title: Factor XI-deficient mice display reduced inflammation, coagulopathy, and bacterial growth during listeriosis.
abstract: In mice infected sublethally with Listeria monocytogenes, fibrin is deposited at low levels within hepatic tissue, where it functions protectively by limiting bacterial growth and suppressing hemorrhagic pathology. Here we demonstrate that mice infected with lethal doses of L. monocytogenes produce higher levels of fibrin and display evidence of systemic coagulopathy (i.e., thrombocytopenia, fibrinogen depletion, and elevated levels of thrombin-antithrombin complexes). When the hepatic bacterial burden exceeds 1×10(6) CFU, levels of hepatic fibrin correlate with the bacterial burden, which also correlates with levels of hepatic mRNA encoding the hemostatic enzyme factor XI (FXI). Gene-targeted FXI-deficient mice show significantly improved survival upon challenge with high doses of L. monocytogenes and also display reduced levels of hepatic fibrin, decreased evidence of coagulopathy, and diminished cytokine production (interleukin-6 [IL-6] and IL-10). While fibrin limits the bacterial burden during sublethal listeriosis in wild-type mice, FXI-deficient mice display a significantly improved capacity to restrain the bacterial burden during lethal listeriosis despite their reduced fibrin levels. They also show less evidence of hepatic necrosis. In conjunction with suboptimal antibiotic therapy, FXI-specific monoclonal antibody 14E11 improves survival when administered therapeutically to wild-type mice challenged with high doses of L. monocytogenes. Together, these findings demonstrate the utility of murine listeriosis as a model for dissecting qualitative differences between protective and pathological host responses and reveal novel roles for FXI in exacerbating inflammation and pathogen burden during a lethal bacterial infection.
authors: Trudeau Institute, Saranac Lake, New York, USA.
authors: Deyan
authors: D
authors: Luo
authors: Frank M
authors: FM
authors: Szaba
authors: Lawrence W
authors: LW
authors: Kummer
authors: Lawrence L
authors: LL
authors: Johnson
authors: Erik I
authors: EI
authors: Tucker
authors: Andras
authors: A
authors: Gruber
authors: David
authors: D
authors: Gailani
authors: Stephen T
authors: ST
authors: Smiley
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000906:Antibodies / Q000627:therapeutic use; D004211:Disseminated Intravascular Coagulation / Q000382:microbiology; D004359:Drug Therapy, Combination; D005173:Factor XI Deficiency; D007249:Inflammation / Q000473:pathology; D008089:Listeria monocytogenes / Q000254:growth & development / Q000472:pathogenicity*; D008088:Listeriosis / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D008099:Liver / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D000906:Antibodies