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 of Listeria monocytogenes, neutrophils are depleted despite high granulocyte-colony stimulating factor induction. In contrast to a low-dose innocuous L. monocytogenes infection, 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 innocuous L. monocytogenes infection reproduced these effects, once again leading to overwhelming bacterial propagation. The same stimuli also severely aggravated Salmonella typhimurium, Staphylococcus aureus, and Streptococcus pyogenes systemic infection. These data implicate systemic innate immune stimulation as a mechanism of bone marrow neutrophil exhaustion which negatively influences the outcome of bacterial infections.Listeria monocytogenes ͉ neutropenia ͉ TLR2 ͉ sepsis ͉ exhaustion

Neutrophils Select Hypervirulent CovRS Mutants of M1T1 Group A Streptococcus during Subcutaneous Infection of Mice

“…All of these virulence factors except for the M protein and ScpA are regulated by CovRS. All these studies suggest that neutrophils mount critical innate immune responses against GAS, which is supported by a number of studies examining GAS killing by neutrophils (55)(56)(57)(58)(59).…”

Neutrophil survival and c-kit+-progenitor proliferation in Staphylococcus aureus–infected skin wounds promote resolution

“…Mice challenged in vivo with a lethal inoculum of Listeria monocytogenes had rapid PMN apoptosis via a TLR2-dependent mechanism. 33 In contrast, infection with lower sublethal inocula of L monocytogenes resulted in robust PMN trafficking to infected tissue, which was associated with successful bacterial clearance. Our findings are consistent with these previous studies demonstrating that the bacterial burden plays a key role in PMN survival and extent of influx, which is likely triggered by antiapoptotic signals generated during the infection and local production of chemokines.…”

The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection

“…In this model, animals experience spreading necrosis, followed by bacteremia and mortality closely resembling severe necrotizing fasciitis in humans (21,22). We investigated TTP function in this infection model by using TTP ΔM mice, which lack TTP in neutrophils, monocytes, and macrophages (12), all of which are essential for defense against S. pyogenes infection (23)(24)(25)(26). Infection of Ttp fl/fl control animals (referred to herein as TTP fl/fl mice) led to 90% lethality (humane endpoint) 5 days post infection (p.i.…”