Canonical and unconventional mechanisms of secretion in many eukaryotic cells are relatively well known. In contrast to the situation in animal cells, mechanisms of secretion in fungi must include the capacity for trans-cell wall passage of macromolecules to the extracellular space. Although these mechanisms remain somewhat elusive, several studies in recent years have suggested that vesicular transport is required for trans-cell wall secretion of large molecules. Several fungal molecules, including proteins, lipids, polysaccharides and pigments, are released to the extracellular space in vesicles. In pathogenic fungi, a number of these vesicular components are associated with fungal virulence. Indeed, extracellular vesicles produced by fungi can interfere with the immunomodulatory activity of host cells. Fungal vesicles share many functional aspects with mammalian exosomes and extracellular vesicles produced by bacteria, plants and protozoa, but their cellular origin remains unknown. Here, we discuss the involvement of vesicular transport systems in fungal physiology and pathogenesis, making parallels with the mammalian, bacterial, protozoan and plant cell literature.
Cryptococcus neoformans; extracellular vesicles; fungal pathogens; secretion
Clostridium perfringens uses its arsenal of >16
toxins to cause histotoxic and intestinal infections in humans and animals. It
has been unclear why this bacterium produces so many different toxins,
especially since many target the plasma membrane of host cells. However, it is
now established that C. perfringens uses chromosomally encoded
alpha toxin (a phospholipase C) and perfringolysin O (a pore-forming toxin)
during histotoxic infections. In contrast, this bacterium causes intestinal
disease by employing toxins encoded by mobile genetic elements, including
C. perfringens enterotoxin, necrotic enteritis toxin
B-like, epsilon toxin and beta toxin. Like perfringolysin O, the toxins with
established roles in intestinal disease form membrane pores. However, the
intestinal disease-associated toxins vary in their target specificity, when they
are produced (sporulation vs vegetative growth), and in their sensitivity to
intestinal proteases. Producing many toxins with diverse characteristics likely
imparts virulence flexibility to C. perfringens so it can cause
an array of diseases.
animal disease; avian necrotic enteritis; Clostridium perfringens; enterocolitis; enterotoxemia; food poisoning; gas gangrene; human disease; toxins
Dengue viruses (DENV) cause significantly more human disease than any other arbovirus, with hundreds of thousands of cases leading to severe disease in thousands annually. Antibodies and T cells induced by primary infection with DENV have the potential for both positive (protective) and negative (pathological) effects during subsequent DENV infections. In this review, we summarize studies that have examined T-cell responses in humans following natural infection and vaccination. We discuss studies that support a role for T cells in protection against and those that support a role for the involvement of T cells in the pathogenesis of severe disease. The mechanisms that lead to severe disease are complex, and T-cell responses are an important component that needs to be further evaluated for the development of safe and efficacious DENV vaccines.
dengue; immune response; immunopathology; nonstructural proteins; primary infection; secondary infection; T lymphocyte; vaccine
Macrophages are the front line of immune defense against invading microbes. Microbes, however, have evolved numerous and diverse mechanisms to thwart these host immune defenses and thrive intracellularly. Legionella pneumophila, a Gram-negative pathogen of amoebal and mammalian phagocytes, is one such microbe. In humans, it causes a potentially fatal pneumonia referred to as Legionnaires' disease. Armed with the Icm/Dot type IV secretion system, which is required for virulence, and approximately 300 translocated proteins, Legionella is able to enter host cells, direct the biogenesis of its own vacuolar compartment, and establish a replicative niche, where it grows to high levels before lysing the host cell. Efforts to understand the pathogenesis of this bacterium have focused on characterizing the molecular activities of its many effectors. In this article, we highlight recent strides that have been made in understanding how Legionella effectors mediate host-pathogen interactions.
autophagy; intracellular pathogen; Legionella pneumophila; macrophages; protein translocation
Newcastle Disease Virus (NDV) is an avian paramyxovirus, which has been demonstrated to possess significant oncolytic activity against mammalian cancers. This review summarizes the research leading to the elucidation of the mechanisms of NDV-mediated oncolysis as well as the development of novel oncolytic agents through the use of genetic engineering. Clinical trials utilizing NDV strains and NDV-based autologous tumor cell vaccines will expand our knowledge of these novel anti-cancer strategies and will ultimately result in the successful use of the virus in the clinical setting.
NDV; oncolytic; immunotherapy; apoptosis; interferon; cancer
Invasive fungal infections are a major problem in solid organ transplant (SOT) recipients. Overall, the most common fungal infection in SOT is candidiasis, followed by aspergillosis and cryptococcosis, except in lung transplant recipients, where aspergillosis is most common. Development of invasive disease hinges on the interplay between host factors (e.g., integrity of anatomical barriers, innate and acquired immunity) and fungal factors (e.g., exposure, virulence and resistance to prophylaxis). In this article, we describe the epidemiology and clinical features of the most common fungal infections in organ transplantation. Within this context, we review recent advances in diagnostic modalities and antifungal chemotherapy, and their impact on evolving prophylaxis and treatment paradigms.
antifungal; aspergillosis; candidiasis; cryptococcosis; fungal; galactomannan; kidney transplant; liver transplant; lung transplant; transplant
HPVs are the causative agents of cervical and other anogenital cancers. HPVs infect stratified epithelia and link their productive life cycles to cellular differentiation. Low levels of viral genomes are stably maintained in undifferentiated cells and productive replication or amplification is restricted to differentiated suprabasal cells. Amplification is dependent on the activation of the ATM DNA damage factors that are recruited to viral replication centers and inhibition of this pathway blocks productive replication. The STAT-5 protein appears to play a critical role in mediating activation of the ATM pathway in HPV-positive cells. While HPVs need to activate the DNA damage pathway for replication, cervical cancers contain many genomic alterations suggesting that this pathway is circumvented during progression to malignancy.
amplification; ATM; CHK2; differentiation; DNA damage; papillomaviruses; replication foci; STAT-5
Candida commonly adheres to implanted medical devices, growing as a resilient biofilm capable of withstanding extraordinarily high antifungal concentrations. As currently available antifungals have minimal activity against biofilms, new drugs to treat these recalcitrant infections are urgently needed. Recent investigations have begun to shed light on the mechanisms behind the profound resistance associated with the biofilm mode of growth. This resistance appears to be multifactorial, involving both mechanisms similar to conventional, planktonic antifungal resistance, such as increased efflux pump activity, as well as mechanisms specific to the biofilm lifestyle. A unique biofilm property is the production of an extracellular matrix. Two components of this material, β-glucan and extracellular DNA, promote biofilm resistance to multiple antifungals. Biofilm formation also engages several stress response pathways that impair the activity of azole drugs. Resistance within a biofilm is often heterogeneous, with the development of a subpopulation of resistant persister cells. In this article we review the molecular mechanisms underlying Candida biofilm antifungal resistance and their relative contributions during various growth phases.
antifungal resistance; biofilm; calcineurin; Candida; efflux pumps; extracellular matrix; glucan; persister cells
Human infections with arthropod-borne Rickettsia species remain a major global health issue, causing significant morbidity and mortality. Epidemic typhus due to Rickettsia prowazekii has an established reputation as the ‘scourge of armies’, and as a major determinant of significant ‘historical turning points’. No suitable vaccines for human use are currently available to prevent rickettsial diseases. The unique lifestyle features of rickettsiae include obligate intracellular parasitism, intracytoplasmic niche within the host cell, predilection for infection of microvascular endothelium in mammalian hosts, association with arthropods and the tendency for genomic reduction. The fundamental research in the field of Rickettsiology has witnessed significant recent progress in the areas of pathogen adhesion/invasion and host immune responses, as well as the genomics, proteomics, metabolomics, phylogenetics, motility and molecular manipulation of important rickettsial pathogens. The focus of this review article is to capture a snapshot of the latest developments pertaining to the mechanisms of rickettsial pathogenesis and immunity.
endothelium; genomics; innate immunity; metabolomics; pathogenesis; plasmids; proteomics; Rickettsia; spotted fever; typhus
Coxiella burnetii is an extremely infectious, zoonotic agent that causes Q fever in humans. With the exception of New Zealand, the bacterium is distributed worldwide. Coxiella is classified as a select agent based on its past and potential use as a bioweapon and its threat to public health. Despite decades of research, we know relatively little regarding Coxiella’s molecular pathogenesis, and a vaccine is not widely available. This article briefly reviews the unusual genetics of C. burnetii; a pathogen that retains telltale genetic mementos collected over the course of its evolutionary path from a free-living bacterium to an obligate intracellular parasite of eukaryotic host cell phagosomes. Understanding why these genetic elements are maintained may help us better understand the biology of this fascinating pathogen.
chromosome; Coxiella; genome reduction; genomics; genotype; plasmids; Q fever; selfish genetic elements
Previously, we showed that radioimmunotherapy (RIT) for cryptococcal
infections using radioactively labeled antibodies recognizing the
cryptococcal capsule reduced fungal burden and prolonged survival of mice
infected with Cryptococcus neoformans. Here, we investigate
the effects of RIT on bystander mammalian cells.
Materials & methods
Heat-killed C. neoformans bound to anticapsular
antibodies, unlabeled or labeled with the β-emitter
rhenium-188 (16.9-h half-life) or the α-emitter bismuth-213 (46-min
half-life), was incubated with macrophage-like J774.16 cells or
epithelial-like Chinese hamster ovary cells. Lactate dehydrogenase activity,
crystal violet uptake, reduction of tetrazolium dye
nitric oxide production were measured.
The J774.16 and Chinese hamster ovary cells maintained membrane
integrity, viability and metabolic activity following exposure to
radiolabeled C. neoformans.
RIT of C. neoformans is a selective therapy with
minimal effects on host cells and these results are consistent with
observations that RIT-treated mice with cryptococcal infection lacked
RIT-related pathological changes in lungs and brain tissues.
bystander effects; Cryptococcus neoformans; fungal infection; NO production; particulate radiation; radioimmunotherapy
The human colon plays host to a diverse and metabolically complex community of microorganisms. While the colonic microbiome has been suggested to contribute to the development of colorectal cancer (CRC), a definitive link has not been made. The role in which the colon microflora could contribute to the initiation and/or progression of CRC is explored in this review. Potential mechanisms of bacterial oncogenesis are presented, along with lines of evidence derived from animal models of microbially induced CRC. Particular focus is given to the oncogenic capabilities of enterotoxigenic Bacteroides fragilis. Recent progress in defining the microbiome of CRC in the human population is evaluated, and the future challenges of linking specific etiologic agents to CRC are emphasized.
bacterial toxin; chronic inflammation; colonic microbiome; colorectal cancer; genotoxins; oncogenesis
Chlamydia trachomatis infections are a global health problem. This obligate intracellular bacterial pathogen comprises lymphogranuloma venereum (L1–L3), ocular (A–C) and genital (D–K) serovars. Although genetically similar, each serovar group differs in disease severity and tissue tropism through mechanisms that are not well understood. It is clear that host genetic differences also play a role in chlamydial disease outcome and key host polymorphisms are beginning to emerge from both human and experimental animal studies. In this review, we will highlight pathogen and host genes that link genetic diversity, disease severity and tissue tropism. We will also use this information to provide new insights that may be helpful in developing improved management strategies for these important pathogens.
Chlamydia trachomatis; disease severity; gene polymorphisms; genetic variation; genital tract infections; tissue tropism
Most of the newly discovered compounds showing promise for the treatment of TB, notably multidrug-resistant TB, inhibit aspects of Mycobacterium tuberculosis cell envelope metabolism. This review reflects on the evolution of the knowledge that many of the front-line and emerging products inhibit aspects of cell envelope metabolism and in the process are bactericidal not only against actively replicating M. tuberculosis, but contrary to earlier impressions, are effective against latent forms of the disease. While mycolic acid and arabinogalactan synthesis are still primary targets of existing and new drugs, peptidoglycan synthesis, transport mechanisms and the synthesis of the decaprenyl-phosphate carrier lipid all show considerable promise as targets for new products, older drugs and new combinations. The advantages of whole cell- versus target-based screening in the perpetual search for new targets and products to counter multidrug-resistant TB are discussed.
antibiotic; arabinogalactan; cell envelope; Mycobacterium; mycolic acids; peptidoglycan; tuberculosis
Evolution of bacterial pathogen populations has been detected in a variety of ways including phenotypic tests, such as metabolic activity, reaction to antisera and drug resistance and genotypic tests that measure variation in chromosome structure, repetitive loci and individual gene sequences. While informative, these methods only capture a small subset of the total variation and, therefore, have limited resolution. Advances in sequencing technologies have made it feasible to capture whole-genome sequence variation for each sample under study, providing the potential to detect all changes at all positions in the genome from single nucleotide changes to large-scale insertions and deletions. In this review, we focus on recent work that has applied this powerful new approach and summarize some of the advances that this has brought in our understanding of the details of how bacterial pathogens evolve.
bacteria; evolution; genome sequencing; horizontal gene transfer; mutation; recombination; selection
Increasing antibiotic resistance in Gram-negative bacteria, particularly in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, presents a global medical challenge. No new antibiotics will be available for these ‘superbugs’ in the near future due to the dry antibiotic discovery pipeline. Colistin and polymyxin B are increasingly used as the last-line therapeutic options for treatment of infections caused by multidrug-resistant Gram-negative bacteria. This article surveys the significant progress over the last decade in understanding polymyxin chemistry, mechanisms of antibacterial activity and resistance, structure–activity relationships and pharmacokinetics/pharmacodynamics. In the ‘Bad Bugs, No Drugs’ era, we must pursue structure–activity relationship-based approaches to develop novel polymyxin-like lipopeptides targeting polymyxin-resistant Gram-negative ‘superbugs’. Before new antibiotics become available, we must optimize the clinical use of polymyxins through the application of pharmacokinetic/pharmacodynamic principles, thereby minimizing the development of resistance.
colistin; lipid A; lipopolysaccharide; pharmacokinetic/pharmacodynamic; polymyxin; resistance; structure–activity relationship
Helicobacter pylori is arguably one of the most successful pathogens; it colonizes the stomachs of more than half of the human population. Colonization and persistence in such an inhospitable niche requires the presence of exquisite adaptive mechanisms. One of the proteins that contributes significantly to the remarkable adaptability of H. pylori is the ferric uptake regulator (Fur), which functions as a master regulator of gene expression. In addition to genes directly related to iron homeostasis, Fur controls expression of several enzymes that play a central role in metabolism and energy production. The absence of Fur leads to severe H. pylori colonization defects and, accordingly, several Fur-regulated genes have been shown to be essential for colonization. Moreover, proteins encoded by Fur-regulated genes have a strong impact on redox homeostasis in the stomach and are major determinants of inflammation. In this review, we discuss the main roles of Fur in the biology of H. pylori and highlight the importance of this regulatory protein in the infectious process.
colonization; ferric uptake regulator; gastric cancer; Helicobacter pylori; inflammation; iron; iron acquisition; iron metabolism; virulence
corticosteroid; Exserohilum rostratum; fungal; meningitis
antibiotic resistance; metallo-β-lactamases; nutritional immunity; periplasm; Zn(II)
Porphyromonas gingivalis is a Gram-negative anaerobic bacterium that colonizes the human oral cavity. It is implicated in the development of periodontitis, a chronic periodontal disease affecting half of the adult population in the USA. To survive in the oral cavity, these bacteria must colonize dental plaque biofilms in competition with other bacterial species. Long-term survival requires P. gingivalis to evade host immune responses, while simultaneously adapting to the changing physiology of the host and to alterations in the plaque biofilm. In reflection of this highly variable niche, P. gingivalis is a genetically diverse species and in this review the authors summarize genetic diversity as it relates to pathogenicity in P. gingivalis. Recent studies revealing a variety of mechanisms by which adaptive changes in genetic content can occur are also reviewed. Understanding the genetic plasticity of P. gingivalis will provide a better framework for understanding the host–microbe interactions associated with periodontal disease.
adaptive virulence; genetic diversity; genetic variability; horizontal DNA transfer; pan-genome; Porphyromonas gingivalis
It has been nearly a decade since caspofungin was approved for clinical use as the first echinocandin class antifungal agent, followed by micafungin and anidulafungin. The echinocandin drugs target the fungal cell wall by inhibiting the synthesis of α-1,3-d-glucan, a critical cell wall component of many pathogenic fungi. They are fungicidal for Candida spp. and fungistatic for moulds, such as Aspergillus fumigatus, where they induce abnormal morphology and growth properties. The echinocandins have a limited antifungal spectrum but are highly active against most Candida spp., including azole-resistant strains and biofilms. As they target glucan synthase, an enzyme absent in mammalian cells, the echinocandins have a favorable safety profile. They show potent MIC and epidemiological cutoff values against susceptible Candida and Aspergillus isolates, and the frequency of resistance is low. When clinical breakthrough occurs, it is associated with high MIC values and mutations in Fks subunits of glucan synthase, which can reduce the sensitivity of the enzyme to the drug by several thousand-fold. Such strains were not adequately captured by an early clinical breakpoint for susceptibility prompting a revised lower value, which addresses the FKS resistance mechanism and new pharmacokinetic/pharmacodynamic studies. Elevated MIC values unlinked to therapeutic failure can occur and result from adaptive cell behavior, which is FKS-independent and involves the molecular chaperone Hsp90 and the calcineurin pathway. Mutations in FKS1 and/or FKS2 alter the kinetic properties of glucan synthase, which reduces the relative fitness of mutant strains causing them to be less pathogenic. The echinocandin drugs also modify the cell wall architecture exposing buried glucans, which in turn induce a variety of important host immune responses. Finally, the future for glucan synthase inhibitors looks bright with the development of new orally active compounds.
anidulafungin; caspofungin; echinocandin; FKS; fungal infection; glucan synthase; MIC; micafungin
Noroviruses are now recognized as the major cause of acute gastroenteritis in the developed world, yet our ability to prevent and control infection is limited. Recent work has highlighted that, while typically an acute infection in the population, immunocompromised patients often experience long-term infections that may last many years. This cohort of patients and those regularly exposed to infectious material, for example, care workers and others, would benefit greatly from the development of a vaccine or antiviral therapy. While a licensed vaccine or antiviral has yet to be developed, work over the past 10 years in this area has intensified and trials with a vaccine candidate have proven promising. Numerous antiviral targets and small molecule inhibitors that have efficacy in cell culture have now been identified; however, further studies in this area are required in order to make these suitable for clinical use.
antiviral; calicivirus; gastroenteritis; host factors; norovirus; vaccine; viral polymerase; virus-like particles; VLP
C. elegans; epithelial defense; exotoxin A; innate immunity; P. aeruginosa; patterns of pathogenesis; surveillance immunity; translation