Malaria and helminth co-infection: Investigations into malaria pathogenesis, immunology, parasite transmission, and vaccine response

Approximately 500 million people suffer from clinical malaria each year, with an estimated 2 million dying from the disease. Helminths likewise infect approximately 2 billion people worldwide. As the epidemiologic distributions of these parasites often overlap in space, time, and populations, co-infection is a common occurrence. A spectrum of interactions between helminths and malaria has been described in humans, ranging from exacerbation of malaria to protection from cerebral malaria. However, mechanisms contributing to these outcomes have yet to be clearly defined. Here, we developed a rodent model of co-infection, using the gastrointestinal trematode, Echinostoma caproni, to examine the effect of helminth infection on malaria pathogenesis, transmission potential, immune response and vaccine response. We found that chronic E. caproni infection in BALB/c mice significantly increased malaria parasitemia and fatality rate compared to mice infected only with non-lethal Plasmodium yoelii. This exacerbation applied to both sporozoite and blood-stage induced malaria infections, and was completely reversible through clearance of worms prior to malaria infection. We also found that chronic E. caproni infection facilitated increased malaria parasite transmission, as mosquitoes fed on co-infected mice had a greater rate of infectivity and parasite burdens than those fed on malaria-only infected mice. Furthermore, we found that infection with either E. caproni or the intestinal nematode parasite, Heligmosomoides polygyrus, significantly inhibited vaccine response following immunization of mice with a DNA transmission blocking vaccine based on PA25. Interestingly, this impairment was not observed when E. caproni or H. polygyrus-infected mice were immunized with irradiated P. yoelii sporozoites. To further characterize these interactions, we examined the immune response during the course of P. yoelii infection in E. caproni - or H. polygyrus-co-infected mice. We found that co-infected mice had a deficit in production of IFN-gamma, a cytokine critical for malaria protection, and that suppression was largely correlated with the relative production of IL-4 by the two helminth parasites. Furthermore, these interactions did not appear to be IL-10-dependent. Taken together, these results indicate that helminths can negatively impact malaria and host response to select vaccine constructs.