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Many microbial pathogens bind host-cell integrin receptors. These interactions are promoted either by a host protein binding the microorganism or by a surface-localized ligand encoded by the pathogen. Attachment facilitates extracellular adhesion of the microorganism or internalization by the host cell.
Exploiters (parasites and predators) are thought to play a significant role in diversification, and ultimately speciation, of their hosts or prey. Exploiters may drive sympatric (within-population) diversification if there are a variety of exploiter-resistance strategies or fitness costs associated with exploiter resistance. Exploiters may also drive allopatric (between-population) diversification by creating different selection pressures and increasing the rate of random divergence. We examined the effect of a virulent viral parasite (phage) on the diversification of the bacterium Pseudomonas fluorescens in spatially structured microcosms. Here we show that in the absence of phages, bacteria rapidly diversified into spatial niche specialists with similar patterns of diversity across replicate populations. In the presence of phages, sympatric diversity was greatly reduced, as a result of phage-imposed reductions in host density decreasing competition for resources. In contrast, allopatric diversity was greatly increased as a result of phage-imposed selection for resistance, which caused populations to follow divergent evolutionary trajectories. These results show that exploiters can drive diversification between populations, but may inhibit diversification within populations by opposing diversifying selection that arises from resource competition.
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Cysteine proteases have been implicated as important virulence factors in a wide range of prokaryotic and eukaryotic pathogens, but little direct evidence has been presented to support this notion. Virtually all strains of the human bacterial pathogen Streptococcus pyogenes express a highly conserved extracellular cysteine protease known as streptococcal pyrogenic exotoxin B (SpeB). Two sets of isogenic strains deficient in SpeB cysteine protease activity were constructed by integrational mutagenesis using nonreplicating recombinant plasmids containing a truncated segment of the speB gene. Immunoblot analyses and enzyme assays confirmed that the mutant derivatives were deficient in expression of enzymatically active SpeB cysteine protease. To test the hypothesis that the cysteine protease participates in host mortality, we assessed the ability of serotype M3 and M49 wild-type strains and isogenic protease-negative mutants to cause death in outbred mice after intraperitoneal inoculation. Compared to wild-type parental organisms, the serotype M3 speB mutant lost virtually all ability to cause mouse death (P < 0.00001), and similarly, the virulence of the M49 mutant was detrimentally altered (P < 0.005). The data unambiguously demonstrate that the streptococcal enzyme is a virulence factor, and thereby provide additional evidence that microbial cysteine proteases are critical in host-pathogen interactions.
A fundamental question in host-pathogen interaction is to determine if the immune system activates fusion with the lysosomes to eradicate pathogens. We recently reported that this task is accomplished by the interaction between CD40 expressed on macrophages and CD154 expressed on activated CD4+ T cells. CD40 stimulation of macrophages induces vacuole-lysosome fusion through autophagy and results in killing of the obligate intracellular pathogen Toxoplasma gondii. This response is independent of IFN-gamma, STAT1 and p47 GTPases. We now report that vacuole-lysosome fusion is dependent on synergy between TRAF6 signaling downstream of CD40 and TNF-alpha. These studies identified a new paradigm by which T cells eradicate an intracellular pathogen within macrophages.
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PURPOSE OF REVIEW: As the molecular networks that connect innate and adaptive immunity are untangled, the prominence of natural killer (NK) cells in host defense continues to emerge. Herein we highlight recent findings pertaining to NK cell development, trafficking, and interactions with other innate and adaptive immune cells in the context of predicting how NK cells may be involved in a wider range of clinical immunodeficiency. RECENT FINDINGS: NK cells contribute vital roles in innate and adaptive immunity, especially in collaboration with dendritic cells (DC). Fascinating new details have been reported about cell surface integrins and receptors that regulate NK functions, as well as the cytokine/chemokine networks that provide for NK-DC interactions. Moreover, NK cells appear to play an important role in the attenuation or resolution of an immune response through either action against CD8 T cells or indirect control of certain DC. These findings shed important insights as to how NK cells and DC cooperate to control primary infections and shape the subsequent adaptive immune responses. SUMMARY: Natural killer cells are heterogeneous lymphocytes that provide an essential function in host defense. NK cells respond early to microbial assault and interact with other cells of the innate immune system, but they recognize and intercept pathogenic infections through highly specific mechanisms that are similar to T cells. Thus, NK cells are positioned as a cellular bridge between innate and adaptive immunity. It is imperative, then, to include a careful assessment of NK cell populations and functions in most cases of suspected immunodeficiency.
The inflammatory bowel diseases (IBDs) are characterized by intestinal inflammation of unknown etiology. Two distinct disorders, Crohn's disease and ulcerative colitis, have been identified. Three theories of IBD etiology are currently under consideration: 1) reaction to a persistent intestinal infection, 2) existence of a defective mucosal barrier to luminal antigens, and 3) a dysregulated host immune response to ubiquitous antigens. In each of these theories, either pathogenic or resident luminal bacteria constantly stimulate the mucosal and systemic immune systems to perpetuate the inflammatory cascade. Chronicity of inflammation results from an interaction of the persistent stimulus of microbial antigens with genetically determined host susceptibility factors that determine the individual's immune response or mucosal barrier function. The pathogenesis of IBD involves a series of steps, beginning with the breach of the intestinal mucosal barrier by infectious agents or toxins. The defective barrier exposes lamina propria immune cells to the continual presence of resident luminal bacteria, bacterial products, or dietary antigens, which perpetuates the inflammatory cascade. Many immunoregulatory abnormalities are noted in IBD, including the ratio of proinflammatory to immunosuppressive cytokines, selective activation of T(H) lymphocyte subsets, and abnormalities in epithelial antigen presentation. When activated during the initial inflammatory process, macrophages and T lymphocytes secrete a host of cytokines, which recruit other inflammatory cell types, thereby continuing the process. Tissue injury is the net result of the soluble products of the activated inflammatory cells. Knowledge of the pathogenesis in IBD suggests that the ultimate goals of therapy should be to block the proinflammatory mediators toward the proximal, rather than the distal, end of the cascade, to decrease the constant antigenic drive of luminal bacteria, and to correct the dysregulated immune response.
Long-term interactions between Helicobacter pylori and humans significantly increase the risk for peptic ulcer disease and noncardia gastric adenocarcinoma. The vast majority of infected persons remain persistently colonized unless a targeted antibiotic regimen is employed; thus regulation of inflammation by H. pylori is governed by levels of host-bacteria equilibria that are not found during cellular interactions with acute enteric pathogens. It is important to gain insight into mechanisms that regulate immune evasion by H. pylori not only to develop more effective treatments for disease, but also because such knowledge may serve as a paradigm for the role that other chronic infectious agents play in the genesis of pathological lesions that arise from inflammatory foci.
Collectins are a family of collagenous calcium-dependent defense lectins in animals. Their polypeptide chains consist of four regions: a cysteine-rich N-terminal domain, a collagen-like region, an alpha-helical coiled-coil neck domain and a C-terminal lectin or carbohydrate-recognition domain. These polypeptide chains form trimers that may assemble into larger oligomers. The best studied family members are the mannan-binding lectin, which is secreted into the blood by the liver, and the surfactant proteins A and D, which are secreted into the pulmonary alveolar and airway lining fluid. The collectins represent an important group of pattern recognition molecules, which bind to oligosaccharide structures and/or lipid moities on the surface of microorganisms. They bind preferentially to monosaccharide units of the mannose type, which present two vicinal hydroxyl groups in an equatorial position. High-affinity interactions between collectins and microorganisms depend, on the one hand, on the high density of the carbohydrate ligands on the microbial surface, and on the other, on the degree of oligomerization of the collectin. Apart from binding to microorganisms, the collectins can interact with receptors on host cells. Binding of collectins to microorganisms may facilitate microbial clearance through aggregation, complement activation, opsonization and activation of phagocytosis, and inhibition of microbial growth. In addition, the collectins can modulate inflammatory and allergic responses, affect apoptotic cell clearance and modulate the adaptive immune system.
Beneficial plant-associated microbes can profoundly influence plant health by suppressing disease, enhancing nutrient uptake, fixing atmospheric nitrogen, and promoting plant growth. Host variation, among cultivars or plant genotypes, for response to beneficial microorganisms suggests that plant genes play a role in supporting these interactions. Such host variation can be found among diverse groups of microorganisms including rhizobia, mycorrhizal fungi, and microbial biocontrol agents. Discrete variation among plant genotypes for interaction with beneficial microbes has led to the discovery of single genes that specify compatible interactions. Continuous variation for interaction phenotypes such as disease suppression, plant growth, or nutrient uptake have led to hypotheses, and in some cases genetic descriptions, of multigenic control of these interactions. Future research into the role of plant genes involved in hosting beneficial plant-associated microbes will provide greater insight into this relatively unexplored area of biology and should provide new tools to improve plant health in agriculture.
The ability to study the early events in the pathogenesis of pulmonary tuberculosis in guinea pigs following very low dose (3-5 cfu) infection by the respiratory route has revealed that early (10-14 days) extrapulmonary dissemination results in reseeding of previously uninfected lobes of the lung by the hematogenous route. Thus, in every guinea pig, the lung is challenged twice, once by the airway and 2-3 weeks later by the circulatory system. The so called "secondary" pulmonary lesions which result from the bacillemia differ fundamentally from the primary lesions, in part, because the host has already developed a strong T cell mediated immunity when the hematogenous reseeding occurs. Secondary lung lesions in non-vaccinated guinea pigs behave similarly to primary lung lesions in previously vaccinated guinea pigs. Since the secondary, blood-borne lesions are thought to be the "reactivatable foci" which result in reactivation tuberculosis following prolonged persistent infection, it is important to understand the nature of the host-pathogen interaction in secondary lesions. The guinea pig model provides a unique opportunity to examine both the microbial and host factors which constitute that interface.
Analysis of large-scale data-independent acquisition mass spectrometry metaproteomics data remains a computational challenge. Here, we present a computational pipeline called metaExpertPro for metaproteomics data analysis. This pipeline encompasses spectral library generation using data-dependent acquisition MS, protein identification and quantification using data-independent acquisition mass spectrometry, functional and taxonomic annotation, as well as quantitative matrix generation for both microbiota and hosts. By integrating FragPipe and DIA-NN, metaExpertPro offers compatibility with both Orbitrap and timsTOF MS instruments. To evaluate the depth and accuracy of identification and quantification, we conducted extensive assessments using human fecal samples and benchmark tests. Performance tests conducted on human fecal samples indicated that metaExpertPro quantified an average of 45,000 peptides in a 60-min diaPASEF injection. Notably, metaExpertPro outperformed three existing software tools by characterizing a higher number of peptides and proteins. Importantly, metaExpertPro maintained a low factual false discovery rate of approximately 5% for protein groups across four benchmark tests. Applying a filter of five peptides per genus, metaExpertPro achieved relatively high accuracy (F-score = 0.67-0.90) in genus diversity and showed a high correlation (rSpearman = 0.73-0.82) between the measured and true genus relative abundance in benchmark tests. Additionally, the quantitative results at the protein, taxonomy, and function levels exhibited high reproducibility and consistency across the commonly adopted public human gut microbial protein databases IGC and UHGP. In a metaproteomic analysis of dyslipidemia patients, metaExpertPro revealed characteristic alterations in microbial functions and potential interactions between the microbiota and the host.
Animals defend themselves against invading pathogenic micro-organisms by utilizing cationic anti-microbial peptides, which rapidly kill various micro-organisms without exerting toxicity against the host. Physicochemical peptide-lipid interactions provide attractive mechanisms for innate immunity. Many of these peptides form amphipathic secondary structures (alpha-helices and beta-sheets) which can selectively interact with anionic bacterial membranes by electrostatic interaction. Rapid, peptide-induced membrane permeabilization is an effective mechanism of anti-microbial action. Magainin 2 from frog skin forms a dynamic peptide-lipid supramolecular-complex pore that allows mutually coupled transmembrane transport of ions and lipids. The peptide molecule is internalized upon the disintegration of the pore. Several anti-microbial peptides are known to work synergistically.
The gastrointestinal tracts of developed animals are colonized by an extremely complex and diverse microbial ecosystem. The host and its microbiota are in close interaction with each other, and the host's genetic characteristics have been suggested to have an influence on the composition of fecal bacteria. However, different sections of gastrointestinal tract harbor microbes typical of each particular section and knowledge of the effect of the host's genotype on the microbiota in the different parts of the gastrointestinal tract is limited. In this study, mice from two inbred strains, C57BL/6J and BALB/c, were raised in identical conditions. Bacterial samples were collected from four parts of the gastrointestinal tract and analyzed for bacterial fatty acids using gas-liquid chromatography (GLC). Significant differences between the microbiota in the feces, in the cecum, in the small bowel and in the stomach were observed. Cecal samples produced more diverse bacterial fatty acid profiles than any of the other samples, revealing a higher bacterial density and a higher number of bacterial species. Further, a significant difference between the two strains of mice was observed throughout the gastrointestinal tract. These findings indicate that the host's genotype has an influence on the gastrointestinal microbiota as a whole, and provide further evidence that the cecum is the most species-rich region of the murine gut.
It is probably one of the most complex tasks to understand the mutual relationship between members of the microbial community in the gut and their interaction with the host. Although many animals including humans can live without gut flora, it is beneficial for the growth and protection of the host against pathogens. On the other hand, clinical and experimental intestinal inflammatory reactions have been attributed to immune recognition of the intestinal microflora. This review discusses recent and old findings on function and immunological relevance of the endogenous microflora.
Streptococcal pyrogenic exotoxin B (SPE B), a conserved extracellular cysteine protease expressed by the human pathogenic bacterium Streptococcus pyogenes, was purified and shown to cleave inactive human interleukin 1 beta precursor (pIL-1 beta) to produce biologically active IL-1 beta. SPE B cleaves pIL-1 beta one residue amino-terminal to the site where a recently characterized endogenous human cysteine protease acts. IL-1 beta resulting from cleavage of pIL-1 beta by SPE B induced nitric oxide synthase activity in vascular smooth muscle cells and killed of the human melanoma A375 line. Two additional naturally occurring SPE B variants cleaved pIL-1 beta in a similar fashion. By demonstrating that SPE B catalyzes the formation of biologically active IL-1 beta from inactive pIL-1 beta, our data add a further dimension to an emerging theme in microbial pathogenesis that bacterial and viral virulence factors act directly on host cytokine pathways. The data also contribute to an enlarging literature demonstrating that microbial extracellular cysteine proteases are important in host-parasite interactions.