Specific sequences of infectious challenge lead to secondary hemophagocytic lymphohistiocytosis-like disease in mice

Abstract

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a highly mortal complication associated with sepsis. In adults, it is often seen in the setting of infections, especially viral infections, but the mechanisms that underlie pathogenesis are unknown. sHLH is characterized by a hyperinflammatory state and the presence hemophagocytosis. We found that sequential challenging of mice with a nonlethal dose of viral toll-like receptor (TLR) agonist followed by a nonlethal dose of TLR4 agonist, but not other permutations, produced a highly lethal state that recapitulates many aspects of human HLH. We found that this hyperinflammatory response could be recapitulated in vitro in bone marrow-derived macrophages. RNA sequencing analyses revealed dramatic up-regulation of the red-pulp macrophage lineage-defining transcription factor SpiC and its associated transcriptional program, which was also present in bone marrow macrophages sorted from patients with sHLH. Transcriptional profiling also revealed a unique metabolic transcriptional profile in these macrophages, and immunometabolic phenotyping revealed impaired mitochondrial function and oxidative metabolism and a reliance on glycolytic metabolism. Subsequently, we show that therapeutic administration of the glycolysis inhibitor 2-deoxyglucose was sufficient to rescue animals from HLH. Together, these data identify a potential mechanism for the pathogenesis of sHLH and a potentially useful therapeutic strategy for its treatment.

Interferon target-gene expression and epigenomic signatures in health and disease

“…The effect of IFN-γ on macrophage function is reflected in the high expression of the IFN-γ-induced chemokines CXCL10 and CXCL9 and the IFN-γinduced protein neopterin. A role for IFNs and IRFs in HLH and the related macrophageactivation syndrome is supported by findings in animal models [138][139][140][141] . Therapeutic targeting of IFN-γ with a specific monoclonal antibody (emapalumab) reverses clinical and laboratory manifestations of HLH in some patients 142 , and emapalumab has recently been approved by the US Food and Drug Administration for the treatment of patients with primary HLH with refractory, recurrent or progressive disease 143 .…”

Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes

“…To determine the potential therapeutic benefit of blocking this pathway in other diseases and syndromes associated with cytokine storm, we tested the efficacy of neutralizing antibodies against TNF-α and IFN-γ in other models. Poly I:C priming followed by LPS challenge recapitulates most aspects of HLH, a severe systemic inflammatory syndrome associated with life-threatening symptoms (Wang et al, 2019). Treatment with the combination of TNF-α and IFN-γ blocking antibodies provided 100% protection against the lethality induced by poly I:C and LPS challenge (Figure 7C) .…”

Antiviral Inflammation during Early Pregnancy Reduces Placental and Fetal Growth Trajectories

“…Dams were sacrificed on GD13.5 to assess for fetal viability. Based on these results, 10 mg/kg PolyI:C was used in all subsequent experiments because there was no difference in litter size or number of resorptions with any of the doses tested, and it is a dose that has been previously used in pregnant dams to elicit longterm metabolic and neurodevelopmental problems in offspring (20)(21)(22)(23)(24). For experiments in which fetal and placental growth were analyzed, dams were sacrificed on GD8.5 (6 h after maternal saline or PolyI:C injection), GD13.5 (5 d after maternal saline or PolyI:C injection), or GD18.5 (10 d after maternal saline or PolyI:C injection) using mild carbon dioxide inhalation until respiratory failure, followed by cardiac puncture or decapitation.…”