Scientific Publications by FDA Staff

Microbes Infect 2007 Jan;9(1):55-62

Brucella abortus bacA mutant induces greater pro-inflammatory cytokines than the wild-type parent strain.

Parent MA, Goenka R, Murphy E, Levier K, Carreiro N, Golding B, Ferguson G, Roop RM 2nd, Walker GC, Baldwin CL

Baldwin CL (reprint author), Univ Massachusetts, Dept Vet & Anim Sci, 161 Holdsworthy, Amherst, MA 01003 USA Univ Massachusetts, Dept Vet & Anim Sci, Amherst, MA 01003 USA MIT, Dept Biol, Cambridge, MA 02139 USA US FDA, Ctr Biol Evaluat & Res, Div Hematol, Bethesda, MD 20892 USA E Carolina Univ, Sch Med, Dept Microbiol & Immunol, Greenville, NC 27858 USA

The inner-membrane protein BacA affects Brucella LPS structure. A bacA deletion mutant of Brucella abortus, known as KL7 (bacA(mut)-KL7), is attenuated in BALB/c mice and protects against challenge. Thus, bacA mutation was a candidate for incorporation into live attenuated vaccines. We assessed bacA(mut)-KL7 in 2 additional mouse strains: the more resistant C57BL/6 that produces interferon-gamma throughout the infection and the highly susceptible interferon-gamma-deficient C57BL/6 in which brucellae exhibit continual exponential growth. While it was hypothesized that bacA(mut)-KL7 would exhibit even greater attenuation relative to its parent strain B. abortus 2308 in C57BL/6 mice than it did in BALB/c mice, this was not the case. Moreover, it was more pathogenic in C57BL/6 interferon-gamma-deficient mice than 2308 causing abscesses and wasting even though the splenic loads of bacA(mut)-KL7 were significantly lower. These 2 observations were correlated, respectively, with an ability of IFNgamma-activated macrophages to equivalently control strains 2308 and bacA(mut)-KL7 and the ability of bacA(mut)-KL7 organism and its LPS to induce greater amounts of pro-inflammatory cytokines than 2308. We conclude that attenuation properties of bacA mutation are dependent upon the nature of the host but more importantly that bacterial gene deletion can result in increased host pathology without an increase in bacterial load, crucial considerations for vaccine design.