Commensal Bacteria Calibrate the Activation Threshold of Innate Antiviral Immunity
ABSTRACT Signals from commensal bacteria can influence immune cell development and susceptibility to infectious or inflammatory diseases. However, the mechanisms by which commensal bacteria regulate protective immunity after exposure to systemic pathogens remain poorly understood. Here, we demonstrate that antibiotic-treated (ABX) mice exhibit impaired innate and adaptive antiviral immune responses and substantially delayed viral clearance after exposure to systemic LCMV or mucosal influenza virus. Furthermore, ABX mice exhibited severe bronchiole epithelial degeneration and increased host mortality after influenza virus infection. Genome-wide transcriptional profiling of macrophages isolated from ABX mice revealed decreased expression of genes associated with antiviral immunity. Moreover, macrophages from ABX mice exhibited defective responses to type I and type II IFNs and impaired capacity to limit viral replication. Collectively, these data indicate that commensal-derived signals provide tonic immune stimulation that establishes the activation threshold of the innate immune system required for optimal antiviral immunity.
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ABSTRACT: Although vaccinesVaccines against influenza are widely available, control of the disease remains elusive. In part, this is due to the inability of current vaccines to induce durable, broadly protective immune responses. Prevention of influenza depends primarily on effective antibodyAntibody responses that block virus entry. Following infection, high-affinity IgAAntibody IgA antibodies are generated in the respiratory tract that lead to immune exclusion, while IgGAntibody IgG prevents systemic spread. These are effective and long-lasting but also exert immune pressure. Mutation of the antigenic determinants of influenza therefore rapidly leads to emergence of novel variants that evade previously generated protective responses. Not only do vaccines suffer from this strain-specific limitation, but also they are suboptimal in their ability to induce durable immunity. However, recent evidence has demonstrated the possibility of inducing broadly cross-reactive antibodyAntibody broadly cross-reactive antibody responses. Further understanding of the ways in which high-titer, long-lived antibody responses directed against such cross-reactive epitopes can be induced would lead to the development of novel vaccines that may remove the requirement for recurrent vaccination.Current topics in microbiology and immunology 09/2014; DOI:10.1007/82_2014_425 · 3.47 Impact Factor
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ABSTRACT: The biology of RNA viruses is closely linked to the type I and type III interferon (IFN) response of the host. These viruses display a range of molecular patterns that may be detected by host cells resulting in the induction of IFNs. Consequently, there are many examples of mechanisms employed by RNA viruses to block or delay IFN induction and reduce the expression of IFN-stimulated genes (ISGs), a necessary step in the virus lifecycle because of the capacity of IFNs to block virus replication. Efficient transmission of viruses depends, in part, on maintaining a balance between virus replication and host survival; specialized host cells, such as plasmacytoid dendritic cells, can sense viral molecular patterns and produce IFNs to help maintain this balance. There are now many examples of RNA viruses inducing type I and type III IFNs, and although these IFNs act through different receptors, in many systems studied, they induce a similar spectrum of genes. However, there may be a difference in the temporal expression pattern, with more prolonged expression of ISGs in response to type III IFN compared with type I IFN. There are also examples of synergy between type I and type III IFNs to induce antiviral responses. Clearly, it is important to understand the different roles of these IFNs in the antiviral response in vivo. One of the most striking differences between these 2 IFN systems is the distribution of the receptors: type I IFN receptors are expressed on most cells, yet type III receptor expression is restricted primarily to epithelial cells but has also been demonstrated on other cells, including dendritic cells. There is increasing evidence that type III IFNs are a key control mechanism against RNA viruses that infect respiratory and enteric epithelia.Journal of Interferon & Cytokine Research 01/2014; DOI:10.1089/jir.2014.0066. · 3.90 Impact Factor
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ABSTRACT: Segmented Filamentous Bacteria (SFB) are present in the gut microbiota of a large number of vertebrate species where they are found intimately attached to the intestinal epithelium. SFB has recently attracted considerable attention due to its outstanding capacity to stimulate innate and adaptive host immune responses without causing pathology. Recent genomic analysis placed SFB between obligate and facultative symbionts, unraveled its highly auxotrophic needs, and provided a rationale for the complex SFB life-style in close contact with the epithelium. Herein, we examine how the SFB life-style may underlie its potent immunostimulatory properties and discuss how the trade-off set up between SFB and its hosts can simultaneously help to establish and maintain the ecological niche of SFB in the intestine and drive the post-natal maturation of the host gut immune barrier.Seminars in Immunology 10/2013; DOI:10.1016/j.smim.2013.09.001 · 6.12 Impact Factor