Innate immune-induced depletion of bone marrow neutrophils aggravates systemic bacterial infections.
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.
Navarini
Alexander A
AA
Institute for Experimental Immunology and Department of Pathology, University Hospital Zürich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland. alexander.navarini@usz.ch
Lang
Karl S
KS
Verschoor
Admar
A
Recher
Mike
M
Zinkernagel
Annelies S
AS
Nizet
Victor
V
Odermatt
Bernhard
B
Hengartner
Hans
H
Zinkernagel
Rolf M
RM
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology*; D016908:Gram-Positive Bacterial Infections / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology* / Q000276:immunology*; D012481:Salmonella Infections, Animal / Q000276:immunology*; D013203:Staphylococcal Infections / Q000276:immunology; D013290:Streptococcal Infections / Q000276:immunology; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism
C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2