Skip to Navigation
London School of Hygiene & Tropical Medicine Malaria Centre

Malaria research in immunology and vaccination

Mechanisms of impaired resistance to Salmonella in malaria patients.

LSHTM investigators:
Aubrey Cunnnington & Eleanor Riley.
External collaborators:
Michael Walther (Medical Research Council, The Gambia) & Brian de Souza (University College London, UK).
Funding body:
Medical Research Council, UK.

In sub-Saharan Africa, invasive nontyphoid Salmonella (NTS) infection is a common and often fatal complication of Plasmodium falciparum infection. Induction of heme oxygenase-1 (HO-1) mediates tolerance to the cytotoxic effects of heme during malarial hemolysis.

We hypothesised that HO-1 might impair resistance to NTS by limiting production of bactericidal reactive oxygen species. We have shown that co-infection of mice with Plasmodium yoelii 17XNL (Py17XNL) and Salmonella enterica serovar Typhimurium 12023 (Salmonella typhimurium) causes acute, fatal bacteremia with high bacterial load. S. typhimurium localized predominantly in granulocytes. We found that malaria infection caused premature mobilization of granulocytes from bone marrow with a quantitative defect in the oxidative burst. Inhibition of HO by tin protoporphyrin abrogated the impairment of resistance to S. typhimurium by hemolysis Cunnington et al, 2012, Nature Medicine 18: 120-127). Since our data suggest that HO inhibitors might  be useful adjunctive therapy for NTS infection in the context of hemolysis, studies were undertaken in The Gambia to determine whether similar defects in neutrophil function occur in malaria patients.

Acute, uncomplicated malaria caused the appearance of a population of neutrophils with reduced oxidative burst activity, which gradually normalized over 8 weeks of follow-up.  The degree of oxidative burst impairment correlated significantly with markers of hemolysis. HO-1 expression was increased in blood during an acute malaria episode. Together these data suggest that neutrophil dysfunction also occurs in children with P. falciparum malaria and may explain the associated susceptibility to NTS infection.