Chronic Murine Typhoid Fever Is a Natural Model of Secondary Hemophagocytic Lymphohistiocytosis
Open Access
- 26 February 2010
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 5 (2), e9441
- https://doi.org/10.1371/journal.pone.0009441
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory clinical syndrome associated with neoplastic disorders especially lymphoma, autoimmune conditions, and infectious agents including bacteria, viruses, protozoa and fungi. In both human and veterinary medicine, hemophagocytic histiocytic disorders are clinically important and frequently fatal. HLH in humans can be a primary (familial, autosomal recessive) or secondary (acquired) condition, with both types generally precipitated by an infectious agent. Previously, no mouse model for secondary HLH has been reported. Using Salmonella enterica serotype Typhimurium by oral gavage to mimic naturally-occurring infection in Sv129S6 mice, we characterized the clinical, hematologic and morphologic host responses to disease thereby describing an animal model with the clinico-pathologic features of secondary HLH as set forth by the Histiocyte Society: fever, splenomegaly, cytopenias (anemia, thrombocytopenia), hemophagocytosis in bone marrow and spleen, hyperferritinemia, and hypofibrinogenemia. Disease severity correlates with high splenic and hepatic bacterial load, and we show disease course can be monitored and tracked in live animals. Whereby secondary HLH is known to occur in human patients with typhoid fever and other infectious diseases, our characterization of a viable natural disease model of secondary HLH offers an important means to elucidate pathogenesis of poorly understood mechanisms of secondary HLH and investigation of novel therapies. We characterize previously unreported secondary HLH in a chronic mouse model of typhoid fever, and novel changes in hematology including decreased tissue ferric iron storage that differs from classically described anemia of chronic disease. Our studies demonstrate S. Typhimurium infection of mice is a natural infectious disease model of secondary HLH that may have utility for elucidating disease pathogenesis and developing novel therapies.This publication has 59 references indexed in Scilit:
- Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivoProceedings of the National Academy of Sciences of the United States of America, 2009
- Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndromeProceedings of the National Academy of Sciences of the United States of America, 2009
- A Griscelli syndrome type 2 murine model of hemophagocytic lymphohistiocytosis (HLH)European Journal of Immunology, 2008
- Histiocytic sarcoma of macrophage origin in a cat: case report with a literature review of feline histiocytic malignancies and comparison with canine hemophagocytic histiocytic sarcomaVeterinary Clinical Pathology, 2008
- Hemophagocytic Macrophages Harbor Salmonella enterica during Persistent InfectionPLoS Pathogens, 2007
- Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosisBritish Journal of Haematology, 2007
- Pyruvate kinase deficiency confers susceptibility to Salmonella typhimurium infection in miceThe Journal of Experimental Medicine, 2007
- Oral infection of mice with Salmonella entericaserovar Typhimurium causes meningitis and infection of the brainBMC Infectious Diseases, 2007
- Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosisThe Journal of Experimental Medicine, 2007
- Hemophagocytic macrophages constitute a major compartment of heme oxygenase expression in sepsisEuropean Journal of Haematology, 2006