Transmission of P. falciparum from patients with variant hemoglobin genotypes

Physicians who care for patients with malaria or who study malaria pathogenesis have been most concerned with merozoites, the asexual form of the parasite that infects red blood cells and that is responsible for the pathological manifestations of the disease. From evolutionary and public health perspectives, however, we need to pay more attention to gametocytes, the sexual forms that are transmitted to mosquitoes. Malaria parasites have evolved life history strategies that maximize their transmission to mosquitoes and then on to new hosts, and this has presumably involved optimizing the production and transmissibility of gametocytes over the course of an infection. Inhibition of the proliferation of merozoites, either by drugs or by the host’s immune response, leads to increased gametocyte production, by mechanisms that are not yet well understood (Paul, Brey, and Robert 2002). A recent report by Gouagna et al. (2010) shows that the production and transmission of P. falciparum gametocytes are also increased in patients with hemoglobin variants HbS or HbC, in whom the asexual growth of P. falciparum is impaired.

Gouagna and colleagues carried out two epidemiological investigations in Burkina Faso, in which they measured the gametocyte rate (percentage of infected patients who had detectable gametocytes in their blood) and gametocyte densities in people with different hemoglobin genotypes. Although there were some discrepancies between these two studies, perhaps because they were carried out at different seasons, they demonstrate that people with either the AC or CC genotype have higher gametocyte rates, higher gametocyte densities, and a higher ratio of gametocytes to merozoites than do people with AA genotype. These investigators then studied transmission of P. falciparum from infected patients to mosquitoes. In these experiments, mosquitoes fed on blood from infected patients, either in vivo, directly from the patients, or ex vivo, indirectly, through a plastic membrane. Results of the ex vivo experiments were more dramatic but the in vivo studies showed the same trends: mosquitoes that fed on blood of patients with AC, CC, or AS genotypes showed higher rates of infection and greater densities of oocysts (the structures formed after fertilization, in which sporozoites develop) in their guts than did mosquitoes that fed on AA blood; oocyst densities were especially high in mosquitoes that fed on AS blood.

These studies refocus attention on the regulation of gametocyte production and transmission in P. falciparum and highlight our need to learn more about the natural history of P. falciparum infections in patients with different hemoglobin genotypes. This research also has important public health implications. People with AC, CC, or AS genotypes who become infected with malaria typically have mild illnesses and may not seek medical attention; in this way, they may serve as undetected reservoirs for malaria transmission. Reducing the burden of malaria will require that more effort be made to detecting and treating these patients, and to shielding them from mosquitoes.

References

Gouagna, L. C., et al. 2010. Genetic variation in human hbb is associated with plasmodium falciparum transmission. Nat Genet 42(4):328-31.

Paul, R. E., P. T. Brey, and V. Robert. 2002. Plasmodium sex determination and transmission to mosquitoes. Trends Parasitol 18(1):32-8.