Scientific Publications by FDA Staff

J Immunol 2006 Jun 1;176(11):6888-99

Immunologic consequences of Francisella tularensis live vaccine strain infection: role of the innate immune response in infection and immunity.

Cole LE, Elkins KL, Michalek SM, Qureshi N, Eaton LJ, Rallabhandi P, Cuesta N, Vogel SN

Vogel SN, Univ Maryland, Dept Microbiol & Immunol, Sch Med, 660 W Redwood St,Room 324, Baltimore, MD 21201 USA Univ Maryland, Dept Microbiol & Immunol, Sch Med, Baltimore, MD 21201 USA US FDA, Ctr Biol Evaluat & Res, Div Bacterial Allergen & Parasit Prod, Lab Mycobacterial Dis & Cellular Immunol, Rockville, MD 20852 USA Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA Univ Missouri, Sch Med, Trauma Res Ctr, Dept Basic Med Sci & Surg Shock, Kansas City, MO 64108 USA List Biol Labs, Campbell, CA 95008 USA

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.