(C) for simulated infections in which model innate response cleared mature and immature gametocytes at the same rate that it clears asexual forms. against the transmissible forms. 1475-2875-12-206-S2.pdf (218K) GUID:?D68760A1-F0E9-4856-8B7D-F3AD4A3333A7 Abstract Background 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 Dinoprost tromethamine 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, and 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 species, but especially parasites within their hosts [1-3], these forms Dinoprost tromethamine cannot survive in the mosquito vectors of the diseases. Instead, by a process not fully understood [4,5], specialized sexual forms called gametocytes arise within the host, as progeny of asexual forms, and it is these cells which propagate the infection. The mating gametes emerge within the midgut of the mosquito from gametocytes harbored in the blood meal. The resultant zygote becomes an ookinete and then an Hoxa oocyst that produces thousands of sporozoites which invade the salivary Dinoprost tromethamine glands of the vector and thereby carry the infection to a new host when the mosquito feeds [6-8]. Since species infect vertebrates, gametocytes along with the asexual intrahost forms have to contend with vertebrate immune responses. 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, thus blocking transmission of the pathogen. Production of such antibodies (reaching from the host into the vector) has been demonstrated during infections in chickens [9,10], mice [11], Rhesus monkeys [12], and human infections with can reduce the number of oocysts in mosquitoes [16,17]. The effects of a hosts acquired immunity upon the intrahost gametocytes before Dinoprost tromethamine uptake by mosquitoes are less clear. A 1977 study [18] of eleven Gambian children who carried gametocytes found that four subjects had antibodies against gametocytes, but these antibodies did not interact with the surface of erythrocytes parasitized by gametocytes. The Dinoprost tromethamine seven subjects without antibodies to gametocytes still were able to eliminate them. Since this study, though, newer evidence suggests a reconsideration of transmission blocking due to acquired immunity to eliminate or otherwise cripple gametocytes before uptake by the vector [19]. In particular a 2008 study of Gambian children showed that 34% of them had antibodies to antigens on the surface of erythrocytes parasitized with mature gametocytes (referred to gametocyte surface antigens or GSAs) of the 3D7 strain of parasites sensitive to these drugs [21]). In addition to activating acquired immune responses, gametocytes, along with other intrahost stages, interact with host innate immune responses as well [22]. Studies of infections in toque monkeys showed that cytokines TNF and INF- were needed for the killing of gametocytes [23]. Another experiment demonstrated that white blood cells need nitric oxide to kill gametocytes of and showed that blockage of the TNF receptor (by antibodies to this receptor) increased the transmissibility of this parasite [25]. Finally, epidemiological evidence suggest species-dependent differences in human immune responses. Gametocytemia was found to correlate with high fever in infection, but not in infection, in two studies: one of malaria patients in Peru and Thailand [26], and another of neurosyphilis patients undergoing malariatherapy [27]. Thus, gametocyte-host immune system interactions remain an active area of research for many reasons. Although host responses to infection are extremely complex, one can apply the logic of computation to determine the infection and transmission outcome for a hypothetical set of host responses if one suspects those responses to be.