Commensal Bacteria Calibrate the Activation Threshold of Innate Antiviral Immunity

Department of Microbiology and Institute for Immunology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Immunity (Impact Factor: 21.56). 06/2012; 37(1):158-70. DOI: 10.1016/j.immuni.2012.04.011
Source: PubMed


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.

Download full-text


Available from: Travis Doering, Sep 18, 2015
  • Source
    • "Moreover, evidence that the intestinal microbiota influences peripheral immune responses is mounting. For example, commensals influence the systemic immune response to viruses by inducing expression of inflammatory genes in phagocytes required for protective immunity (Abt et al., 2012; Ganal et al., 2012). Recognition of circulating, commensal-derived cell wall components can also enhance systemic innate immunity, killing of Gram positive pathogens, and induce monocyte emigration from the bone marrow (Clarke et al., 2010; Shi et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The intestinal commensal microbiota is essential for many host physiological processes, but its impact on infectious diseases is poorly understood. Here we investigate the influence of the gut microbiota during oral Salmonella infection. We report a higher bacterial burden in mesenteric lymph nodes (MLN) of intragastrically infected germ-free (GF) mice compared to conventionally-raised (CONV-R) animals, despite similar inflammatory phagocyte recruitment. Salmonella penetration into the lamina propria of the small intestine and splenic bacterial burden were not altered in the absence of the microbiota. Intragastrically infected GF mice also displayed a higher frequency of IFN-γ-producing NK, NKT, CD4+ and CD8+ T cells in the MLN despite IL-12 levels similar to infected CONV-R mice. However, infecting mice intraperitoneally abrogated the difference in MLN bacterial load and IFN-γ-producing cells observed in intragastrically-infected animals. Moreover, mice treated with antibiotics (ABX) and intragastrically infected with Salmonella had a greater bacterial burden and frequency of IFN-γ-producing cells in the MLN. In ABX mice the number of Salmonella correlated with the frequency of IFN-γ-producing lymphocytes in the MLN, while no such correlation was observed in the MLN of infected GF mice. Overall, the data show that the lack of the microbiota influences pathogen colonization of the MLN, and the increased IFN-γ in the MLN of infected GF mice is not only due to the absence of commensals at the time of infection but the lack of immune signals provided by the microbiota from birth.
    Full-text · Article · Dec 2015 · Frontiers in Cellular and Infection Microbiology
  • Source
    • "Most individuals susceptible to L. pneumophila infection are immunocompromised (Kumpers et al., 2008), suggesting that this bacterium does not effectively evade immune detection. The immune system recognizes L. pneumophila by employing an arsenal of germ-line coded Pattern-Recognition-Receptor (PRRs) distributed on different cellular locales to perceive the presence of associated Pathogen-Associated-Molecular-Pattern (PAMPs), or by detecting alterations of the cellular activities imposed by the bacterium (Abt et al., 2012) The PRRs are categorized based on the subcellular location where the receptor initiates the signaling. Toll-like-receptors (TLRs) and C-type lectins are among the most well-characterized membrane associated receptors that mainly function to recognize extracellular ligands (some TLRs are located in endosomes that recognize intracellular ligands) (Lee and Kim, 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Legionella pneumophila is a facultative intracellular pathogen capable of replicating within a broad range of hosts. One unique feature of this pathogen is the cohort of ca. 300 virulence factors (effectors) delivered into host cells via its Dot/Icm type IV secretion system. Study of these proteins has produced novel insights into the mechanisms of host function modulation by pathogens, the regulation of essential processes of eukaryotic cells and of immunosurveillance. In this review, we will briefly discuss the roles of some of these effectors in the creation of a niche permissive for bacterial replication in phagocytes and recent advancements in the dissection of the innate immune detection mechanisms by challenging immune cells with L. pneumophila.
    Full-text · Article · Nov 2015 · Science China. Life sciences
    • "Moreover, oral consumption of B. infantis 35624 in humans is associated with enhanced IL-10 expression in human peripheral blood (Konieczna, Akdis, Quigley, Shanahan, & O'Mahony, 2012; Konieczna, Groeger, et al., 2012). Indeed, mononuclear phagocytes in germ-free mice were less capable of producing type I and type II interferons (IFN), which resulted in defects in antiviral immunity , implicating microbiota signals in making the distal immune system competent (Abt et al., 2012; Ganal et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The gut microbiome comprises the collective genome of the trillions of microorganisms residing in our gastrointestinal ecosystem. The interaction between the host and its gut microbiome is a complex relationship whose manipulation could prove critical to preventing or treating not only various gut disorders, like irritable bowel syndrome (IBS) and ulcerative colitis (UC), but also central nervous system (CNS) disorders, such as Alzheimer's and Parkinson's diseases. The purpose of this review is to summarize what is known about the gut microbiome, how it is connected to the development of disease and to identify the bacterial and biochemical targets that should be the focus of future research. Understanding the mechanisms behind the activity and proliferation of the gut microbiome will provide us new insights that may pave the way for novel therapeutic strategies.
    No preview · Article · Nov 2015 · Pharmacology [?] Therapeutics
Show more