Innate immune-induced depletion of bone marrow neutrophils aggravates systemic bacterial infections

Abstract

Neutrophils are the most abundant leukocytes in circulation and provide a primary innate immune defense function against bacterial pathogens before development of a specific immune response. These specialized phagocytes are short lived (12–24 hours) and continuously replenished from bone marrow. We found that if the host is overwhelmed by a high inoculum ofListeria monocytogenes,neutrophils are depleted despite high granulocyte-colony stimulating factor induction. In contrast to a low-dose innocuousL. monocytogenesinfection, high-dose Listeria challenge blocks neutrophil recruitment to infectious abscesses and bacterial proliferation is not controlled, resulting in lethal outcomes. Administering synthetic TLR2-ligand or heat-killed bacteria during the innocuousL. monocytogenesinfection reproduced these effects, once again leading to overwhelming bacterial propagation. The same stimuli also severely aggravatedSalmonella typhimurium,Staphylococcus aureus,andStreptococcus pyogenessystemic infection. These data implicate systemic innate immune stimulation as a mechanism of bone marrow neutrophil exhaustion which negatively influences the outcome of bacterial infections.