Chronic Murine Typhoid Fever Is a Natural Model of Secondary Hemophagocytic Lymphohistiocytosis

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.

Salmonella Infection Enhances Erythropoietin Production by the Kidney and Liver, Which Correlates with Elevated Bacterial Burdens

“…1B). These data are in broad agreement with results of previous reports describing Salmonella infection-induced anemia and splenic erythroid expansion and splenomegaly (33,38,49). Next, we examined whether LPS alone was sufficient to initiate erythroid dysfunction by regular i.v.…”

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

“…65 Infection of Sv129S6 mice with Salmonella enterica serotype Typhimurium led to a syndrome of secondary HLH consistent with human disease. 66 This model has not yet been carefully immunologically dissected to provide insight into the mechanisms of disease.…”

Increased Ferroportin-1 Expression and Rapid Splenic Iron Loss Occur with Anemia Caused by Salmonella enterica Serovar Typhimurium Infection in Mice

“…For instance, mice lacking the cation transporter Nramp1 (Slc11a1), a regulator of cellular iron metabolism, are extremely sensitive to infection. Nramp1 ϩ mice are considered resistant to S. Typhimurium, because infection is generally nonfatal (6)(7)(8). Resistant mice infected by natural oral inoculation develop systemic infection with an acute hematopathological syndrome similar to that of humans with typhoid fever, including fever, anemia, inflammatory disease characterized by peripheral blood neutrophilia and monocytosis, bone marrow myeloid hyperplasia and hemophagocytosis, and splenomegaly secondary to extramedullary hematopoiesis (EMH) and phagocyte infiltration (7,8).…”

“…Nramp1 ϩ mice are considered resistant to S. Typhimurium, because infection is generally nonfatal (6)(7)(8). Resistant mice infected by natural oral inoculation develop systemic infection with an acute hematopathological syndrome similar to that of humans with typhoid fever, including fever, anemia, inflammatory disease characterized by peripheral blood neutrophilia and monocytosis, bone marrow myeloid hyperplasia and hemophagocytosis, and splenomegaly secondary to extramedullary hematopoiesis (EMH) and phagocyte infiltration (7,8). The bacteria reside within tissue macrophages (6,9) and hemophagocytic macrophages (10,56), which have phagocytosed intact erythrocytes and leukocytes.…”