IFNs induce prolonged hematopoietic suppression via IL-18-induced cell death during shock-like Ehrlichial infection

Abstract

Abstract The long-term effects of shock-like infection on hematopoietic stem and progenitor cells (HSC/HSPC) has not been carefully investigated. Using Ixodes ovatus ehrlichia (IOE), a tick-born pathogen that causes severe shock-like illness and bone marrow (BM) aplasia, we explored mechanisms that cause hematopoietic suppression. During IOE infection, type I IFNs promote loss of HSPCs via direct (cell death) and indirect mechanisms (quiescence). Mice lacking IFNαβ receptor (IFNαR−/−) had improved survival relative to WT mice. IFNγR−/− mice had profound BM aplasia and mortality, like WT mice, however mice lacking both type I and II IFN receptors (IFNαR;IFNγR−/−) had protected HSPCs and improved survival, even relative to IFNαR−/− mice. WT and IFNγR−/− mice had reduced HSPCs and increased levels of IL-18 relative to IFNαR−/− and IFNαR;IFNγR−/− mice, while IL-18R expression induced during IOE required IFNγ signaling. IL-18-deficiency prevented IOE-induced BM aplasia and reduced HSC quiescence and necrotic (7AAD+) cells. To test whether IL-18R-signaling acted on HSPCs directly, we generated WT: IL-18R−/− mixed BM chimeras. IL-18R−/− cells had an advantage over WT cells and IL-18R was intrinsically required for increased HSPC cell death. In mixed BM chimeras given antibiotics to allow recovery from acute infection, we found that two weeks post-infection IL-18R−/− HSPCs were present at higher numbers and IL-18R−/− cells had greater functional output in colony-forming unit assays. Our data support IFN driven hematopoietic suppression through IFNαR-dependent induction of IL-18 and IFNγR-dependent IL-18R expression, and that direct effects of IL-18 on HSPCs during infection-induced shock may have long-lasting effects on HSCs.