Enteropathogenic Escherichia coli (EPEC) strains continue to cause severe and sometimes fatal infantile diarrhea, particularly in Africa. Increased efforts at diagnosis, defining the clinical spectrum of disease, understanding pathogenic mechanisms, and delineating immune responses are desperately needed to develop new strategies to combat EPEC.
translational research; diarrhea; mortality; infants; immunity; vaccines
Recent findings indicate that fungi use vesicular transport to deliver substances across their cell walls. Fungal vesicles are similar to mammalian exosomes and could originate from cytoplasmic multivesicular bodies. Vesicular transport enables the export of large molecules across the cell wall, and vesicles contain lipids, proteins and polysaccharides, many of which are associated with virulence. Concentration of fungal products in vesicles could increase their efficiency in food acquisition and/or delivering potentially noxious substances to other cells, such as amoebae or phagocytes. The discovery of vesicular transport in fungi opens many new avenues for investigation in basic cell biology and pathogenesis.
Staphylococcus aureus employs numerous pore-forming cytotoxins to injure host immune cells and promote infection. Until recently, it was unclear how these cytotoxins targeted specific cell types for lysis. Membrane lipids were initially postulated to be cytotoxin receptor candidates. However, the cell-type specificity and species-dependent targeting of these toxins did not support lipids as sole receptors. The recent identification of proteinaceous receptors for several S. aureus cytotoxins now provides an explanation for the observed tropism. These findings also have important implications for the implementation of animal models to study S. aureus pathogenesis, and for the development of novel therapeutics.
Pore-forming toxins; toxin receptors; membrane proteins Staphylococcus aureus
The actin cytoskeleton plays a key role during the replication cycle of human immunodeficiency virus-1 (HIV-1). HIV-1 infection is affected by cellular proteins that influence the clustering of viral receptors or the subcortical actin cytoskeleton. Several of these actin-adaptor proteins are controlled by the second messenger phosphatidylinositol 4,5-biphosphate (PIP2), an important regulator of actin organization. PIP2 production is induced by HIV-1 attachment and facilitates viral infection. However, the importance of PIP2 in regulating cytoskeletal proteins and thus HIV-1 infection has been overlooked. This review examines recent reports describing the roles played by actin-adaptor proteins during HIV-1 infection of CD4+ T cells, highlighting the influence of the signaling lipid PIP2 in this process.
PIP2; actin-binding proteins; HIV-1
Recent studies have revealed that several Gram-negative species utilize variations of the well-known chemotaxis signaling cascade to switch lifestyles in order to survive environmental stress. Two survival strategies covered in this review are the development of dormant cyst cells and biofilm formation. Both of these two types of structures involve exopolysaccharide-mediated cell-cell interactions which result in multicellular communities that confer resistance to stress conditions such as desiccation and antibiotics. This review is centered on recent advances in the understanding of phosphate flow and novel output signals in chemosensory signaling pathways that are involved in cyst formation and biofilms.
Chemotaxis-Like; Signal; Transduction; Systems
Type I interferons (IFN-I) are a broad family of cytokines that are central to the innate immune response. These proteins have long been appreciated for the critical roles they play in restraining viral infections and shaping antiviral immune responses. However, in recent years there has been increased awareness of the immunosuppressive actions of these proteins as well. While there are many current therapeutic applications to manipulate IFN-I pathways we have limited understanding of the mechanisms by which these therapies are actually functioning. In this review we highlight the diversity and temporal impact of IFN-I signaling, discuss the current therapeutic uses of IFN-I, and explore the strategy of blocking IFN-I to alleviate immune dysfunction in persistent virus infections.
type I interferon; persistent; virus; LCMV; immunosuppression; therapy; immune activation; HIV
Bacteria inhabit enormously diverse niches and have a correspondingly large array of regulatory mechanisms to adapt to often inhospitable and variable environments. The stringent response allows bacteria to quickly reprogram transcription in response to changes in nutrient availability. Although the proteins controlling this response are conserved in almost all bacterial species, recent work has illuminated considerable diversity in the starvation cues and regulatory mechanisms that activate stringent signaling proteins in bacteria from different environments. In this review we describe the signals and genetic circuitries that control the stringent signaling systems of a copiotroph, a bacteriovore, an oligotroph and a mammalian pathogen – Escherichia coli, Myxococcus xanthus, Caulobacter crescentus and Mycobacterium tuberculosis, respectively – and discuss how control of the stringent response in these species is adapted to their particular lifestyles.
stringent response; niche; ppGpp; RelA; SpoT; stress response
Standard treatment for tuberculosis (TB) is lengthy, complex and significantly toxic. Drug development for TB has stagnated for decades; but in recent years renewed commitment and coordinated research has generated a modest pipeline of new drugs that hold the potential to make treatment more effective, shorter, less complex and less toxic in the near future. With a particular focus on bedaquiline (TMC207), the first antituberculosis drug of a novel class to be FDA-approved in 40 years, this review summarizes the recent evidence behind new developments in tuberculosis treatment. Novel drug classes, repurposed drugs and host-directed therapies are reviewed. In parallel to these exciting developments in drug-discovery, we propose that it is crucial to develop more rapid and comprehensive diagnostics that will allow for the timely selection of the best regimen for individual patients.
Tuberculosis; Bedaquiline; PA-824; Delamanid; Clofazimine; Oxazolidinones
The key viral gene responsible for initiating the replicative cycle of Epstein–Barr virus (EBV), termed BZLF1, encodes the multifunctional protein Zta (ZEBRA or Z). It interacts with DNA as both a transcription and a replication factor, modulates both intracellular signal transduction and the DNA-damage response and manipulates cell cycle progression. Muller and colleagues have resolved the structure of Zta bound to DNA, which confirms some structural predictions but reveals an unexpected twist and a complex dimerization interface. Because EBV is associated with human disease, Zta presents a prime target for drug design.
•Metabolic adaptation impacts upon Candida albicans pathogenicity at multiple levels.•Carbon sources influence virulence factor expression and innate immune surveillance.•Nutrients also affect stress resistance and antifungal drug susceptibility.•Candida pathogenicity and immunogenicity therefore must differ between host niches.
Metabolism is integral to the pathogenicity of Candida albicans, a major fungal pathogen of humans. As well as providing the platform for nutrient assimilation and growth in diverse host niches, metabolic adaptation affects the susceptibility of C. albicans to host-imposed stresses and antifungal drugs, the expression of key virulence factors, and fungal vulnerability to innate immune defences. These effects, which are driven by complex regulatory networks linking metabolism, morphogenesis, stress adaptation, and cell wall remodelling, influence commensalism and infection. Therefore, current concepts of Candida–host interactions must be extended to include the impact of metabolic adaptation upon pathogenicity and immunogenicity.
metabolic adaptation; stress adaptation; cell wall; virulence factors; regulatory networks; fungal immunology
Language used to describe clinical research represents a powerful opportunity to educate volunteers. In the case of HIV cure research there is an emerging need to manage expectations by using the term ‘experiment’. Cure experiments are proof-of-concept studies designed to evaluate novel paradigms to reduce persistent HIV-1 reservoirs, without any expectation of medical benefit.
HIV cure research; experiments; trials; expectations
Although increasing evidence suggests a relationship between bacterial dysbiosis and colorectal cancer (CRC), few studies have identified specific microbes as etiologic factors. Recent studies have implicated overabundance of Fusobacterium species in association with colorectal adenomas and cancer. Two articles published in the current issue of Cell Host and Microbe provide insights into the mechanisms for this Fusobacterium-CRC relationship.
•Cryoelectron tomography reveals details of the intact flagellar export machinery.•Mechanistic studies reveal discrete stages of the flagellar subunit export pathway.•Unanticipated chain mechanism for constant rate of flagellum growth.
Flagella, the helical propellers that extend from the bacterial surface, are a paradigm for how complex molecular machines can be built outside the living cell. Their assembly requires ordered export of thousands of structural subunits across the cell membrane and this is achieved by a type III export machinery located at the flagellum base, after which subunits transit through a narrow channel at the core of the flagellum to reach the assembly site at the tip of the nascent structure, up to 20 μm from the cell surface. Here we review recent findings that provide new insights into flagellar export and assembly, and a new and unanticipated mechanism for constant rate flagellum growth.
bacterial flagellum; rotary nanomotor; cell motility; protein export; type III secretion system; chain mechanism
Autophagy is an important membrane transport pathway that is conserved among eukaryotic cells. Although first described as an intracellular catabolic pathway used to break down self components, autophagy has been found to play an important role in the elimination of intracellular pathogens. A variety of host mechanisms exist for recognizing and targeting intracellular bacteria to autophagosomes. Several intracellular bacteria have evolved ways to manipulate, inhibit, or avoid autophagy in order to survive in the cell. Thus, the autophagy pathway can be viewed as an evolutionarily conserved host response to infection.
autophagy; xenophagy; intracellular bacteria
Vertebrate hosts actively sequester iron, and fungal and other pathogens must therefore adapt to a severe limitation in iron availability to cause disease. Recent studies reveal that the pathogenic fungus Cryptococcus neoformans overcomes iron limitation by multiple mechanisms that target transferrin and heme. The regulation of iron uptake is mediated by an interconnected set of transcription factors that include the master iron regulator Cir1 and the pH-responsive factor Rim 101. These factors integrate iron homeostasis with a myriad of other functions including pH sensing, nutrient and stress signaling pathways, virulence factor elaboration and cell wall biogenesis.
Heme; capsule; melanin; virulence; fungal pathogenesis; pH; cell wall; signaling
•Bacteria are typically found within complex microbial communities in nature.•Molecular interactions between co-infecting bacteria can profoundly affect disease prognosis and treatment.•In vivo models and genomic tools are providing new insights into interbacterial behavior during infection.•There is potential to target interbacterial interactions as part of a therapeutic strategy.
Polybacterial diseases involve multiple organisms that act collectively to facilitate disease progression. Although this phenomenon was highlighted early in the 20th century, recent technological advances in diagnostics have led to the appreciation that many infections are far more complex than originally believed. Furthermore, it is apparent that although most treatments focus on the dominant bacterial species in an infection, other microbes, including commensals, can have a profound impact on both the response to therapy and virulence. Very little is known about the molecular mechanisms that underpin interactions between bacteria during such infections. Here, we discuss recent studies identifying and characterizing mechanisms of bacterial interaction and the biological processes they govern during certain diseases. We also highlight how possible strategies for targeting these interbacterial interactions may afford a route towards development of new therapies, with consequences for disease control.
polybacterial disease; synergy; infection; metatranscriptomics; cell–cell signaling; polymicrobial infection
Rodents have long been recognized as the principal reservoirs of hantaviruses. However, with the discovery of genetically distinct and phylogenetically divergent lineages of hantaviruses in multiple species of shrews, moles, and insectivorous bats from widely separated geographic regions, a far more complex landscape of hantavirus host distribution, evolution, and phylogeography is emerging. Detailed phylogenetic analyses, based on partial and full-length genomes of previously described rodent-borne hantaviruses and newly detected non-rodent-borne hantaviruses, indicate an Asian origin and support the emerging concept that ancestral non-rodent mammals may have served as the hosts of primordial hantaviruses.
hantavirus; Eulipotyphla; Chiroptera; evolution; host-switching
The contribution of fungal infections to the morbidity and mortality of HIV-infected individuals is largely unrecognized. A recent meeting highlighted several priorities that need to be urgently addressed, including improved epidemiological surveillance, increased availability of existing diagnostics and drugs, more training in the field of medical mycology, and better funding for research and provision of treatment, particularly in developing countries.
HIV; AIDS; fungal infection; mortality; translational research; immunity
The invasion and stimulation of normally non-phagocytic host cells, such as epithelial and endothelial cells, is a key step in the pathogenesis of many fungal infections. In most cases, host cell invasion and/or stimulation of a pro-inflammatory response is induced when proteins or carbohydrates on the fungal cell surface bind to receptors on the host cell. While many of these fungal–host cell interactions have only been investigated in vitro, the therapeutic efficacy of blocking the host cell receptors for Candida albicans and Rhizopus oryzae has been demonstrated in experimental animal models of infection. Here we summarize recent studies of the fungal receptors on normally non-phagocytic host cells and the therapeutic implications of blocking these receptors.
epithelial cells; endothelial cells; fungi; receptor; pathogenesis
Detection of pathogen-derived nucleic acids by pattern recognition receptors (PRRs) is essential for the host to mount an appropriate immune response, which for viruses involves the induction of type I interferons (IFNs). On the other hand, inappropriate activation of PRRs by self nucleic acids can lead to autoimmunity. Recent developments in PRR research have uncovered important new molecular details as to how Toll-like receptors and RIG-I-like receptors distinguish pathogen- from self-RNA, while the discovery of cytosolic DNA sensing pathways for IFN induction has revealed completely new innate signaling mechanisms, and also questions how innate immunity discriminates between self- and non-self DNA, if at all.
Toll-like receptors; RIG-I; antiviral immunity; cytosolic DNA sensing; STING
Early innate and cell-intrinsic responses are essential to protect host cells against pathogens. In turn, viruses have developed sophisticated mechanisms to establish productive infections, counteracting the host innate immune responses. Increasing evidence indicates that these antiviral factors may have a dual role by directly inhibiting viral replication, as well as by sensing and transmitting signals to induce antiviral cytokines. Recent studies have pointed at new, unappreciated mechanisms of viral evasion of host innate protective responses including manipulating the host ubiquitin system. Viral inhibition of antiviral factors by ubiquitin-dependent degradation is emerging as critical evasion mechanism of the antiviral response. In addition, recent studies have uncovered new mechanisms by which viral encoded proteins inhibit ubiquitin and ubiquitin-like modification of host proteins involved innate immune signaling pathways. Here we discuss recent findings and novel strategies that viruses have developed to counteract these early innate antiviral defenses.
Antiviral; Evasion of Innate immunity; Restriction Factors; Ubiquitin System
The development of a safe, effective vaccine to prevent human immunodeficiency virus (HIV) infection is a key step for controlling the disease on a global scale. However, many aspects of HIV biology make vaccine design problematic, including the sequence diversity and structural variability of the surface envelope glycoproteins and the poor accessibility of neutralization-sensitive epitopes on the virus. In this review, we discuss recent progress in understanding HIV in a structural context using emerging tools in 3D electron microscopy, and outline how some of these advances could be important for a better understanding of mechanisms of viral entry and for vaccine design.
Cryo-electron tomography; ion abrasion scanning electron microscopy (IA-SEM); focused ion beam scanning electron microscopy (FIB-SEM); vaccine design; virus–cell interaction
The Lyme disease spirochetes, Borrelia burgdorferi (sensu lato), must cause persistent, disseminated infection to be maintained in the natural enzootic cycle. In human Lyme disease, spirochetes spread from the site of a tick bite to colonize multiple tissue sites, causing multisystem clinical manifestations. The Lyme spirochetes produce many adhesive surface proteins that collectively recognize diverse host substrates and cell types and are likely to promote dissemination and chronic infection in a variety of tissues. Recent application of state-of-the-art in vivo imaging technologies is illuminating mechanisms of interaction of B. burgdorferi with the host and the importance of multiple adhesins during mammalian infection.
Lyme disease; Borrelia burgdorferi; adhesins; intravital imaging; dissemination; transmigration
The biosynthesis and export of bacterial cell-surface polysaccharides is known to occur through several distinct mechanisms. Recent advances in the biochemistry and structural biology of several proteins in synthase-dependent polysaccharide secretion systems have identified key conserved components of this pathway in Gram-negative bacteria. These components include an inner-membrane-embedded polysaccharide synthase, a periplasmic tetratricopeptide repeat (TPR)-containing scaffold protein, and an outer-membrane β-barrel porin. There is also increasing evidence that many synthase-dependent systems are post-translationally regulated by the bacterial second messenger bis-(3′-5′)-cyclic dimeric guanosine monophosphate (c-di-GMP). Here, we compare these core proteins in the context of the alginate, cellulose, and poly-β-D-N-acetylglucosamine (PNAG) secretion systems.
PMID: 23117123 CAMSID: cams4570
synthase; exopolysaccharide; alginate; cellulose; poly-β-D-N-acetylglucosamine