Microbial Exposure Enhances Immunity to Pathogens Recognized by TLR2 but Increases Susceptibility to Cytokine Storm through TLR4 Sensitization

• Published in: Cell reports (Cambridge) Vol. 28; no. 7; pp. 1729 - 1743.e5
• Main Authors: Huggins, Matthew A., Sjaastad, Frances V., Pierson, Mark, Kucaba, Tamara A., Swanson, Whitney, Staley, Christopher, Weingarden, Alexa R., Jensen, Isaac J., Danahy, Derek B., Badovinac, Vladimir P., Jameson, Stephen C., Vezys, Vaiva, Masopust, David, Khoruts, Alexander, Griffith, Thomas S., Hamilton, Sara E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.08.2019; Elsevier
• Subjects: Animals; Cytokines - metabolism; Female; Immunity, Innate - immunology; infection; Inflammation - immunology; Inflammation - metabolism; Inflammation - pathology; Listeria monocytogenes; Listeria monocytogenes - immunology; Listeriosis - immunology; Listeriosis - metabolism; Listeriosis - pathology; Macrophages - immunology; Macrophages - metabolism; Macrophages - microbiology; Mice; Mice, Inbred C57BL; microbiome; Phagocytes - immunology; Phagocytes - metabolism; Phagocytes - pathology; physiological microbial exposure; polymicrobial sepsis; Sepsis - immunology; Sepsis - metabolism; Sepsis - pathology; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Listeria monocytogenes; Toll-like receptors; infection; physiological microbial exposure; microbiome; polymicrobial sepsis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.07.028

Microbial exposures can define an individual’s basal immune state. Cohousing specific pathogen-free (SPF) mice with pet store mice, which harbor numerous infectious microbes, results in global changes to the immune system, including increased circulating phagocytes and elevated inflammatory cytokines. How these differences in the basal immune state influence the acute response to systemic infection is unclear. Cohoused mice exhibit enhanced protection from virulent Listeria monocytogenes (LM) infection, but increased morbidity and mortality to polymicrobial sepsis. Cohoused mice have more TLR2+ and TLR4+ phagocytes, enhancing recognition of microbes through pattern-recognition receptors. However, the response to a TLR2 ligand is muted in cohoused mice, whereas the response to a TLR4 ligand is greatly amplified, suggesting a basis for the distinct response to Listeria monocytogenes and sepsis. Our data illustrate how microbial exposure can enhance the immune response to unrelated challenges but also increase the risk of immunopathology from a severe cytokine storm. [Display omitted] •Cohousing elevates basal cytokine and chemokine levels•Cohousing alters immune responsiveness to new challenges•Cohoused mice have an altered microbiome composition•TLR4 expression and LPS sensitivity are increased after microbial exposure Cohousing of laboratory mice with pet store animals changes the immune system and alters responsiveness to future challenges. Huggins et al. demonstrate that microbial exposure results in alterations to immune cells, serum cytokines, and microbiome composition. This study shows that cohousing alters the ability to detect pathogens through pattern-recognition receptors.