Model of Differential Susceptibility to Mucosal Burkholderia pseudomallei Infection

Abstract

Burkholderia pseudomallei is the causative agent of melioidosis, an infectious disease with protean clinical manifestations. The major route of infection is thought to be through subcutaneous inoculation of contaminated soil and water, although ingestion and inhalation of contaminated aerosols are also possible. This study examines infection through the intranasal route in a murine model to mimic infection through inhalation. Two strains of mice, C57BL/6 and BALB/c, exhibit differential susceptibilities to the infection, with the C57BL/6 mice being considerably more resistant. To examine host factors that could contribute to this difference, bacterial loads and cytokine profiles in the two strains of mice were compared. We found that infected BALB/c mice exhibited higher bacterial loads in the lung and spleen and that they produced significantly higher levels of gamma interferon (IFN-␥) in the serum than C57BL/6 mice. Although tumor necrosis factor alpha and interleukin-1 could be detected in the nasal washes and sera of both strains of mice, the production in serum was transient and much lower than that of IFN-␥. C57BL/6 mice also exhibited memory responses to bacteria upon reinfection, with the production of serum immunoglobulin G (IgG) and mucosal IgA antibodies. Thus, it is possible that the production of systemic and mucosal antibodies is important for protection against disease in C57BL/6 mice.

Pathogenicity of High-Dose Enteral Inoculation of Burkholderia pseudomallei to Mice

“…Unlike intravenous and intranasal infection models, we did not observe a survival difference between mouse strains. 14,15 The enteral dose required for lethality in both strains is substantially higher than the approximately 5 × 10 2 CFU/lung that is lethal in an inhalation model of murine melioidosis (West TE, unpublished data). How this translates to infectious doses in humans is presently unclear.…”

Suppression of Host Innate Immune Response by Burkholderia pseudomallei through the Virulence Factor TssM

“…This is supported by our finding that there was no significant differences in bacterial organ loads between tssMinfected or wild-type bacteria-infected mice. Furthermore, if the latter case were true, all the cytokines and chemokines examined should be increased in the mutant-infected mice when compared with wild-type-infected mice (34,57,58). Hyperinflammation in acute melioidosis corresponded with increased tissue pathology and had been proposed to contribute to host tissue damage and death (34,(57)(58)(59).…”

“…Furthermore, if the latter case were true, all the cytokines and chemokines examined should be increased in the mutant-infected mice when compared with wild-type-infected mice (34,57,58). Hyperinflammation in acute melioidosis corresponded with increased tissue pathology and had been proposed to contribute to host tissue damage and death (34,(57)(58)(59). Following acute infection, the loss of TssM could also be correlated with increased tissue pathology as demonstrated in the spleens of tssM-infected mice and accelerated host death.…”

“…B. pseudomallei tssM, bsa T3SS, and T6SS-5 mutants were generated in KHW strain (34) by replacement of the respective gene or gene clusters with antibiotic-resistant cassettes. Briefly, ∼1-kb fragments upstream and downstream of the genes were amplified from genomic DNA and cloned into pK18mobsacB (35).…”

Genetic Control of Survival and Weight Loss during Pneumonic Burkholderia pseudomallei (Bp) Infection

“…Other risk factors include heavy alcohol use, chronic pulmonary disease, and cancer [3,21]. Furthermore, since melioidosis is associated with a broad range of clinical presentations, there is a possibility that the route of infection is one of the many factors that may influence disease outcome [46].…”