Scientific Publications by FDA Staff

J Infect Dis 2008 Jul 15;198(2):284-92

The Membrane Form of Tumor Necrosis Factor Is Sufficient to Mediate Partial Innate Immunity to Francisella tularensis Live Vaccine Strain.

Cowley SC, Goldberg MF, Ho JA, Elkins KL

Cowley, SC (reprint author), CBER FDA, 1401 Rockville Pike,HFM 431, Rockville, MD 20852 USA US FDA, Ctr Biol Res & Evaluat, Lab Mycobacterial Dis & Cellular Immunol, Rockville, MD 20857 USA

Here we characterize Francisella tularensis live vaccine strain (LVS) infection in total tumor necrosis factor (TNF) knockout (KO) mice and in transgenic mice expressing only the membrane form of TNF (memTNF). MemTNF mice, but not TNF KO mice, survived low-dose, sublethal LVS infections. Splenic nitric oxide production was impaired in infected memTNF mice and was absent in infected TNF KO mice. Spleen cell production of interferon-gamma, RANTES, and monocyte chemotactic protein-1 was elevated in TNF KO mice, compared with that in WT mice, by days 4-5 after infection, along with transiently increased numbers of CCR2(+) cells, whereas memTNF mice had an intermediate phenotype. By day 6 after infection, TNF KO mice, but not memTNF mice, exhibited massive apoptosis in spleens and livers, which shortly preceded their death. Thus, memTNF partially functions to regulate chemokine expression, cell recruitment, and nitric oxide production during primary LVS infection and protects against the induction of apoptosis observed in TNF KO mice.