Stressed Erythrophagocytosis as a Modifier of the Innate Immune Response to Klebsiella pneumoniae

• Main Author: Olonisakin, Tolani Folajimi
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2020
• Subjects: Immunology; Microbiology; Pathology
• ISBN: 9798357529855

Macrophages are main effectors of heme metabolism, increasing transiently in the liver during heightened disposal of damaged or senescent red cells (sRBC). Macrophages are also essential in defense against microbial threats, but pathologic states of heme excess may be immunosuppressive. Here, we uncover a novel mechanism whereby an acute rise in sRBC disposal by macrophages leads to an immunosuppressive phenotype following intrapulmonary Klebsiella pneumoniae infection characterized by increased extrapulmonary dissemination and reduced survival in mice. The impaired immunity to K. pneumoniae during heightened sRBC disposal is independent of iron acquisition by bacterial siderophores, as K. pneumoniae mutant lacking siderophore function recapitulates findings observed with wildtype strain. Rather, we show that sRBC disposal induces a liver transcriptomic profile notable for suppression of Stat1 and interferon-related responses during K. pneumoniae infection. Excess heme handling by macrophages recapitulates STAT1 suppression during infection that requires synergistic NRF1 and NRF2 activation but is independent of heme oxygenase-1 induction. Whereas iron is dispensable, the porphyrin moiety of heme is sufficient to mediate suppression of STAT1- dependent responses in human and mouse macrophages and promote liver dissemination of K. pneumoniae in vivo. Thus, dysfunction in cellular heme metabolism negatively regulates the STAT1 pathway with implications in host defense.