Last Updated: 01/05/2025
The relationship between malarial anaemia, neutrophil function and susceptibility to invasive bacterial disease
Objectives
The aim of this research is to determine the extent to which persistent, low density, “asymptomatic” malaria infection impairs immunity to secondary bacterial infections; to further characterise neutrophil dysfunction; and to test whether anti-malarial treatment reverses these defects and restores functional immunity to NTS. Preliminary experiments in mouse models of anaemia will be followed by cross-sectional studies of Gambian children with persistent “asymptomatic” malaria and a proof-of-principle study of the impact of antimalarial therapy on neutrophil function.
A recent episode of clinical malaria is a known risk for subsequent life-threatening invasive bacterial disease, due primarily (but not exclusively) to non-Typhoidal Salmonella (NTS) infection. It has been shown that malaria-induced haemolysis increases plasma concentrations of heme and heme-oxygenase-1 (HO-1), which in turn leads to profound neutrophil dysfunction and failure to control NTS. Observations in a mouse model (Cunnington et al., 2012, Nature Medicine) were subsequently verified in children with acute malaria infection (Cunnington et al., 2012, J. Immunol).
Neutrophil dysfunction is further compounded by reduced resistance to bacterial colonization (Mooney et al., 2015, Sci Rep.) and impaired mucosal immunity (Mooney et al., 2014, Mucosal Immunol.), leading to dissemination of bacteria from the gut to the periphery (Lokken, Mooney et al., 2014, PLoS Pathog.). However, in most malaria-endemic settings, the major burden of malarial anaemia is due to chronic, low-grade (often, erroneously, described as “asymptomatic”) infections. “Asymptomatically” infected individuals thus represent a large, hitherto unrecognized, population that may be at high risk of invasive bacterial disease due to persistent neutrophil dysfunction. If so, treatment of “asymptomatic” infections might restore neutrophil function and reduce the burden of bacteraemia in malaria-endemic communities.
Aug 2017 — Jan 2020
$625,638
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