The consequences of mixed-species malaria parasite co-infections in mice and mosquitoes for disease severity, parasite fitness, and transmission success

Abstract

The distributions of human malaria parasite species overlap in most malarious regions of the world, and co-infections involving two or more malaria parasite species are common. Little is known about the consequences of interactions between species during co-infection for disease severity and parasite transmission success. Anti-malarial interventions can have disproportionate effects on malaria parasite species, and may locally differentially reduce the number of species in circulation. Thus, it is important to have a clearer understanding of how the interactions between species affect disease and transmission dynamics. Controlled competition experiments using human malaria parasites are impossible, and thus we assessed the consequences of mixed-species infections on parasite fitness, disease severity, and transmission success using the rodent malaria parasite species Plasmodium chabaudi, P.yoelii yoelii, and P. vinckei lentum. We compared the fitness of individual species within single species and co-infections in mice. We also assessed the disease severity of single versus mixed infections in mice by measuring mortality rates, anaemia, and weight loss. Finally, we compared the transmission success of parasites in single or mixed species infections by quantifying oocyst development in Anopheles stephensi mosquitoes. We found that coinfections of P. yoelii with either P. vinckei or P. chabaudi led to a dramatic increase in infection virulence, with 100% mortality observed in mixed species infections, compared to no mortality for P. yoelii and P. vinckei single infections, and 40% mortality for P. chabaudi single infections. The increased mortality in the mixed infections was associated with an inability to clear parasitaemia, with the non-P. yoelii parasite species persisting at higher parasite densities than in single infections. P. yoelii growth was suppressed in all mixed infections compared to single infections. Transmissibility of P. vinckei and P. chabaudi to mosquitoes was also reduced in the presence of P. yoelii in co-infections compared to single infections. The increased virulence of co-infections containing P. yoelii (reticulocyte restricted) and P. chabaudi or P. vinckei (predominantly normocyte restricted) may be due to parasite cell tropism and/or immune modulation of the host. We explain the reduction in transmission success of species in co-infections in terms of inter-species gamete incompatibility.Eight malaria parasite species are infectious to humans; namely, Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale wallikeri, Plasmodium ovale curtisii, Plasmodium knowlesi, Plasmodium cynomolgi, and Plasmodium simium. The latter three species are parasites of non-human primates, but also cause zoonotic malaria in humans [1][2][3]. In large parts of the tropical world the ranges of at least some of these species overlap, they are often vectored by the same mosquitoes [4], and mixed-species infections are common [5][6][7].Mixed species infections of human malaria parasites a...

Malaria Parasite Species Composition of Plasmodium Infections Among Asymptomatic and Symptomatic School-Age Children in Rural and Urban Areas of Kinshasa, Democratic Republic of Congo

“…It is also possible that in symptomatic P. falciparum infections, this species competitively excludes co-infecting species due to increased parasitaemia. This exclusion could result from within-host competition for resources (66). Or through host-immune mediated mechanisms in which the innate immune response triggered by the high parasitaemia P. falciparum disproportionately affects the less dominant of the species in the co-infection.…”

High prevalence of Plasmodium malariae and Plasmodium ovale in co-infections with Plasmodium falciparum in asymptomatic malaria parasite carriers in Southwest Nigeria

“…The prevalence of mixed P. malariae and P. falciparum co-infections was much higher in asymptomatic compared to symptomatic parasite carriers, the latter of which were almost exclusively infected with single species P. falciparum . Interactions between malaria parasite species can have profound impacts on the severity of disease (Tang et al, 2019). This observation is consistent with those of Black et al (1994), who found 27-32% of asymptomatic children under nine years old in the Ivory Coast harboured mixed P. falciparum and P. malariae infections, while no mixed infections were observed in symptomatic children (Black et al, 1994).…”

“…The absence of P. malariae co-infection in symptomatic patients may be caused by the overgrowth of one or more clones of P. falciparum . This could have lead to the competetive exclusion of P. malariae either through within host-competition for host blood cells (Tang et al, 2019), or through the raising of an acute inate immune response in the host that kills off the slower growing species (Molineaux et al, 1980). Supporting this is our observation that the multiplicity of P. falciparum infection in symptomatic patients is significantly lower than in asymptomatic parasite carriers.…”

Plasmodium interspecies interactions during a period of increasing prevalence of Plasmodium ovale in symptomatic individuals seeking treatment: an observational study

“…7 Plasmodium species occur sympatrically globally and as simultaneous infections in host and vectors, but their salient biology sustains their species distinctiveness. Studies on mixed Plasmodium species biology suggest that interactions between co-infecting Plasmodium species shape infection dynamics, virulence, 8 species frequency due to altered resource allocation, 9 and the response of each species to both human host and vector immunity. Some studies associate these interactions with preventing development of severe malaria disease 10 and modulating transmission 8,11,12 for certain species in an infection.…”

“…Studies on mixed Plasmodium species biology suggest that interactions between co-infecting Plasmodium species shape infection dynamics, virulence, 8 species frequency due to altered resource allocation, 9 and the response of each species to both human host and vector immunity. Some studies associate these interactions with preventing development of severe malaria disease 10 and modulating transmission 8,11,12 for certain species in an infection. Mixed Plasmodium species infections pose an intervention challenge due to the variability in case management and transmission prevention.…”