Immunologic consequences of Francisella tularensis live vaccine strain infection: role of the innate immune response in infection and immunity.
Francisella tularensis (Ft), a Gram-negative intracellular bacterium, is the etiologic agent of tularemia. Although attenuated for humans, i.p. infection of mice with <10 Ft live vaccine strain (LVS) organisms causes lethal infection that resembles human tularemia, whereas the LD50 for an intradermal infection is >10(6) organisms. To examine the immunological consequences of Ft LVS infection on the innate immune response, the inflammatory responses of mice infected i.p. or intradermally were compared. Mice infected i.p. displayed greater bacterial burden and increased expression of proinflammatory genes, particularly in the liver. In contrast to most LPS, highly purified Ft LVS LPS (10 microg/ml) was found to be only minimally stimulatory in primary murine macrophages and in HEK293T cells transiently transfected with TLR4/MD-2/CD14, whereas live Ft LVS bacteria were highly stimulatory for macrophages and TLR2-expressing HEK293T cells. Despite the poor stimulatory activity of Ft LVS LPS in vitro, administration of 100 ng of Ft LVS LPS 2 days before Ft LVS challenge severely limited both bacterial burden and cytokine mRNA and protein expression in the absence of detectable Ab at the time of bacterial challenge, yet these mice developed a robust IgM Ab response within 2 days of infection and survived. These data suggest that prior administration of Ft LVS LPS protects the host by diminishing bacterial burden and blunting an otherwise overwhelming inflammatory response, while priming the adaptive immune response for development of a strong Ab response.
Cole
Leah E
LE
Department of Microbiology and Immunology, University of Maryland, Baltimore, School of Medicine, Baltimore, MD 21201, USA.
Elkins
Karen L
KL
Michalek
Suzanne M
SM
Qureshi
Nilofer
N
Eaton
Linda J
LJ
Rallabhandi
Prasad
P
Cuesta
Natalia
N
Vogel
Stefanie N
SN
D000818:Animals; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000276:immunology*; D002460:Cell Line; D005604:Francisella tularensis / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology; D014406:Tularemia / Q000276:immunology* / Q000382:microbiology; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology
D001428:Bacterial Vaccines; D008070:Lipopolysaccharides; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014613:Vaccines, Attenuated