B cell role in susceptibility to Pneumocystis murina infection in murine strains with a single point mutation in either IRF4 or IKZF3 2309604

Abstract Introduction B cells are typically recognized for their role in producing antibodies as part of the adaptive immune response. However, B cells have other functions in coordinating the immune response to infection, including secreting cytokines and presenting antigen to T follicular helper cells within germinal centers. Recent studies have identified heterozygous germline point mutations in two separate human transcription factors, IRF4 (p.T95R) and IKZF3 (p.N160S) that were associated with B cell dysfunction and an increase in susceptibility to opportunistic infections such as Pneumocystis pneumonia (PCP). PCP cases are increasing among patients without HIV infection, and the World Health Organization has included Pneumocystis, the causative agent of Pneumocystis pneumonia, among the most dangerous fungal pathogens. Methods Two strains of mice were developed with homologous mutations, Irf4T95R and Ikzf3N159S and appear to recapitulate the patients’ immunologic phenotypes. We utilized these mice in a co-housing model of Pneumocystis exposure to further explore the role and function of B cells in a natural infection model. Results By 5 — 6 weeks post initial exposure, all mice were infected with Pneumocystis murina. We found the Irf4T95R homozygous mice, but not the heterozygous mice to be exceptionally susceptible to Pneumocystis infection. Surprisingly, both the homozygous and heterozygous Ikzf3N159S mice were able to clear infection despite the homozygous mice having a delayed antibody response and known dysfunction with B cell development. Conclusion This is supported by prior research demonstrating that while B cells have been shown to be incredibly important in controlling Pneumocystis infection, antibody production alone is not enough to clear infection. Therefore, further studies are needed to understand the role B cells play in coordinating a complete and effective immune response to Pneumocystis infection. Funding Source Intramural Research Program of the NIH Clinical Center Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)