Project description:Canonically, the complement system is known for its rapid response to remove microbes in the bloodstream. However, relatively little is known about a functioning complement system on intestinal mucosal surfaces. Herein we report the local synthesis of complement component 3 (C3) in the gut, primarily by stromal cells. C3 is expressed upon commensal colonization, is regulated by the composition of the microbiota in healthy humans and mice, leading to an individual host’s specific luminal C3 levels. The absence of membrane attack complex (MAC) components in the gut ensures that C3 deposition does not result in the lysis of commensals. Pathogen infection triggers the immune system to recruit neutrophils to the infection site for pathogen clearance. Basal C3 levels directly correlate with protection against enteric infection. Our study reveals the gut complement system as a novel innate immune mechanism acting as a vigilant sentinel that combats pathogens and spares commensals.
Project description:Canonically, the complement system is known for its rapid response to remove microbes in the bloodstream. However, relatively little is known about a functioning complement system on intestinal mucosal surfaces. Herein we report the local synthesis of complement component 3 (C3) in the gut, primarily by stromal cells. C3 is expressed upon commensal colonization, is regulated by the composition of the microbiota in healthy humans and mice, leading to an individual host’s specific luminal C3 levels. The absence of membrane attack complex (MAC) components in the gut ensures that C3 deposition does not result in the lysis of commensals. Pathogen infection triggers the immune system to recruit neutrophils to the infection site for pathogen clearance. Basal C3 levels directly correlate with protection against enteric infection. Our study reveals the gut complement system as a novel innate immune mechanism acting as a vigilant sentinel that combats pathogens and spares commensals.
Project description:Several lines of evidence suggest that inflammation plays a pivotal role in the development and progression of CRC and can be unleashed by the loss of innate immunosurveillance. The complement system is a well characterized first line of defense against pathogens and a central component of the immune responses. As such, the complement system is an important determinant in the maintenance of intestinal homeostasis and emerging evidences suggest that complement dysregulation is involved in the development and progression of CRC. Here we show that in CRC patients CpG island methylation occurs in the gene encoding for the complement anaphylatoxin C3a receptor (c3aR) and strong C3aR down-regulation resulted in decreased overall survival and events-free survival in CRC patients. Ablation of c3ar in mouse models of CRC resulted in the establishment of a pro-inflammatory microbial flora, which fostered strong Th1/Th17 immune responses and a striking increase in tumor incidence and growth that were both dependent on the microbiota. Our findings highlight a previously unrecognized tumor oncosuppressive role for C3aR in CRC that could be exploited as a biomarker for more effective therapeutic intervention.
Project description:Suppression of chronic Arabidopsis immune responses is a widespread but typically strain-specific trait across the major bacterial lineages of the plant microbiota. Here, through phylogenetic analysis of 1,765 Xanthomonadales genomes, we show that immunomodulation is a highly conserved, ancestral trait across this core order of the plant microbiota, and preceded specialization of these bacteria as host-adapted pathogens. Rhodanobacter R179, from the deepest branch of the Xanthomonadales, activates immune responses which are dependent on EFR and SOBIR1 cell-surface receptor complexes, yet root transcriptomics suggest the commensal evades host recognition upon prolonged association. This commensal camouflage is likely due to the combined activities of the conserved ABC transporter permease (dssA) and the TonB-dependent transporter (dssB) and the selective elimination of immunogenic elicitors produced by R179, other microbiota members, and the plant host. The ability of R179 to mask itself and other commensals from host recognition is consistent with a convergence of distinct root transcriptomes triggered by immunosuppressive or non-suppressive synthetic communities upon R179 co-inoculation. Although root load of R179 on wild-type and efr fls2 sobir1 mutant plants was indistinguishable in mono-associations, immunomodulation through dssAB provided R179 with a competitive advantage in a community context in the absence of other immunosuppressive bacteria. Furthermore, root colonization of diverse commensal Xanthomonadales strains varied 1,000-fold without detrimental impacts on the host. We propose that conservation of immunomodulation by Xanthomonadales is related to their adaptation to terrestrial habitats and might have contributed to variation in strain-specific root association, which together accounts for their prominent role in plant microbiota establishment.
Project description:Rhabdoviruses are a large and ecologically diverse family of negative-sense RNA viruses (Mononegavirales: Rhabdoviridae). These viruses are capable of infecting an unexpectedly wide variety of plants, vertebrates, and invertebrates distributed over all human-inhabited continents. However, only a few rhabdoviruses are known to infect humans: a ledantevirus (Le Dantec virus), several lyssaviruses (in particular, rabies virus), and several vesiculoviruses (e.g., Chandipura virus, vesicular stomatitis Indiana virus). Recently, several novel rhabdoviruses have been discovered in the blood of both healthy and severely ill individuals living in Central and Western Africa. These viruses-Bas-Congo virus, Ekpoma virus 1, and Ekpoma virus 2-are members of the little-understood rhabdoviral genus Tibrovirus. Other than the basic genomic architecture, tibroviruses bear little resemblance to well-studied rhabdoviruses such as rabies virus and vesicular stomatitis Indiana virus. These three human tibroviruses are quite divergent from each other, and each of them clusters closely with tibroviruses currently known only from biting midges or healthy cattle. Seroprevalence studies suggest that human tibrovirus infections may be common but are almost entirely unrecognized. The pathogenic potential of this diverse group of viruses remains unknown. Although certain tibroviruses may be benign and well-adapted to humans, others could be newly emerging and produce serious disease. Here, we review the current knowledge of tibroviruses and argue that assessing their impact on human health should be an urgent priority.
Project description:Plants are colonized by a variety of microorganisms, the plant microbiota. In the phyllosphere, the above-ground parts of plants, bacteria are the most abundant inhabitants. Most of these microorganisms are not pathogenic and the plant responses to commensals or to pathogen infection in the presence of commensals are not well understood. We report the Arabidopsis leaf transcriptome after 3 to 4 weeks of colonization by Methylobacterium extorquens PA1 and Sphingomonas melonis Fr1, representatives of two abundant genera in the phyllosphere, compared to axenic plants. In addition, we also sequenced the transcriptome of Arabidopsis 2 and 7 days after spray-infection with a low dose of P. syringae DC3000 and in combination with the commensals.
Project description:The complement system is an important part of the innate defense against invading pathogens. The ability to resist complement-mediated killing is considered to be an important virulence trait for the human-restricted respiratory tract pathogen M. catarrhalis, as most disease-associated M. catarrhalis isolates are complement-resistant. Here we studied the molecular basis of M. catarrhalis complement-resistance by transcriptome profiling upon exposure to 10% normal human serum (NHS).
Project description:Neuroinflammatory and neuroimmune mechanisms, as exemplified by infiltrating immune cells and activation of resident endothelial/glial cells, respectively, are known to be involved in the establishment and maintenance of chronic pain. An immune system pathway that may be involved in the activation of both immune and glial cells is complement. The complement pathway is made up of a large number of distinct plasma proteins which react with one another to opsonize pathogens and induce a series of inflammatory responses to help fight infection. Cleaved products and complexes produced by complement activation are responsible for a range of effects including mediation of immune infiltration, activation of phagocytes, opsonization/lysis of pathogens and injured cells, and production of vasoactive amines such as histamine and serotonin. Gene-expression microarray-analysis was performed on the rat spinal nerve ligation (SNL) model of neuropathic pain Keywords: organ type comparison, disease state analysis and drug treatment