Immunglobulin M-degrading enzyme of Streptococcus suis (IdeSsuis): modulation of B-cell function and consequences for mucosal colonization

• Applicants: Professor Dr. Christoph Baums; Privatdozent Dr. Uwe Müller, since 2/2023
• Subject Area: Veterinary Medical Science
• Term: from 2014 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 263322059

Streptococcus suis is one of the most important porcine pathogens and an emerging human pathogen. In pigs, S. suis colonizes very efficiently the upper respiratory mucosa including nasopharynx, tonsils (the putative entry port), and retropharyngeal lymph nodes. S. suis is unique among bacterial pathogens in expressing an immunoglobulin (Ig) M degrading enzyme, designated IdeSsuis which we identified as a cysteine protease. In the preceding Project we demonstrated that IdeSsuis–mediated IgM cleavage is a novel complement evasion mechanism leading to reduced opsonisation and enhanced bacterial survival. We found, however, that IgM cleavage by IdeSsuis is not crucial during invasive infection leading to meningitis. However, cleavage of IgM by IdeSsuis might be relevant for S. suis colonization of mucosal surfaces where IgM concentrations are lower than in serum. Thus, we hypothesize that IdeSsuis–mediated IgM proteolysis by colonizing streptococci is sufficient to diminish IgM-dependent effector functions in this compartment. Colonization of S. suis-free piglets with wild-type and mutant S. suis strains will be induced experimentally to quantitatively determine colonization efficacy and IgM degradation on mucosal surfaces. We will test the hypothesis that S. suis-expressed IdeSsuis is effective on B cells expressing membrane IgM (i.e. B cell receptor, BCR) especially at mucosal sites of colonization. Recently we have generated evidence that IdeSsuis not only cleaves soluble IgM but also the IgM BCR expressed on conventional B cells (i.e. B2 cells) as well as on non-conventional B1-like cells. IgM and IgM-BCR cleavage by IdeSsuis is expected to result in a defective mucosal B cell response and reduced antibody production to S. suis, even more so as pigs lack IgD. In detail, IdeSsuis may disrupt the binding of S. suis to the IgM-BCR. Subsequently we expect reduced internalization of S. suis by B cells which should result in reduced antigen presentation on MHC-II and reduced interaction with follicular T helper (TfH) cells in the lymph node. Experimental colonization of the upper respiratory tract of S. suis-free piglets with encapsulated S. suis or its unencapsulated isogenic mutant will be conducted to analyze B1-like cells activated by capsular polysaccharides. In a further animal experiment we specifically investigate the hypothesis that S. suis colonization modulates adaptive immunity through IgM cleavage by IdeSsuis at mucosal sites leading to impaired protective immunity upon challenge. This experiment will include comparison of state-of-the-art complemented S.°suis mutants expressing either wild-type IdeSsuis or a point-mutated variant of IdeSsuis deficient in IgM cleavage. The data generated in this proposal is expected to lead to a better understanding of the role of IgM degradation during colonization and to explain why IgM proteolysis is a highly conserved phenotype in all investigated S. suis serotypes.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Dr. Gottfried Alber, until 2/2023