Reactive nitrogen intermediates and the pathogenesis of Salmonella and mycobacteria

Over the past decade, reactive nitrogen intermediates joined reactive oxygen intermediates as a biochemically parallel and functionally non-redundant pathway for mammalian host resistance to many microbial pathogens. The past year has brought a new appreciation that these two pathways are partially redundant, such that each can compensate in part for the absence of the other. In combination, their importance to defense of the murine host is greater than previously appreciated. In addition to direct microbicidal actions, reactive nitrogen intermediates have immunoregulatory effects relevant to the control of infection. Genes have been characterized in Mycobacterium tuberculosis and Salmonella typhimurium that may regulate the ability of pathogens to resist reactive nitrogen and oxygen intermediates produced by activated macrophages.     

Viral community analysis in a marine oxygen minimum zone indicates increased potential for viral manipulation of microbial physiological state

Microbial communities in oxygen minimum zones (OMZs) are known to have significant impacts on global biogeochemical cycles, but viral influence on microbial processes in these regions are much less studied. Here we provide baseline ecological patterns using microscopy and viral metagenomics from the Eastern Tropical North Pacific (ETNP) OMZ region that enhance our understanding of viruses in these climate-critical systems. While extracellular viral abundance decreased below the oxycline, viral diversity and lytic infection frequency remained high within the OMZ, demonstrating that viral influences on microbial communities were still substantial without the detectable presence of oxygen. Viral community composition was strongly related to oxygen concentration, with viral populations in low-oxygen portions of the water column being distinct from their surface layer counterparts. However, this divergence was not accompanied by the expected differences in viral-encoded auxiliary metabolic genes (AMGs) relating to nitrogen and sulfur metabolisms that are known to be performed by microbial communities in these low-oxygen and anoxic regions. Instead, several abundant AMGs were identified in the oxycline and OMZ that may modulate host responses to low-oxygen stress. We hypothesize that this is due to selection for viral-encoded genes that influence host survivability rather than modulating host metabolic reactions within the ETNP OMZ. Together, this study shows that viruses are not only diverse throughout the water column in the ETNP, including the OMZ, but their infection of microorganisms has the potential to alter host physiological state within these biogeochemically important regions of the ocean.Subject terms: Microbial biooceanography, Microbial ecology     

Effects of polymicrobial communities on host immunity and response

Microorganisms grow as members of microbial communities in unique niches, such as the mucosal surfaces of the human body. These microbial communities, containing both commensals and opportunistic pathogens, serve to keep individual pathogens 'in check' through a variety of mechanisms and complex interactions, both between the microorganisms themselves and the microorganisms and the host. Recent studies shed new light on the diversity of microorganisms that form the human microbial communities and the interactions these microbial communities have with the host to stimulate immune responses. This occurs through their recognition by dendritic cells or their ability to induce differential cytokine and defensin profiles. The differential induction of defensins by commensals and pathogens and the ability of the induced defensins to interact with the antigens from these microorganisms may attenuate proinflammatory signaling and trigger adaptive immune responses to microbial antigens in a multistep process. Such an activity may be a mechanism that the host uses to sense what is on its mucosal surfaces, as well as to differentiate among commensals and pathogens.     

In Vitro Communities Derived from Oral and Gut Microbial Floras Inhibit the Growth of Bacteria of Foreign Origins

The gastrointestinal (GI) tract is home to trillions of microbes. Within the same GI tract, substantial differences in the bacterial species that inhabit the oral cavity and intestinal tract have been noted. While the influence of host environments and nutritional availability in shaping different microbial communities is widely accepted, we hypothesize that the existing microbial flora also plays a role in selecting the bacterial species that are being integrated into the community. In this study, we used cultivable microbial communities isolated from different parts of the GI tract of mice (oral cavity and intestines) as a model system to examine this hypothesis. Microbes from these two areas were harvested and cultured using the same nutritional conditions, which led to two distinct microbial communities, each with about 20 different species as revealed by PCR-based denaturing gradient gel electrophoresis analysis. In vitro community competition assays showed that the two microbial floras exhibited antagonistic interactions toward each other. More interestingly, all the original isolates tested and their closely related species displayed striking community preferences: They persisted when introduced into the bacterial community of the same origin, while their viable count declined more than three orders of magnitude after 4 days of coincubation with the microbial flora of foreign origin. These results suggest that an existing microbial community might impose a selective pressure on incoming foreign bacterial species independent of host selection. The observed inter-flora interactions could contribute to the protective effect of established microbial communities against the integration of foreign bacteria to maintain the stability of the existing communities.     

Gut microbial diversity across a contact zone for California voles: Implications for lineage divergence of hosts and mitonuclear mismatch in the assembly of the mammalian gut microbiome

Gut microbial diversity is thought to reflect the co‐evolution of microbes and their hosts as well as current host‐specific attributes such as genetic background and environmental setting. To explore interactions among these parameters, we characterized variation in gut microbiome composition of California voles (Microtus californicus) across a contact zone between two recently diverged lineages of this species. Because this contact zone contains individuals with mismatched mitochondrial‐nuclear genomes (cybrids), it provides an important opportunity to explore how different components of the genotype contribute to gut microbial diversity. Analyses of bacterial 16S rRNA sequences and joint species distribution modelling revealed that host genotypes and genetic differentiation among host populations together explained more than 50% of microbial community variation across our sampling transect. The ranked importance (most to least) of factors contributing to gut microbial diversity in our study populations were: genome‐wide population differentiation, local environmental conditions, and host genotypes. However, differences in microbial communities among vole populations (β‐diversity) did not follow patterns of lineage divergence (i.e., phylosymbiosis). Instead, among‐population variation was best explained by the spatial distribution of hosts, as expected if the environment is a primary source of gut microbial diversity (i.e., dispersal limitation hypothesis). Across the contact zone, several bacterial taxa differed in relative abundance between the two parental lineages as well as among individuals with mismatched mitochondrial and nuclear genomes. Thus, genetic divergence among host lineages and mitonuclear genomic mismatches may also contribute to microbial diversity by altering interactions between host genomes and gut microbiota (i.e., hologenome speciation hypothesis).     

Microbial considerations in genetically engineered mouse research

Microbial infections have long been of concern to scientists using laboratory rodents because of their potential to confound and invalidate research. With the explosion of genetically engineered mice (GEM), new concerns over the impact of microbial agents have emerged because these rodents in many cases are more susceptible to disease than their inbred or outbred counterparts. Moreover, interaction between microbe and host and the resulting manifestation of disease conceivably differ between GEM and their inbred and outbred counterparts. As a result, infections may alter the GEM phenotype and confound interpretation of results and conclusions about mutated gene function. In addition, because GEM are expensive to produce and maintain, contamination by pathogens or opportunists has severe economic consequences. This review addresses how microbial infections may influence phenotype, how immunomodulation of the host as the result of induced mutations may modify host susceptibility to microbial infections, how novel host:microbe interactions have led to the development of new animal models for disease, how phenotype changes have led to the discovery of new pathogens, and new challenges associated with prevention and control of microbial infections in GEM. Although the focus is on naturally occurring infections, extensive literature on the use of GEM in studies of microbial pathogenesis also exists, and the reader is referred to this literature if microbial infection is a suspected culprit in phenotype alteration.     

The players may change but the game remains: network analyses of ruminal microbiomes suggest taxonomic differences mask functional similarity

By mapping translated metagenomic reads to a microbial metabolic network, we show that ruminal ecosystems that are rather dissimilar in their taxonomy can be considerably more similar at the metabolic network level. Using a new network bi-partition approach for linking the microbial network to a bovine metabolic network, we observe that these ruminal metabolic networks exhibit properties consistent with distinct metabolic communities producing similar outputs from common inputs. For instance, the closer in network space that a microbial reaction is to a reaction found in the host, the lower will be the variability of its enzyme copy number across hosts. Similarly, these microbial enzymes that are nearby to host nodes are also higher in copy number than are more distant enzymes. Collectively, these results demonstrate a widely expected pattern that, to our knowledge, has not been explicitly demonstrated in microbial communities: namely that there can exist different community metabolic networks that have the same metabolic inputs and outputs but differ in their internal structure.     

Oral microbial communities in sickness and in health

The relationship between humans and their oral microflora begins shortly after birth and lasts a lifetime. Up until fairly recently, the associations between the host and oral bacteria were considered in terms of a multiplicity of single species interactions. However, it is becoming more apparent that the oral microbes comprise a complex community, and that oral health or disease depends on the interface between the host and the microbial community as a whole. Although it is important to continue studies of the pathogenic properties of specific microbes, these are relevant only in the context of the properties of the community within which they reside. Understanding the microbial communities that drive sickness or health is a key to combating human oral diseases.     

The world within: Quantifying the determinants and outcomes of a host's microbiome

The fungal, bacterial, and viral microbial communities embedded as endosymbionts within all free-living organisms are extremely diverse and encode the vast majority of genes in the biosphere. Microbes in a human, for example, account for 100 times more genes than their host; similar results are emerging for virtually all free-living organisms. Disease is the best studied host–microbe interaction, but endosymbiotic microbial populations and communities also are responsible for critical functions in their hosts including nutrient uptake (plants), reduction in inflammatory responses (animals), digestion (animals), anti-herbivore defenses (plants), and pathogen resistance. In spite of the tremendous diversity and functional importance of the microbial biome to free-living organisms, we have little predictive understanding of the biotic and abiotic factors controlling within-host microbial community composition or the spatial scales at which anthropogenic changes affect host and microbial community interactions and functions. Current research suggests that anthropogenic changes to nutrient supply and food web composition can affect biological systems at scales ranging from individuals to continents. However, while current studies are clarifying the effects of some of these drivers on the structure and functioning of ecosystems, we have far less knowledge of their effects on microbial communities residing within hosts. Given the accelerating progress in metagenome studies, we are poised to make rapid advances in understanding the determinants and effects of within-host microbial communities.     

NADPH oxidases contribute to autophagy regulation

Reactive oxygen species (ROS) are emerging as regulators of autophagy in various cellular contexts. There are many cellular sources of ROS in eukaryotic cells. In phagocytes, the critical immune cells for host defense, the Nox2 NADPH oxidase generates ROS during phagocytosis and plays a central role in microbial killing. Toll-like receptors (TLRs) are important membrane microbial sensing receptors, which can activate Nox2,¹ and were recently demonstrated to signal autophagy targeting of phagosomes to promote their maturation.² Our recent study reveals that Nox2 activity and its generated ROS are key signals that induce TLR-activated autophagy of phagosomes. Our results provide the first evidence that ROS from the Nox2 NADPH oxidase can contribute to regulating autophagy in host defense against bacteria. The association of TLR, Nox2 and autophagy with inflammatory bowel disease (IBD) suggests a significant role of this antibacterial pathway in these diseases.     

Colonization of germ-free transgenic mice with genotyped Helicobacter pylori strains from a case-control study of gastric cancer reveals a correlation between host responses and HsdS components of type I restriction-modification systems

Helicobacter pylori infects the stomachs of half of all humans. It has a relatively benign relationship with most hosts but produces severe pathology, including gastric cancer, in others. Identifying the relative contributions of host, microbial, and environmental factors to the outcome of infection has been challenging. Here we describe one approach for identifying microbial genes that affect the magnitude of host responses to infection. Single colony purified H. pylori isolates were obtained from 25 cases and 71 controls in a Swedish case-control study of gastric cancer. Strains were first phenotyped based on their ability to produce adhesins that recognize two classes of human gastric epithelial receptors. Thirteen binding strains and two non-binding controls were then subjected to whole genome genotyping using H. pylori DNA microarrays. A cohort of "variable" genes was identified based on a microarray-determined call of "absent" in at least one member of the strain panel. Each strain was subsequently introduced into two types of germ-free transgenic mice, each programmed to express a different host factor postulated to pose increased risk for development of severe pathology. Expression of biomarkers of host defense was quantitated 4 weeks after inoculation, and the magnitude of the response correlated with bacterial genotype. The proportion of genes encoding HsdS homologs (specificity subunit of hetero-oligomeric type I restriction-modification systems) was significantly higher in the pool of 18 variable genes whose presence directly correlated with a robust host response than their proportion in the remaining 352 members of the variable gene pool. This suggests that the functions of these HsdS homologs may include control of expression of microbial determinants that affect the extent of gastric responses to this potentially virulent pathogen.     

Disaster taxa in microbially mediated metazoans: how endosymbionts and environmental catastrophes influence the adaptive capacity of reef corals

Reef corals are examples of metazoans that engage in mutualisms with a variety of microorganisms, including dinoflagellates, Bacteria, Archaea, and viruses. The high adaptive capacity of these microbial symbionts can be co‐opted by their coral hosts, and various emergent traits of these associations, such as thermotolerance, are undergoing strong selection due to climate change. This selection may spur the rise of microbial ‘disaster taxa’: opportunistic, cosmopolitan generalists that can proliferate and increase host survivorship following disturbances. Coral bleaching (a stress‐induced loss of dinoflagellates) constitutes one type of catastrophic disturbance for resident symbiont communities, and opens novel patches of host for colonization by microbial disaster taxa. Moreover, the compartmentalization of microbial symbionts within coral polyps reduces their effective population size and thus facilitates the spread of disaster taxa during times of environmental change. These phenomena suggest that, despite widespread loss of coral cover as a result of climate disturbances, the potential spread of resilient microbial disaster taxa in surviving colonies can have important implications for coral reef persistence over the coming decades.     

The host selects mucosal and luminal associations of coevolved gut microorganisms: a novel concept

Along the human gastrointestinal tract, microorganisms are confronted with multiple barriers. Besides selective physical conditions, the epithelium is regularly replaced and covered with a protective mucus layer trapping immune molecules. Recent insights into host defense strategies show that the host selects the intestinal microbiota, particularly the mucosa-associated microbial community. In this context, humans coevolved with thousands of intestinal microbial species that have adapted to provide host benefits, while avoiding pathogenic behavior that might destabilize their host interaction. While mucosal microorganisms would be crucial for immunological priming, luminal microorganisms would be important for nutrient digestion. Further, we propose that the intestinal microorganisms also coevolved with each other, leading to coherently organized, resilient microbial associations. During disturbances, functionally redundant members become more abundant and are crucial for preserving community functionality. The outside of the mucus layer, where host defense molecules are more diluted, could serve as an environment where microorganisms are protected from disturbances in the lumen and from where they can recolonize the lumen after perturbations. This might explain the remarkable temporal stability of microbial communities. Finally, commensals that become renegade or a decreased exposure to essential coevolved microorganisms may cause particular health problems such as inflammatory bowel diseases, obesity or allergies.     

Movement ecology and sex are linked to barn owl microbial community composition

The behavioural ecology of host species is likely to affect their microbial communities, because host sex, diet, physiology, and movement behaviour could all potentially influence their microbiota. We studied a wild population of barn owls (Tyto alba) and collected data on their microbiota, movement, diet, size, coloration, and reproduction. The composition of bacterial species differed by the sex of the host and female owls had more diverse bacterial communities than their male counterparts. The abundance of two families of bacteria, Actinomycetaceae and Lactobacillaceae, also varied between the sexes, potentially as a result of sex differences in hormones and immunological function, as has previously been found with Lactobacillaceae in the microbiota of mice. Male and female owls did not differ in the prey they brought to the nest, which suggests that dietary differences are unlikely to underlie the differences in their microbiota. The movement behaviour of the owls was associated with the host microbiota in both males and females because owls that moved further from their nest each day had more diverse bacterial communities than owls that stayed closer to their nests. This novel result suggests that the movement ecology of hosts can impact their microbiota, potentially on the basis of their differential encounters with new bacterial species as the hosts move and forage across the landscape. Overall, we found that many aspects of the microbial community are correlated with the behavioural ecology of the host and that data on the microbiota can aid in generating new hypotheses about host behaviour.     

Interfaces between microbes and membranes of host epithelial cells in hemipteran midguts

Certain families of plant-feeding insects in the order Hemiptera (infraorder Pentatomomorpha) have established symbiotic relationships with microbes that inhabit specific pouches (caeca) of their midgut epithelium. The placement of these caeca in a well-delineated region at the most posterior end of the midgut bordering the hindgut is conserved in these families; in situ the convoluted midgut is predictably folded so that this caecal region lies adjacent to the anterior-most region of the midgut. Depending on the hemipteran family, caeca vary in their number and configuration at a given anterior–posterior location. At the host-microbe interface, epithelial plasma membranes of midgut epithelial cells interact with nonself antigens of microbial surfaces. In the different hemipteran species examined, a continuum of interactions is observed between microbes and host membranes. Bacteria can exist as free living cells within the midgut lumen without contacting host membranes while other host cells physically interact extensively with microbial surfaces by extending numerous processes that interdigitate with microbes; and, in many instances, processes completely envelope the microbes. The host cells can embrace the foreign microbes, completely enveloping each with a single host membrane or sometimes enveloping each with the two additional host membranes of a phagosome.     

病原体调控宿主细胞周期致病机制的研究进展

病原体在长期进化中形成多种策略以利于自身增殖,进而导致多种疾病.这些策略包括干扰宿主免疫反应、调控细胞周期与凋亡等.近年来,人们越来越关注病原体通过干扰宿主细胞周期致病的机制,有助于更好了解病原体与宿主的相互作用.本文综述了病原体引起宿主细胞周期停滞在不同时期的机制,特别是一些细菌分泌毒力因子引起宿主细胞周期紊乱并导致...     

Q&A: Friends (but sometimes foes) within: the complex evolutionary ecology of symbioses between host and microbes

Over the past decade, there has been a pronounced shift in the study of host–microbe associations, with recognition that many of these associations are beneficial, and often critical, for a diverse array of hosts. There may also be pronounced benefits for the microbes, though this is less well empirically understood. Significant progress has been made in understanding how ecology and evolution shape simple associations between hosts and one or a few microbial species, and this work can serve as a foundation to study the ecology and evolution of host associations with their often complex microbial communities (microbiomes).     

Population bottlenecks constrain host microbiome diversity and genetic variation impeding fitness

It is becoming increasingly clear that microbial symbionts influence key aspects of their host’s fitness, and vice versa. This may fundamentally change our thinking about how microbes and hosts interact in influencing fitness and adaptation to changing environments. Here we explore how reductions in population size commonly experienced by threatened species influence microbiome diversity. Consequences of such reductions are normally interpreted in terms of a loss of genetic variation, increased inbreeding and associated inbreeding depression. However, fitness effects of population bottlenecks might also be mediated through microbiome diversity, such as through loss of functionally important microbes. Here we utilise 50 Drosophila melanogaster lines with different histories of population bottlenecks to explore these questions. The lines were phenotyped for egg-to-adult viability and their genomes sequenced to estimate genetic variation. The bacterial 16S rRNA gene was amplified in these lines to investigate microbial diversity. We found that 1) host population bottlenecks constrained microbiome richness and diversity, 2) core microbiomes of hosts with low genetic variation were constituted from subsets of microbiomes found in flies with higher genetic variation, 3) both microbiome diversity and host genetic variation contributed to host population fitness, 4) connectivity and robustness of bacterial networks was low in the inbred lines regardless of host genetic variation, 5) reduced microbial diversity was associated with weaker evolutionary responses of hosts in stressful environments, and 6) these effects were unrelated to Wolbachia density. These findings suggest that population bottlenecks reduce hologenomic variation (combined host and microbial genetic variation). Thus, while the current biodiversity crisis focuses on population sizes and genetic variation of eukaryotes, an additional focal point should be the microbial diversity carried by the eukaryotes, which in turn may influence host fitness and adaptability with consequences for the persistence of populations.     

Hemoglobin-based blood substitutes and the hazards of blood radicals

Cell-free hemoglobins, chemically altered or genetically expressed in microbial host systems, have been developed as oxygen-carrying therapeutics. Sitedirected modifications are introduced and serve to stabilize the protein molecules in a tetrameric and/or a polymeric functional form. Animal studies, as well as recent clinical studies, have suggested these proteins probably deliver oxygen to tissues. However, concerns still persist regarding the interference of hemoglobin and its oxidation products with the vascular redox balance, potentially impeding its clinical usefulness. This article reviews our current understanding of heme-mediated toxicities and some of the emerging protective strategies used to overcome hemoglobin side reactions.     

Role of oxygen gradients in shaping redox relationships between the human intestine and its microbiota

The unique anatomy and physiology of the intestine in conjunction with its microbial content create the steepest oxygen gradients in the body, which plunge to near anoxia at the luminal midpoint. Far from static, intestinal oxygen gradients ebb and flow with every meal. This in turn governs the redox effectors nitric oxide, hydrogen sulfide, and reactive oxygen species of both host and bacterial origin. This review illustrates how the intestine and microbes utilize oxygen gradients as a backdrop for mechanistically shaping redox relationships and a functional coexistence.