MyD88-dependent signaling prolongs survival and reduces bacterial burden during pulmonary infection with virulent Francisella tularensis.
Francisella tularensis is the causative agent of the debilitating febrile illness tularemia. The severe morbidity associated with F. tularensis infections is attributed to its ability to evade the host immune response. Innate immune activation is undetectable until more than 48 hours after infection. The ensuing inflammatory response is considered pathological, eliciting a septic-like state characterized by hypercytokinemia and cell death. To investigate potential pathological consequences of the innate immune response, mice deficient in a key innate immune signaling molecule, MyD88, were studied. MyD88 knockout (KO) mice were infected with the prototypical virulent F. tularensis strain, Schu S4. MyD88 KO mice succumbed to infection more rapidly than wild-type mice. The enhanced pathogenicity of Schu S4 in MyD88 KO mice was associated with greater bacterial burdens in lungs and distal organs, and the absence of IFN-γ in the lungs, spleens, and sera. Cellular infiltrates were not observed on histological evaluation of the lungs, livers, or spleens of MyD88 KO mice, the first KO mouse described with this phenotype to our knowledge. Despite the absence of cellular infiltration, there was more cell death in the lungs of MyD88 KO mice. Thus, the host proinflammatory response is beneficial, and MyD88 signaling is required to limit bacterial burden and prolong survival during pulmonary infection by virulent F. tularensis.
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Brian C
BC
Russo
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Matthew J
MJ
Brown
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Electronic address: gjnau@pitt.edu.
Gerard J
GJ
Nau
D000818:Animals; D016923:Cell Death; D017281:Cost of Illness; D016207:Cytokines / Q000378:metabolism; D005604:Francisella tularensis / Q000254:growth & development / Q000472:pathogenicity*; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008171:Lung Diseases / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D014406:Tularemia / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D014774:Virulence
D016207:Cytokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88