Specific sequences of infectious challenge lead to secondary hemophagocytic lymphohistiocytosis-like disease in mice
Open accessAbstract
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.
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The tipping point may also be reached through further TLR4 priming due to secondary bacterial superinfections after initial viral invasion.
“This ‘tipping point’ may also be reached through further TLR4 priming due to secondary bacterial superinfections resulting from the initial viral invasion53.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [53]
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Why and How Is Hyperferritinemic Sepsis Different From Sepsis Without Hyperferritinemia?*
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Sinomenine modulates the metabolic reprogramming induced by sepsis via CHRNA7
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Murine Models of Secondary Cytokine Storm Syndromes
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Red Blood Cells Function as DNA SensorsPreprint
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- Authors
- Wang, A., Pope, S. D., Weinstein, J. S., Yu, S., Zhang, C., Booth, C. J., & Medzhitov, R.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-01-23
- Volume
- 116
- Issue
- 6
- Pages
- 2200-2209
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6369774
- OpenAlex
- W2911494316
- Cited by
- 67
- References
- 58
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 16 · 2023: 5 · 2022: 8 · 2021: 8 · 2020: 12 · 2019: 3
- FWCI
- 5.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute (N/A)
- NIH (T32 AR07107-39, K08 AI128745)
- Else Kröner Fresenius Foundation (N/A)
- Blavatnik Family Foundation (N/A)
- Topics
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Keywords
- secondary hemophagocytic lymphohistiocytosis, sepsis, viral infection, TLR agonists, TLR4, hyperinflammation, hemophagocytosis, bone marrow-derived macrophages, SPIC, red pulp macrophages, immunometabolism, mitochondrial dysfunction, oxidative metabolism, glycolysis, 2-deoxyglucose, macrophage metabolic reprogramming, pathogenesis, mouse model
- MeSH terms
- Animals, Blood Cell Count, Cell Line, Communicable Diseases, Disease Models, Animal, Lipopolysaccharides, Macrophages, Male, Biomarkers, Cytokines, Mice, Knockout, Gene Expression Profiling, Toll-Like Receptors, Lymphohistiocytosis, Hemophagocytic, Mice, Metabolomics
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