LAUSR

Primary hemophagocytic lymphohistiocytosis (HLH) is a life‐threatening hyperinflammatory syndrome caused by inborn errors of cytotoxicity. Patients with biallelic PRF1 null mutations (encoding perforin) usually develop excessive immune cell activation, hypercytokinemia, and life‐threatening immunopathology in the first 6 months of life, often without an apparent infectious trigger. In contrast, perforin‐deficient (PKO) mice only develop HLH after systemic infection with lymphocytic choriomeningitis virus (LCMV). We hypothesized that restricted microbe–immune cell interactions due to specific pathogen‐free (SPF) housing might explain the need for this specific viral trigger in PKO mice. To investigate the influence of a “wild” microbiome in PKO mice, we fostered PKO newborns with Wildling microbiota (‘PKO‐Wildlings’) and monitored them for signs of HLH. PKO‐Wildlings survived long‐term without spontaneous disease. Also, systemic infection with vaccinia virus did not reach the threshold of immune activation required to trigger HLH in PKO‐Wildlings. Interestingly, after infection with LCMV, PKO‐Wildlings developed an altered HLH pattern. This included lower IFN‐γ serum levels along with improved IFN‐γ‐driven anemia, but more elevated levels of IL‐17 and increased liver inflammation compared with PKO‐SPF mice. Thus, wild microbiota alone is not sufficient to trigger HLH in PKO mice, but host–microbe interactions shape inflammatory cytokine patterns, thereby influencing manifestations of HLH immunopathology.