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Host immune constraints on malaria transmission: insights from population biology of within-host parasites.

ABSTRACT: Plasmodium infections trigger complex immune reactions from their hosts against several life stages of the parasite, including gametocytes. These immune responses are highly variable, depending on age, genetics, and exposure history of the host as well as species and strain of parasite. Although the effects of host antibodies that act against gamete stages in the mosquito (due to uptake in the blood meal) are well documented, the effects of host immunity upon within-host gametocytes are not as well understood. This report consists of a theoretical population biology-based analysis to determine constraints that host immunity impose upon gametocyte population growth. The details of the mathematical models used for the analysis were guided by published reports of clinical and animal studies, incorporated plausible modalities of immune reactions to parasites, and were tailored to the life cycl es of the two most widespread human malaria pathogens, Plasmodium falciparum and Plasmodium vivax.For the same ability to bind and clear a target, the model simulations suggest that an antibody attacking immature gametocytes would tend to lower the overall density of transmissible mature gametocytes more than an antibody attacking the mature forms directly. Transmission of P. falciparum would be especially vulnerable to complete blocking by antibodies to its immature forms since its gametocytes take much longer to reach maturity than those of P. vivax. On the other hand, antibodies attacking the mature gametocytes directly would reduce the time the mature forms can linger in the host. Simulation results also suggest that varying the standard deviation in the time necessary for individual asexual parasites to develop and produce schizonts can affect the efficiency of production of transmissible gametocytes.If mature gametocyte density determines the probability of transmission, both Plasmodium species, but especially P. falciparum, could bolster this probability through evasion or suppression of host immune responses against the immature gametocytes. However, if the long term lingering of mature gametocytes at low density in the host is also important to ensure transmission, then evasion or suppression of antibodies against the mature stages would bolster probability of transmission as well.

SUBMITTER: McQueen PG

PROVIDER: S-EPMC3691866 | biostudies-other | 2013 Jun

REPOSITORIES: biostudies-other

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Host immune constraints on malaria transmission: insights from population biology of within-host parasites.

McQueen Philip G PG Williamson Kim C KC McKenzie F Ellis FE

Malaria journal 20130615

<h4>Background</h4>Plasmodium infections trigger complex immune reactions from their hosts against several life stages of the parasite, including gametocytes. These immune responses are highly variable, depending on age, genetics, and exposure history of the host as well as species and strain of parasite. Although the effects of host antibodies that act against gamete stages in the mosquito (due to uptake in the blood meal) are well documented, the effects of host immunity upon within-host gamet ...[more]

PMID: 23767770

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Project description:BackgroundThe combined effects of multiple density-dependent, regulatory processes may have an important impact on the growth and stability of a population. In a malaria model system, it has been shown that the progression of Plasmodium berghei through Anopheles stephensi and the survival of the mosquito both depend non-linearly on parasite density. These processes regulating the development of the malaria parasite within the mosquito may influence the success of transmission-blocking interventions (TBIs) currently under development.MethodsAn individual-based stochastic mathematical model is used to investigate the combined impact of these multiple regulatory processes and examine how TBIs, which target different parasite life-stages within the mosquito, may influence overall parasite transmission.ResultsThe best parasite molecular targets will vary between different epidemiological settings. Interventions that reduce ookinete density beneath a threshold level are likely to have auxiliary benefits, as transmission would be further reduced by density-dependent processes that restrict sporogonic development at low parasite densities. TBIs which reduce parasite density but fail to clear the parasite could cause a modest increase in transmission by increasing the number of infectious bites made by a mosquito during its lifetime whilst failing to sufficiently reduce its infectivity. Interventions with a higher variance in efficacy will therefore tend to cause a greater reduction in overall transmission than a TBI with a more uniform effectiveness. Care should be taken when interpreting these results as parasite intensity values in natural parasite-vector combinations of human malaria are likely to be significantly lower than those in this model system.ConclusionsA greater understanding of the development of the malaria parasite within the mosquito is required to fully evaluate the impact of TBIs. If parasite-induced vector mortality influenced the population dynamics of Plasmodium species infecting humans in malaria endemic regions, it would be important to quantify the variability and duration of TBI efficacy to ensure that community benefits of control measures are not overestimated.

Project description:The two main agents of human malaria, Plasmodium vivax and Plasmodium falciparum, can induce severe anemia and provoke strong, complex immune reactions. Which dynamical behaviors of host immune and erythropoietic responses would foster control of infection, and which would lead to runaway parasitemia and/or severe anemia? To answer these questions, we developed differential equation models of interacting parasite and red blood cell (RBC) populations modulated by host immune and erythropoietic responses. The model immune responses incorporate both a rapidly responding innate component and a slower-responding, long-term antibody component, with several parasite developmental stages considered as targets for each type of immune response. We found that simulated infections with the highest parasitemia tended to be those with ineffective innate immunity even if antibodies were present. We also compared infections with dyserythropoiesis (reduced RBC production during infection) to those with compensatory erythropoiesis (boosted RBC production) or a fixed basal RBC production rate. Dyserythropoiesis tended to reduce parasitemia slightly but at a cost to the host of aggravating anemia. On the other hand, compensatory erythropoiesis tended to reduce the severity of anemia but with enhanced parasitemia if the innate response was ineffective. For both parasite species, sharp transitions between the schizont and the merozoite stages of development (i.e., with standard deviation in intra-RBC development time <or=2.4 h) were associated with lower parasitemia and less severe anemia. Thus tight synchronization in asexual parasite development might help control parasitemia. Finally, our simulations suggest that P. vivax can induce severe anemia as readily as P. falciparum for the same type of immune response, though P. vivax attacks a much smaller subset of RBCs. Since most P. vivax infections are nonlethal (if debilitating) clinically, this suggests that P. falciparum adaptations for countering or evading immune responses are more effective than those of P. vivax.

Dataset Information

Host immune constraints on malaria transmission: insights from population biology of within-host parasites.

Publications

Host immune constraints on malaria transmission: insights from population biology of within-host parasites.

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