate immunity; lung inflammation; Toll-like receptors
Intrinsic innate immune mechanisms are the first line of defense against pathogens, and exist to control infection autonomously in infected cells. Here we show that autophagy, an intrinsic mechanism that can degrade cytoplasmic components, plays a direct anti-viral role against the mammalian viral pathogen Vesicular Stomatitis Virus (VSV) in the model organism Drosophila. We found that the surface glycoprotein, VSVG, is likely the pathogen-associated molecular pattern (PAMP) that initiates this cell-autonomous response. Once activated, autophagy decreases viral replication, and repression of autophagy leads to increased viral replication and pathogenesis in cells and animals. Lastly, we show that the antiviral response is controlled by the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway which normally regulates autophagy in response to nutrient availability. Altogether these data uncover an intrinsic antiviral program that that links viral recognition to the evolutionarily conserved nutrient signaling and autophagy pathways.
Human skin and mucosal surfaces are in constant contact with resident and invasive microbes. Recognition of microbial products by receptors of the innate immune system triggers rapid innate defense and transduces signals necessary for initiating and maintaining the adaptive immune responses. Microbial sensing by innate pattern recognition receptors is not restricted to pathogens. Rather, proper development, function, and maintenance of innate and adaptive immunity rely on continuous recognition of products derived from the microorganisms indigenous to the internal and external surfaces of mammalian host. Tonic immune activation by the resident microbiota governs host susceptibility to intestinal and extra-intestinal infections including those caused by viruses. This review highlights recent developments in innate viral recognition leading to adaptive immunity, and discusses potential link between viruses, microbiota and the host immune system. Further, we discuss the possible roles of microbiome in chronic viral infection and pathogenesis of autoimmune disease, and speculate on the benefit for probiotic therapies against such diseases.
dendritic cells; T cells; viral; inflammation; AIDS; Toll-like receptors/PRR
Summary of recent advances
The immune response to virus infection is initiated when pathogen recognition receptors (PRRs) of the host cell recognize specific non-self motifs within viral products to trigger intracellular signaling events that induce innate immunity, the front line of defense against microbial infection. The replication program of all viruses includes a cytosolic phase of genome amplification and/or mRNA metabolism and viral protein expression. Cytosolic recognition of viral infection by specific PRRs takes advantage of the dependence of viruses on the cytosolic component of their replication programs. Such PRR-PAMP interactions lead to PRR-dependent non-self recognition and the downstream induction of type I interferons and proinflammatory cytokines. These factors serve to induce innate immune programs and drive the maturation of adaptive immunity and inflammation for the control of infection. Recent studies have focused on identifying the particular viral ligands recognized as non-self by cytosolic PRRs, and on defining the nature of the PRRs and their signaling pathways involved in immunity. The RIG-I-like receptors, RIG-I and MDA5, have been defined as essential PRRs for host detection of a variety of RNA viruses. Novel PRRs and their signaling pathways involved in detecting DNA viruses through non-self recognition of viral DNA are also being elucidated. Moreover, studies to identify the PRRs and signaling factors of the host cell that mediate inflammatory signaling through inflammasome activation following virus infection are currently underway and have already revealed specific NOD-like receptors (NLRs) as inflammatory triggers. This review summarizes recent progress and current areas of focus in pathogen recognition and immune triggering by cytosolic PRRs.
Eradication of HCV infection requires a complex and coordinated interplay between innate and adaptive immune responses that, when it fails, leads to chronic infection. Increasing evidence suggest that defects in innate immune recognition and in innate immunity-induced activation of adaptive immune responses play a critical role in failure of HCV clearance. The evolutionarily preserved receptors of viral recognition in immune cells and in hepatocytes sense invading pathogens that results in induction of Type I IFNs, the central players in antiviral immunity. In this review the innate immune mechanisms by which HCV is sensed and by which HCV undermines host defense are discussed. The critical role of dendritic cells in antigen presentation/T cell activation and IFNα-production as well as interference of HCV with innate immune cell functions are reviewed. Finally, current and emerging therapeutic approaches targeting innate immune pathways will be evaluated.
Toll-like receptors; RNA Helicases; Dendritic cell; Macrophages; NK cell; Inflammation
HIV has evolved sophisticated mechanisms to avoid restriction by intracellular innate immune defenses that otherwise serve to control acute viral infection and virus dissemination. Innate defenses are triggered when pattern recognition receptor (PRR) proteins of the host cell engage pathogen-associated molecule patterns (PAMPs) present in viral products. Interferon regulatory factor 3 (IRF3) plays a central role in PRR signaling of innate immunity to drive the expression of type I interferon (IFN) and interferon-stimulated genes (ISGs), including a variety of HIV restriction factors, that serve to limit viral replication directly and/or program adaptive immunity. Productive infection of T cells by HIV is dependent upon the targeted proteolysis of IRF3 that occurs through a virus-directed mechanism that results in suppression of innate immune defenses. However, the mechanisms by which HIV controls innate immune signaling and IRF3 function are not defined. Here, we examined the innate immune response induced by HIV strains identified through their differential control of PRR signaling. We identified viruses that, unlike typical circulating HIV strains, lack the ability to degrade IRF3. Our studies show that IRF3 regulation maps specifically to the HIV accessory protein Vpu. We define a molecular interaction between Vpu and IRF3 that redirects IRF3 to the endolysosome for proteolytic degradation, thus allowing HIV to avoid the innate antiviral immune response. Our studies reveal that Vpu is an important IRF3 regulator that supports acute HIV infection through innate immune suppression. These observations define the Vpu-IRF3 interface as a novel target for therapeutic strategies aimed at enhancing the immune response to HIV.
The innate immune response provides a first line of defense against pathogens by targeting generic differential features that are present in foreign organisms but not in the host. These innate responses generate selection forces acting both in pathogens and hosts that further determine their co-evolution. Here we analyze the nucleic acid sequence fingerprints of these selection forces acting in parallel on both host innate immune genes and ssRNA viral genomes. We do this by identifying dinucleotide biases in the coding regions of innate immune response genes in plasmacytoid dendritic cells, and then use this signal to identify other significant host innate immune genes. The persistence of these biases in the orthologous groups of genes in humans and chickens is also examined. We then compare the significant motifs in highly expressed genes of the innate immune system to those in ssRNA viruses and study the evolution of these motifs in the H1N1 influenza genome. We argue that the significant under-represented motif pattern of CpG in an AU context - which is found in both the ssRNA viruses and innate genes, and has decreased throughout the history of H1N1 influenza replication in humans - is immunostimulatory and has been selected against during the co-evolution of viruses and host innate immune genes. This shows how differences in host immune biology can drive the evolution of viruses that jump into species with different immune priorities than the original host.
The initiation and progression of vascular inflammation are driven by the retention of cholesterol in the artery wall, where its modification by oxidation and/or enzymes triggers the innate immune host response. Although previously considered a broad, primitive defense mechanism against invading pathogens, it has become clear that pattern recognition receptors of the innate immune system can cooperate to precisely regulate signaling pathways essential for the proper initiation of both innate and acquired immunity. Recent evidence suggests that these pattern recognition receptors may orchestrate the host response to modified endogenous ligands involved in sterile chronic inflammatory syndromes, including atherosclerosis. In this review we will summarize the current understanding of innate immune receptors and the putative ligands that regulate the numerous responses that promote this disease, including monocyte recruitment, macrophage cholesterol uptake, and pro-inflammatory signaling cascades. Specific emphasis will be placed on the potential of these innate immune targets for therapeutic interventions to retard the progression of atherosclerosis or to induce its regression.
pattern recognition receptor; atherosclerosis; innate immunity; macrophage; scavenger receptor; chemokine; Toll-like receptor
During virus infection, multiple immune signaling pathways are triggered, both within the host cell and bystander cells of an infected tissue. These pathways act in concert to mediate innate antiviral immunity and to initiate the inflammatory response against infection. The RIG-I-like receptor (RLR) family of pattern recognition receptors (PRRs) is a group of cytosolic RNA helicase proteins that can identify viral RNA as nonself via binding to pathogen associated molecular patter (PAMP) motifs within RNA ligands that accumulate during virus infection. This interaction then leads to triggering of an innate antiviral response within the infected cells through RLR induction of downstream effector molecules such as type I interferon (IFN) and other pro-inflammatory cytokines that serve to induce antiviral and inflammatory gene expression within the local tissue. Cellular regulation of RLR signaling is a critical process that can direct the outcome of infection and is essential for governance of the overall immune response and avoidance of immune toxicity. Mechanisms of positive and negative regulation of RLR signaling have been identified that include signaling crosstalk between RLR pathways and Nuclear Oligomerization Domain (NOD)-Like Receptor (NLR) pathways and Caspase networks. Furthermore, many viruses have evolved mechanisms to target these pathways to promote enhanced replication and spread within the host. These virus-host interactions therefore carry important consequences for host immunity and viral pathogenesis. Understanding the pivotal role of RLRs in immune regulation and signaling crosstalk in antiviral immunity may provide new insights into therapeutic strategies for the control of virus infection and immunity.
RIG-I-like receptors; immunity (author to check)
The innate immune response system is designed to alert the host rapidly to the presence of an invasive microbial pathogen that has breached the integument of multicellular eukaryotic organisms. Microbial invasion poses an immediate threat to survival, and a vigorous defense response ensues in an effort to clear the pathogen from the internal milieu of the host. The innate immune system is able to eradicate many microbial pathogens directly, or innate immunity may indirectly facilitate the removal of pathogens by activation of specific elements of the adaptive immune response (cell-mediated and humoral immunity by T cells and B cells). The coagulation system has traditionally been viewed as an entirely separate system that has arisen to prevent or limit loss of blood volume and blood components following mechanical injury to the circulatory system. It is becoming increasingly clear that coagulation and innate immunity have coevolved from a common ancestral substrate early in eukaryotic development, and that these systems continue to function as a highly integrated unit for survival defense following tissue injury. The mechanisms by which these highly complex and coregulated defense strategies are linked together are the focus of the present review.
coagulation; disseminated intravascular coagulation; inflammation; sepsis; septic shock
Host organisms have developed sophisticated antiviral responses in order to defeat emerging influenza A viruses (IAV). At the same time IAV have evolved immune evasion strategies. The immune system of mammals provides several lines of defense to neutralize invading pathogens or limit their replication. Here, we summarize the mammalian innate and adaptive immune mechanisms involved in host defense against viral infection and review strategies by which IAV avoid, circumvent or subvert these mechanisms. We highlight well-characterized, as well as recently described features of this intriguing virus-host molecular battle.
Positive selection of host proteins that interact with pathogens can indicate factors relevant for infection and potentially be a measure of pathogen driven evolution.
Our analysis of 1439 primate genes and 175 lentivirus genomes points to specific host factors of high genetic variability that could account for differences in susceptibility to disease and indicate specific mechanisms of host defense and pathogen adaptation. We find that the largest amount of genetic change occurs in genes coding for cellular membrane proteins of the host as well as in the viral envelope genes suggesting cell entry and immune evasion as the primary evolutionary interface between host and pathogen. We additionally detect the innate immune response as a gene functional group harboring large differences among primates that could potentially account for the different levels of immune activation in the HIV/SIV primate infection. We find a significant correlation between the evolutionary rates of interacting host and viral proteins pointing to processes of the host-pathogen biology that are relatively conserved among species and to those undergoing accelerated genetic evolution.
These results indicate specific host factors and their functional groups experiencing pathogen driven evolutionary selection pressures. Individual host factors pointed to by our analysis might merit further study as potential targets of antiretroviral therapies.
Epstein-Barr virus (EBV) establishes a persistent infection in the human host and is associated with a variety of human cancers. Persistent infection results from a balance between the host immune response and viral immune evasion mechanisms. EBV infection is controlled initially by the innate immune response and later by T-cell-mediated adaptive immunity. EBV has evolved mechanisms to evade the host immune response so that it can persist for the lifetime of the host. Latent membrane protein 1 (LMP-1) is the EBV oncoprotein essential for B-cell immortalization by EBV. We show here that LMP-1 interacts with Tyk2, a signaling intermediate in the alpha interferon (IFN-α) signaling pathway, via a previously uncharacterized LMP-1 signaling domain. LMP-1 prevents Tyk2 phosphorylation and inhibits IFN-α-stimulated STAT2 nuclear translocation and interferon-stimulated response element transcriptional activity. Long-term culture of EBV+ lymphoblastoid cells in IFN-α is associated with outgrowth of a population expressing elevated LMP-1 protein levels, suggesting that cells expressing higher levels of LMP-1 survive the antiproliferative selective pressure imposed by IFN-α. These results show that LMP-1 can protect EBV+ cells from the IFN-α-stimulated antiviral/antiproliferative response and suggest that chronic IFN-α treatment may encourage the outgrowth of cells expressing elevated, and therefore potentially oncogenic, LMP-1 levels in EBV+ individuals.
Acute virus infection induces a cell-intrinsic innate immune response comprising our first line of immunity to limit virus replication and spread, but viruses have developed strategies to overcome these defenses. HIV-1 is a major public health problem; however, the virus-host interactions that regulate innate immune defenses against HIV-1 are not fully defined. We have recently identified the viral protein Vpu to be a key determinant responsible for HIV-1 targeting and degradation of interferon regulatory factor 3 (IRF3), a central transcription factor driving host cell innate immunity. IRF3 plays a major role in pathogen recognition receptor (PRR) signaling of innate immunity to drive the expression of type I interferon (IFN) and interferon-stimulated genes (ISGs), including a variety of HIV restriction factors, that serve to limit viral replication directly and/or program adaptive immunity. Here we interrogate the cellular responses to target cell infection with Vpu-deficient HIV-1 strains. Remarkably, in the absence of Vpu, HIV-1 triggers a potent intracellular innate immune response that suppresses infection. Thus, HIV-1 can be recognized by PRRs within the host cell to trigger an innate immune response, and this response is unmasked only in the absence of Vpu. Vpu modulation of IRF3 therefore prevents virus induction of specific innate defense programs that could otherwise limit infection. These observations show that HIV-1 can indeed be recognized as a pathogen in infected cells and provide a novel and effective platform for defining the native innate immune programs of target cells of HIV-1 infection.
Acute respiratory tract infection (RTI) is a leading cause of morbidity and mortality worldwide and the majority of RTIs are caused by viruses, among which respiratory syncytial virus (RSV) and the closely related human metapneumovirus (hMPV) figure prominently. Host innate immune response has been implicated in recognition, protection and immune pathological mechanisms. Host-viral interactions are generally initiated via host recognition of pathogen-associated molecular patterns (PAMPs) of the virus. This recognition occurs through host pattern recognition receptors (PRRs) which are expressed on innate immune cells such as epithelial cells, dendritic cells, macrophages and neutrophils. Multiple PRR families, including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and NOD-like receptors (NLRs), contribute significantly to viral detection, leading to induction of cytokines, chemokines and type I interferons (IFNs), which subsequently facilitate the eradication of the virus. This review focuses on the current literature on RSV and hMPV infection and the role of PRRs in establishing/mediating the infection in both in vitro and in vivo models. A better understanding of the complex interplay between these two viruses and host PRRs might lead to efficient prophylactic and therapeutic treatments, as well as the development of adequate vaccines.
PRRs; RSV; hMPV; TLR; RLR; NLR; PAMP; IFN; innate immunity
The emergence of the highly pathogenic SARS coronavirus (SARS-CoV) has reignited interest in coronavirus biology and pathogenesis. An emerging theme in coronavirus pathogenesis is that the interaction between specific viral genes and the host immune system, specifically the innate immune system, functions as a key determinant in regulating virulence and disease outcomes. Using SARS-CoV as a model, we will review the current knowledge of the interplay between coronavirus infection and the host innate immune system in vivo, and then discuss the mechanisms by which specific gene products antagonize the host innate immune response in cell culture models. Our data suggests that the SARS-CoV uses specific strategies to evade and antagonize the sensing and signaling arms of the interferon pathway. We summarize by identifying future points of consideration that will contribute greatly to our understanding of the molecular mechanisms governing coronavirus pathogenesis and virulence, and the development of severe disease in humans and animals.
Innate immunity is the first-line defense against pathogens and relies on phagocytes, soluble components, and cell-surface and cytosolic pattern recognition receptors. Despite using hard-wired receptors and signaling pathways, the innate immune response demonstrates surprising specificity to different pathogens. We determined how combinatorial use of innate immune defense mechanisms defines the response. We describe a novel cooperation between a soluble component of the innate immune system, the mannose-binding lectin, and Toll-like receptor 2 that both specifies and amplifies the host response to Staphylococcus aureus. Furthermore, we demonstrate that this cooperation occurs within the phagosome, emphasizing the importance of engulfment in providing the appropriate cellular environment to facilitate the synergy between these defense pathways.
InnateDB (http://www.innatedb.com) is an integrated analysis platform that has been specifically designed to facilitate systems-level analyses of mammalian innate immunity networks, pathways and genes. In this article, we provide details of recent updates and improvements to the database. InnateDB now contains >196 000 human, mouse and bovine experimentally validated molecular interactions and 3000 pathway annotations of relevance to all mammalian cellular systems (i.e. not just immune relevant pathways and interactions). In addition, the InnateDB team has, to date, manually curated in excess of 18 000 molecular interactions of relevance to innate immunity, providing unprecedented insight into innate immunity networks, pathways and their component molecules. More recently, InnateDB has also initiated the curation of allergy- and asthma-related interactions. Furthermore, we report a range of improvements to our integrated bioinformatics solutions including web service access to InnateDB interaction data using Proteomics Standards Initiative Common Query Interface, enhanced Gene Ontology analysis for innate immunity, and the availability of new network visualizations tools. Finally, the recent integration of bovine data makes InnateDB the first integrated network analysis platform for this agriculturally important model organism.
Despite lacking the adaptive immunity that is found in higher vertebrates, insects are able to defend themselves from a large battery of pathogens by multiple innate immune responses using molecular mechanisms that are strikingly similar to the innate immune responses of other multicellular organisms, including humans. The fruit fly Drosophila melanogaster is therefore an excellent model organism for studying the basic principles of innate immunity using genetic and molecular biology techniques. In Drosophila, invading pathogens that pass through the epithelial barriers (a first line of self-defense) can encounter humoral and cellular responses that utilize pattern-recognition receptors to identify pathogen-associated molecular patterns in the hemolymph or on the immune cell surface. Some pathogens escape recognition and elimination in the hemolymph by invading the host cytoplasm. Some intracellular pathogens such as Listeria monocytogenes are, nevertheless, eliminated by immune reactions such as autophagy through intracellular identification by pattern-recognition receptors.
autophagy; Drosophila; innate immunity; pathogen sensor; peptidoglycan
Nuclear Factor-κB (NF-κB)/Rel transcription factors form an integral part of innate immune defenses and are conserved throughout the animal kingdom. Studying the function, mechanism of activation and regulation of these factors is crucial for understanding host responses to microbial infections. The fruit fly Drosophila melanogaster has proved to be a valuable model system to study these evolutionarily conserved NF-κB mediated immune responses. Drosophila combats pathogens through humoral and cellular immune responses. These humoral responses are well characterized and are marked by the robust production of a battery of anti-microbial peptides. Two NF-κB signaling pathways, the Toll and the IMD pathways, are responsible for the induction of these antimicrobial peptides. Signal transduction in these pathways is strikingly similar to that in mammalian TLR pathways. In this chapter, we discuss in detail the molecular mechanisms of microbial recognition, signal transduction and NF-κB regulation, in both the Toll and the IMD pathways. Similarities and differences relative to their mammalian counterparts are discussed, and recent advances in our understanding of the intricate regulatory networks in these NF-κB signaling pathways are also highlighted.
The necessity for pathogen recognition of viral infection by the innate immune system in initiating early innate and adaptive host defenses is well documented. However, little is known about the role these receptors play in the maintenance of adaptive immune responses and their contribution to resolution of persistent viral infections. Here, we demonstrate a non-redundant functional requirement for both nucleic acid-sensing Toll-like receptors (TLR) and RIG-I-like receptors (RLR) in the control of a mouse model of chronic viral infection. Whereas the RLR pathway was important for production of type I interferons and optimal CD8+ T cell responses, nucleic acid-sensing TLRs were largely dispensable. In contrast, optimal anti-viral antibody responses required intact signaling through nucleic acid-sensing TLRs, and the absence of this pathway correlated with less virus-specific antibody and deficient long-term virus control of a chronic infection. Surprisingly, absence of the TLR pathway had only modest effects on antibody production in an acute infection with a closely related virus strain, suggesting that persistent TLR stimulation may be necessary for optimal antibody responses in a chronic infection. These results indicate that innate virus recognition pathways may play critical roles in the outcome of chronic viral infections through distinct mechanisms.
Innate and adaptive immune systems have important role in the pathogenesis of acute and chronic infection with hepatitis B virus (HBV). These immune responses are mediated through complex interactions between the innate immune response and adaptive immune response. Toll-like receptors (TLRs) are a family of innate immune-recognition receptors that recognize the molecular patterns associated with microbial pathogens. So far, TLR1 to 13 were found in human or mice and investigated to detect the target molecules and the downstream mechanisms of these unique systems. Stimulation by their ligands initiates the activation of complex networks of intracellular signaling transduction and innate and adaptive immune-related cells (NK, NK-T, monocytes, dendritic cells, T cells, B cells, and Tregs, etc.). However, reports on such relationships between HBV and TLRs have been relatively rare in comparison to those on HCV and TLRs, but have recently been increasing. Thus, a review of TLRs involved in the pathogenesis of HBV infection may be needed toward better understanding of the immunopathogenesis of HBV infection.
Although considerable progress has been made in dissecting the signaling pathways involved in the innate immune response, it is now apparent that this response can no longer be productively thought of in terms of simple linear pathways. InnateDB (www.innatedb.ca) has been developed to facilitate systems-level analyses that will provide better insight into the complex networks of pathways and interactions that govern the innate immune response. InnateDB is a publicly available, manually curated, integrative biology database of the human and mouse molecules, experimentally verified interactions and pathways involved in innate immunity, along with centralized annotation on the broader human and mouse interactomes. To date, more than 3500 innate immunity-relevant interactions have been contextually annotated through the review of 1000 plus publications. Integrated into InnateDB are novel bioinformatics resources, including network visualization software, pathway analysis, orthologous interaction network construction and the ability to overlay user-supplied gene expression data in an intuitively displayed molecular interaction network and pathway context, which will enable biologists without a computational background to explore their data in a more systems-oriented manner.
database; gene expression; innate immunity; interaction network; pathway visualization
Recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors triggers an innate immune response to colonizing or invading bacteria. Conversely, many bacteria have evolved mechanisms to dampen this response by downregulating the synthesis of such PAMPs. We have previously demonstrated that Pseudomonas aeruginosa growing in mucopurulent human respiratory mucus from cystic fibrosis patients represses the expression of its flagellin, a potent stimulant of the innate immune response. Here we demonstrate that this phenomenon occurs in response to the presence of neutrophil elastase in such mucus. Nonpurulent mucus from animals had no such repressive effect. Furthermore, lysed neutrophils from human blood reproduced the flagellin-repressive effect ex mucus and, significantly, had no effect on the viability of this organism. Neutrophil elastase, a component of the innate host defense system, has been described to be bactericidal for gram-negative bacteria and to degrade bacterial virulence factors. Thus, the resistance of P. aeruginosa to the bactericidal effect of neutrophil elastase, as well as this organism's ability to sense this enzyme's presence and downregulate the synthesis of a PAMP, may be the key factors in allowing P. aeruginosa to colonize the lungs. These findings demonstrate the dynamic nature of this bacterium's response to host defenses that ensures its success as a colonizer and also highlights the dual nature of defense molecules that confer advantages and disadvantages to both hosts and pathogens.