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.