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The Microbiome Modifies Manifestations of Hemophagocytic Lymphohistiocytosis in Perforin-Deficient Mice
Jasmin Mann1,2, Solveig Runge2,3,4, Christoph Schell5
1Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center- University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Abstract:
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.
Insights
Primary hemophagocytic lymphohistiocytosis (HLH) in perforin-deficient mice requires specific triggers. Introducing a wild microbiome altered HLH patterns but did not spontaneously cause disease, highlighting complex host-microbe interactions.
Area of Science:
- Immunology
- Genetics
- Microbiology
Background:
- Primary hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome linked to genetic defects in cytotoxicity.
- Perforin-deficient (PKO) mice typically develop HLH only after viral infection, unlike humans who can develop it spontaneously.
Purpose of the Study:
- To investigate if a "wild" microbiome, compared to specific pathogen-free (SPF) conditions, influences HLH development in PKO mice.
- To understand the role of host-microbe interactions in modulating HLH pathogenesis.
Main Methods:
- PKO mice newborns were fostered by mothers with a "wild" microbiome (termed PKO-Wildlings).
- PKO-Wildlings were monitored for spontaneous HLH and challenged with vaccinia virus and lymphocytic choriomeningitis virus (LCMV).
- Cytokine profiles (IFN-γ, IL-17) and disease manifestations were compared between PKO-Wildlings and PKO-SPF mice.
Main Results:
- PKO-Wildlings did not develop spontaneous HLH or HLH after vaccinia virus infection.
- LCMV infection in PKO-Wildlings led to an altered HLH pattern with lower IFN-γ, improved anemia, but higher IL-17 and liver inflammation compared to PKO-SPF mice.
- Wild microbiota alone was insufficient to trigger HLH in PKO mice.
Conclusions:
- A wild microbiome does not spontaneously trigger HLH in perforin-deficient mice.
- Host-microbe interactions significantly shape the cytokine milieu and influence the specific immunopathological manifestations of HLH.
- These findings underscore the complexity of HLH pathogenesis and the interplay between genetics, infection, and the microbiome.
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