Abstract
Melioidosis is a disease of humans caused by opportunistic infection with the soil and water bacterium Burkholderia pseudomallei. Melioidosis can manifest as an acute, overwhelming infection or as a chronic, recurrent infection. At present, it is not clear where B. pseudomallei resides in the mammalian host during the chronic, recurrent phase of infection. To address this question, we developed a mouse low-dose mucosal challenge model of chronic B. pseudomallei infection and investigated sites of bacterial persistence over 60 days. Sensitive culture techniques and selective media were used to quantitate bacterial burden in major organs, including the gastrointestinal (GI) tract. We found that the GI tract was the primary site of bacterial persistence during the chronic infection phase, and was the only site from which the organism could be consistently cultured during a 60-day infection period. The organism could be repeatedly recovered from all levels of the GI tract, and chronic infection was accompanied by sustained low-level fecal shedding. The stomach was identified as the primary site of GI colonization as determined by fluorescent in situ hybridization. Organisms in the stomach were associated with the gastric mucosal surface, and the propensity to colonize the gastric mucosa was observed with 4 different B. pseudomallei isolates. In contrast, B. pseudomallei organisms were present at low numbers within luminal contents in the small and large intestine and cecum relative to the stomach. Notably, inflammatory lesions were not detected in any GI tissue examined in chronically-infected mice. Only low-dose oral or intranasal inoculation led to GI colonization and development of chronic infection of the spleen and liver. Thus, we concluded that in a mouse model of melioidosis B. pseudomallei preferentially colonizes the stomach following oral inoculation, and that the chronically colonized GI tract likely serves as a reservoir for dissemination of infection to extra-intestinal sites.
Highlights
Burkholderia pseudomallei is a soil and water bacterium that infects humans and other mammals in southeast Asia, northern Australia, Brazil, and other parts of the world [1,2,3]
To ensure that the environmental survival traits of B. pseudomallei were not responsible for enteric persistence, oral challenge studies were performed with B. thailandensis E264, a closely related but avirulent environmental bacterium [46,47,48]
Preliminary studies demonstrated that growth of 25 clinical and soil B. pseudomallei strains, and 3 B. thailandensis strains, on NAP-A medium was equivalent when compared to growth on Ashdown’s medium (ASH), or LB agar media (Goodyear A., et al; manuscript in preparation)
Summary
Burkholderia pseudomallei is a soil and water bacterium that infects humans and other mammals in southeast Asia, northern Australia, Brazil, and other parts of the world [1,2,3]. Melioidosis is a dangerous disease in humans because of the rapidity with which B. pseudomallei can cause disseminated infection and sepsis and because the organism displays high levels of intrinsic antibiotic resistance [7,8]. These features, plus the fact that the organism is highly persistent in the environment, have caused B. pseudomallei to be classified as a category B select agent by the United States Centers for Disease Control and Prevention [9]. While acute melioidosis has been relatively well-studied, much less is known about how chronic disease develops or where the bacterium persists during long periods of asymptomatic infection
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