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
Acinetobacter baumannii causes a wide range of severe infections among compromised and injured patients worldwide. The relevance of these infections are, in part, due to the ability of this pathogen to sense and react to environmental and host stress signals, allowing it to persist and disseminate in medical settings and the human host. This review summarizes current knowledge on the roles that environmental and cellular stressors play in the ability of A. baumannii to resist nutrient deprivation, oxidative and nitrosative injury, and even the presence of the commonly used antiseptic ethanol, which could serve as a nutrient- and virulence-enhancing signal rather than just being a convenient disinfectant. Emerging experimental evidence supports the role of some of these responses in the pathogenesis of the infections A. baumannii causes in humans and its capacity to resist antibiotics and host response effectors.
antibiotics; ethanol; indole-3-acetic acid; iron; motility; proteomics; reactive species; transcriptomics
Latency-associated nuclear antigen (LANA) is encoded by the Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) open reading frame 73. LANA is expressed during latent KSHV infection of cells, including tumor cells, such as primary effusion lymphoma, KS and multicentric Castleman’s disease. Latently infected cells have multiple extrachromosomal copies of covalently closed circular KSHV genomes (episomes) that are stably maintained in proliferating cells. LANA’s best characterized function is that of mediating episome persistence. It does so by binding terminal repeat sequences to the chromosomal matrix, thus ensuring episome replication with each cell division and efficient DNA segregation to daughter nuclei after mitosis. To achieve these functions, LANA associates with different host cell proteins, including chromatin-associated proteins and proteins involved in DNA replication. In addition to episome maintenance, LANA has transcriptional regulatory effects and affects cell growth. LANA exerts these functions through interactions with different cell proteins.
AIDS; HIV; human herpesvirus 8; Kaposi’s sarcoma; lymphoma; viral latency
Malaria is a disease caused by infection with Plasmodium parasites that are transmitted by mosquito bite. Five different species of Plasmodium infect humans with severe disease, but human malaria is primarily caused by Plasmodium falciparum. The burden of malaria on the developing world is enormous, and a fully protective vaccine is still elusive. One of the biggest challenges in the quest for the development of new antimalarial drugs and vaccines is the lack of accessible animal models to study P. falciparum infection because the parasite is restricted to the great apes and human hosts. Here, we review the current state of research in this field and provide an outlook of the development of humanized small animal models to study P. falciparum infection that will accelerate fundamental research into human parasite biology and could accelerate drug and vaccine design in the future.
animal model; blood stage; humanized mice; infectious disease; liver stage; malaria; Plasmodium falciparum; Plasmodium vivax
In this study, we investigate whether pH (low) insertion peptide (pHLIP) can target regions of lung injury associated with influenza infection.
Materials & methods
Fluorophore-conjugated pHLIP was injected intraperitoneally into mice infected with a sublethal dose of H1N1 influenza and visualized histologically.
pHLIP specifically targeted inflamed lung tissues of infected mice in the later stages of disease and at sites where alveolar type I and type II cells were depleted. Regions of pHLIP-targeted lung tissue were devoid of peroxiredoxin 6, the lung-abundant antioxidant enzyme, and were deficient in pneumocytes. Interestingly, a pHLIP variant possessing mutations that render it insensitive to pH changes was also able to target damaged lung tissue.
pHLIP holds potential for delivering therapeutics for lung injury during influenza infection. Furthermore, there may be more than one mechanism that enables pHLIP variants to target inflamed lung tissue.
delivery; inflammation; influenza; peptide; pHLIP
Many examples of the emergence or re-emergence of infectious diseases involve the adaptation of zoonotic viruses to new amplification hosts or to humans themselves. These include several instances of simple mutational adaptations, often to hosts closely related to the natural reservoirs. However, based on theoretical grounds, arthropod-borne viruses, or arboviruses, may face several challenges for adaptation to new hosts. Here, we review recent findings regarding adaptive evolution of arboviruses and its impact on disease emergence. We focus on the zoonotic alphaviruses Venezuelan equine encephalitis and chikungunya viruses, which have undergone adaptive evolution that mediated recent outbreaks of disease, as well as the flaviviruses dengue and West Nile viruses, which have emerged via less dramatic adaptive mechanisms.
adaptation; alphavirus; emergence; evolution; fitness; flavivirus; mosquito; vector
Borrelia burgdorferi, a pathogen transmitted by Ixodes ticks, is responsible for a prevalent illness known as Lyme disease, and a vaccine for human use is unavailable. Recently, genome sequences of several B. burgdorferi strains and Ixodes scapularis ticks have been determined. In addition, remarkable progress has been made in developing molecular genetic tools to study the pathogen and vector, including their intricate relationship. These developments are helping unravel the mechanisms by which Lyme disease pathogens survive in a complex enzootic infection cycle. Notable discoveries have already contributed to understanding the spirochete gene regulation accounting for the temporal and spatial expression of B. burgdorferi genes during distinct phases of the lifecycle. A number of pathogen and vector gene products have also been identified that contribute to microbial virulence and/or persistence. These research directions will enrich our knowledge of vector-borne infections and contribute towards the development of preventative strategies against Lyme disease.
Borrelia burgdorferi; Ixodes; ticks; Lyme disease; vector–pathogen interaction
Gene- and cell-based therapies hold great potential for the advancement of the personalized medicine movement. Gene therapy vectors have made dramatic leaps forward since their inception. Retroviral-based vectors were the first to gain clinical attention and still offer the best hope for the long-term correction of many disorders. The fear of nonspecific transduction makes targeting a necessary feature for most clinical applications. However, this remains a difficult feature to optimize, with specificity often coming at the expense of efficiency. The aim of this article is to discuss the various methods employed to retarget retroviral entry. Our focus will lie on the modification of gammaretroviral envelope proteins with an in-depth discussion of the creation and screening of envelope libraries.
DNA shuffling; FeLV; library screening; MLV; murine leukemia virus; pseudotyping; retroviral entry; sindbis Env; viral envelopes; viral receptors; viral retargeting
Members of the RTX family of protein toxins are functionally conserved among an assortment of bacterial pathogens. By disrupting host cell integrity through their pore-forming and cytolytic activities, this class of toxins allows pathogens to effectively tamper with normal host cell processes, promoting pathogenesis. Here, we focus on the biology of RTX toxins by describing salient properties of a prototype member, α-hemolysin, which is of ten encoded by strains of uropathogenic Escherichia coli. It has long been appreciated that RTX toxins can have distinct effects on host cells aside from outright lysis. Recently, advances in modeling and analysis of host–pathogen interactions have led to novel findings concerning the consequences of pore formation during host–pathogen interactions. We discuss current progress on longstanding questions concerning cell specificity and pore formation, new areas of investigation that involve toxin-mediated perturbations of host cell signaling cascades and perspectives on the future of RTX toxin investigation.
Akt; evolution; HlyA; host response; membrane repair; mesotrypsin; pore-forming toxin; UPEC; urinary tract infection; uropathogenic Escherichia coli
Respiratory syncytial virus is a single-stranded RNA virus in the Paramyxoviridae family that preferentially assembles and buds from the apical surface of polarized epithelial cells, forming filamentous structures that contain both viral proteins and the genomic RNA. Recent studies have described both viral and host factors that are involved in ribonucleoprotein assembly and trafficking of viral proteins to the cell surface. At the cell surface, viral proteins assemble into filaments that probably require interactions between viral proteins, host proteins and the cell membrane. Finally, a membrane scission event must occur to release the free virion. This article will review the recent literature describing the mechanisms that drive respiratory syncytial virus assembly and budding.
fusion proteins; paramyxovirus; respiratory syncytial viruses; virus assembly; virus filaments
While organized screening programs in industrialized countries have significantly reduced cervical cancer incidence, cytology-based screening has several limitations. Equivocal or mildly abnormal Pap tests require costly retesting or diagnostic work-up by colposcopy and biopsy. In low-resource countries, it has been difficult to establish and sustain cytology-based programs. Advances in understanding human papillomavirus biology and the natural history of human papillomavirus-related precancers and cancers have led to the discovery of a range of novel biomarkers in the past decade. In this article, we will discuss the potential role of new biomarkers for primary screening, triage and diagnosis in high-resource countries and their promise for prevention efforts in resource constrained settings.
accuracy; biomarkers; cervical cancer; HPV; prevention; risk prediction; screening
Burkholderia pseudomallei is the etiologic agent of melioidosis. This multifaceted disease is difficult to treat, resulting in high morbidity and mortality. Treatment of B. pseudomallei infections is lengthy and necessitates an intensive phase (parenteral ceftazidime, amoxicillin–clavulanic acid or meropenem) and an eradication phase (oral trimethoprim–sulfamethoxazole). The main resistance mechanisms affecting these antibiotics include enzymatic inactivation, target deletion and efflux from the cell, and are mediated by chromosomally encoded genes. Overproduction and mutations in the class A PenA β-lactamase cause ceftazidime and amoxicillin–clavulanic acid resistance. Deletion of the penicillin binding protein 3 results in ceftazidime resistance. BpeEF–OprC efflux pump expression causes trimethoprim and trimethoprim–sulfamethoxazole resistance. Although resistance is still relatively rare, therapeutic efficacies may be compromised by resistance emergence due to increased use of antibiotics in endemic regions. Novel agents and therapeutic strategies are being tested and, in some instances, show promise as anti-B. pseudomallei infectives.
antibiotics; Burkholderia pseudomallei; melioidosis; resistance; therapy