Abstract
BackgroundPlasmodium 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.ResultsFor 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.ConclusionsIf 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.
Highlights
IntroductionMany studies have shown that antibodies elicited by intrahost stages of the parasite can interfere with the mating of the gametes in the bolus of the blood meal in the mosquito gut, blocking transmission of the pathogen
The outcomes of simulated malaria infections were determined for thousands of values of model parameters, allowing us to examine a large spectrum of behavior
Severe and potentially fatal cases of both P. falciparum malaria [2] and P. vivax malaria [55] manifest as respiratory distress, cerebral complications, severe anemia, and other symptoms, but for this report it is assumed that the host dies if the uninfected red blood cell counts drops below 60% of normal, either by direct parasitization of erythrocytes or dyserythropoiesis or both
Summary
Many studies have shown that antibodies elicited by intrahost stages of the parasite can interfere with the mating of the gametes in the bolus of the blood meal in the mosquito gut, blocking transmission of the pathogen. Production of such antibodies (“reaching” from the host into the vector) has been demonstrated during Plasmodium infections in chickens [9,10], mice [11], Rhesus monkeys [12], and human infections with Plasmodium falciparum [13] and Plasmodium vivax [14,15]. Other studies have shown that monoclonal antibodies against specific surface antigens on the gametes of P. falciparum can reduce the number of oocysts in mosquitoes [16,17]
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