Severe Listeria monocytogenes Infection Induces Development of Monocytes with Distinct Phenotypic and Functional Features

Abstract

Monocytes perform diverse roles during infection with the facultative intracellular bacterium Listeria monocytogenes. They are essential as bactericidal cells in host defense but can also become Trojan horses transporting bacteria into the brain. To explain these contrasting roles, we characterized bone marrow (BM) monocytes in steady state and generated during lethal and sublethal L.  monocytogenes infection. Ly-6ChighCD11b+ BM monocytes expressed high amounts of M-CSFR/CD115 in steady state and 72 h following sublethal infection. However, infection with increasing numbers of bacteria resulted in progressive loss of CD115 and strongly decreased CD115-encoding c-fms mRNA expression. Conversely, analysis of regulatory molecules showed de novo expression of the nonsignaling IL-1RII, CD121b, under the same conditions. Ly-6ChighCD11b+ monocytes in circulation also acquired a CD115neg/lowCD121bhigh phenotype during lethal infection. These BM monocytes showed upregulation of suppressor of cytokine signaling 1 and 3 and IL-1R–"associated kinase-M to a greater extent and/or earlier compared with cells from sublethal infection and showed decreased LPS-induced IL-6 production despite similar levels of surface TLR4 expression. BM monocytes from uninfected or sublethally infected mice bound and internalized very few L. monocytogenes in vitro. However, both functions were significantly increased in monocytes developing during lethal infection. Nonetheless, these cells did not produce reactive oxygen intermediates, suggesting an inability to kill L. monocytogenes. Together, these data show that systemic infections with lethal and sublethal amounts of bacteria differentially shape developing BM monocytes. This results in distinct phenotypic and functional properties consistent with being Trojan horses rather than bactericidal effector cells.