Malaria and susceptibility to other infections

Malaria is widely perceived as immunosuppressive. Despite extensive phenomenological description, the underlying mechanisms remain poorly described. The aim of this thesis was to identify possible mechanisms by which malaria modifies host defence, and to determine the importance of these mechanisms in a translational system moving from a mouse model to human malaria. The most frequently cited immunological consequences of malaria are: suppression of vaccine responses, susceptibility to bacterial infection, susceptibility to endemic Burkitt lymphoma, and increased HIV viral load. Of these, susceptibility to non-Typhoid Salmonella (NTS) bacteremia, associated with severe hemolysis, was the most consistent between animal and human studies. I hypothesized that hemolysis would induce the immunomodulatory enzyme heme oxygenase-l (HO-l), which is essential for survival in malaria infections in mice, but might impair host defence against NTS. I demonstrate in mice that malaria, chemically-induced hemolysis, or simply administration of heme, cause loss of resistance to NTS, allowing more rapid bacterial growth than in control animals. A new niche for bacterial replication is established within neutrophils, which have impaired oxidative burst and bacterial killing activity. Hemolysis and heme induce HO-1 in neutrophil progenitors in the bone marrow, and this reduces the oxidative burst capacity of maturing neutrophils whilst also causing their premature mobilization into the circulation. Inhibition of HO by the competitive inhibitor SnPP abrogates the impaired resistance to NTS infection. I observed a similar phenomenon in Gambian children with malaria, with prolonged impairment of neutrophil function, the severity of which is related to hemolysis and HO-l induction. In summary I have shown that hemolysis- and HO-l-mediated neutrophil dysfunction occurs in malaria and is important for susceptibility to NTS infection. HO-1 inhibition might offer a novel therapy to alleviate neutrophil dysfunction in malaria patients.