In immunocompetent individuals, non-typhoidal Salmonella enterica serotypes (NTS) are associated withgastroenteritis, a localized infection with low mortality manifesting as diarrhea, vomiting and intestinalcramping. However, suppression of immunity in individuals with underlying disease can result in thedevelopment of life-threatening systemic infections. There is currently an epidemic of disseminated NTSinfections in sub-Saharan Africa, which are associated with bacteremia, meningitis and sepsis, and often havea fatal outcome. Epidemiological associations suggest that while HIV infection is the most commonpredisposing condition for NTS bacteremia in adults, malnutrition and Plasmodium falciparum malaria are themost common underlying factors in children. The magnitude of this infectious disease problem is considerable,however the mechanisms by which malaria increases initial susceptibility to NTS infection are poorlyunderstood. Given the high burden of malaria in children under 5 in sub-Saharan Africa, this gap in knowledgeis important to address. The objective of this application is to define how alterations to the intestinalenvironment during malaria increase the ability of NTS to colonize the intestine after ingestion. Our centralhypothesis is that malaria-induced shifts in the composition of the gut microbiota provide a favorable metabolicenvironment for establishment of Salmonella infection in the intestinal lumen. This hypothesis has beenformulated based on our preliminary data showing that shifts in the microbiota of malaria parasite-infected miceare sufficient to increase infectivity of Salmonella enterica serotype Typhimurium (S. Typhimurium). Theapproach we will use to refine and test our hypothesis comprises two specific aims: (1) Identify metabolicintermediates produced by the microbiota that support increased colonization of S. Typhimurium in theintestinal lumen during malaria; and (2) Determine whether malaria parasite infection generates respiratoryelectron acceptors that promote NTS colonization. Our hypothesis is highly innovative, since malaria istraditionally considered a bloodstream infection, and its effects on the intestine are only beginning to beappreciated. The rationale for the proposed research is that a better understanding of alterations to theintestinal environment during malaria will provide important insights into both malaria pathogenesis andSalmonella colonization, and may ultimately point to potential intervention strategies to protect children againstcolonization by NTS.
|Effective start/end date||8/16/16 → 7/31/18|
- National Institutes of Health: $227,450.00