A single point mutation in IRF4 but not IKZF3 confers susceptibility to Pneumocystis murina 4018

Abstract Description Pneumocystis pneumonia (PCP) remains a life-threatening disease in individuals who are immunocompromised, particularly in patients with HIV infection, and those with specific genetic defects causing disease such as severe combined immunodeficiency. Recent reports identified heterozygous germline point mutations in two separate human transcription factors, IRF4 (p.T95R) and IKZF3 (p.N160S) that were associated predominantly with B cell dysfunction as well as an increased susceptibility to opportunistic infections including PCP. Genetically modified mice with the homologous mutations Irf4T95R and Ikzf3N159S appear to recapitulate the patients’ immunologic phenotypes. We utilized a co-housing model of Pneumocystis exposure to better understand the role of these single point mutations in conferring susceptibility to Pneumocystis infection. By 5 – 6 weeks post initial exposure all mice were infected with Pneumocystis murina. After 10 weeks of infection, only the Irf4T95R homozygous mice continued to have high levels of Pneumocystis organisms in the lungs; they were also unable to produce Pneumocystis-specific antibodies. Although Ikzf3N159S were able to clear infection, their Pneumocystis-specific antibody response was delayed. This study supports prior observations that functional B cells are important in controlling Pneumocystis infection. Additional studies are needed to identify specific pathways defective in B cells and CD4+ T cells that are permissive to development of PCP. Funding Sources Intramural Research Program of the NIH Clinical Center Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)