Helicobacter hepaticus is required for immune targeting of bacterial heat shock protein 60 and fatal colitis in mice

Friedrich, Verena; Forne, Ignasi; Matzek, Dana; Ring, Diana; Popper, Bastian; Jochum, Lara; Spriewald, Stefanie; Straub, Tobias; Imhof, Axel; Krug, Anne; Stecher, Bärbel und Brocker, Thomas (2021): Helicobacter hepaticus is required for immune targeting of bacterial heat shock protein 60 and fatal colitis in mice. In: Gut Microbes, Bd. 13, Nr. 1

Abstract

Gut microbiota and the immune system are in constant exchange shaping both host immunity and microbial communities. Here, improper immune regulation can cause inflammatory bowel disease (IBD) and colitis. Antibody therapies blocking signaling through the CD40-CD40L axis showed promising results as these molecules are deregulated in certain IBD patients. To better understand the mechanism, we used transgenic DC-LMP1/CD40 animals with a constitutive CD40-signal in CD11c(+) cells, causing a lack of intestinal CD103(+) dendritic cells (DCs) and failure to induce regulatory T (iTreg) cells. These mice rapidly develop spontaneous fatal colitis, accompanied by dysbiosis and increased inflammatory IL-17(+)IFN-gamma (+) Th17/Th1 and IFN-gamma (+) Th1 cells. In the present study, we analyzed the impact of the microbiota on disease development and detected elevated IgA- and IgG-levels in sera from DC-LMP1/CD40 animals. Their serum antibodies specifically bound intestinal bacteria, and by proteome analysis, we identified a 60 kDa chaperonin GroEL (Hsp60) from Helicobacter hepaticus (Hh) as the main specific antigen targeted in the absence of iTregs. When re-derived to a different Hh-free specific-pathogen-free (SPF) microbiota, mice showed few signs of disease, normal microbiota, and no fatality. Upon recolonization of mice with Hh, the disease developed rapidly. Thus, the present work identifies GroEL/Hsp60 as a major Hh-antigen and its role in disease onset, progression, and outcome in this colitis model. Our results highlight the importance of CD103(+) DC- and iTreg-mediated immune tolerance to specific pathobionts to maintain healthy intestinal balance.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1949-0976
• Sprache: Englisch