Vector transmission regulates immune control of Plasmodium virulence

Abstract

Defining mechanisms by which Plasmodium virulence is regulated is central to understanding the pathogenesis of human malaria. Serial blood passage of Plasmodium through rodents1-3, primates4 or humans5 increases parasite virulence, suggesting that vector transmission regulates Plasmodium virulence within the mammalian host. In agreement, disease severity can be modified by vector transmission6-8, which is assumed to ‘reset’ Plasmodium to its original character3. However, direct evidence that vector transmission regulates Plasmodium virulence is lacking. Here we utilise mosquito transmission of serially blood passaged (SBP) Plasmodium chabaudi chabaudi9 to interrogate regulation of parasite virulence. Analysis of SBP P.c. chabaudi before and after mosquito transmission demonstrates that vector transmission intrinsically modifies the asexual blood-stage parasite, which in turn, modifies the elicited mammalian immune response, which in turn, attenuates parasite growth and associated pathology. Attenuated parasite virulence associates with modified expression of the pir multi-gene family. Vector transmission of Plasmodium therefore regulates gene expression of probable variant antigens in the erythrocytic cycle, modifies the elicited mammalian immune response, and thus regulates parasite virulence. These results place the mosquito at the centre of our efforts to dissect mechanisms of protective immunity to malaria for the development of an effective vaccine.

Avian malaria: a new lease of life for an old experimental model to study the evolutionary ecology ofPlasmodium

“…In particular, as shown in earlier studies [30] we show that the mode of transmission (intraperitoneal or via mosquitoes) affects subsequent withinbird dynamics and deserves further investigation. In addition, the number of serial passages had an effect on parasitaemia but not on gametocytaemia.…”

Plasmodium berghei Sporozoites Acquire Virulence and Immunogenicity during Mosquito Hemocoel Transit

“…It is plausible that the first parasite-host cross talk can modulate disease outcome of an infection with an otherwise virulent parasite. One recent study comparing natural and transfusion-mediated infection with Plasmodium chabaudi provided compelling evidence for virulence regulation by vector transmission (51). However, in most Plasmodium-host combinations, including human infections, parasitemia and clinical development of sporozoite-and asexual blood-stage-induced infections are indistinguishable (8,28,29,40,52,53).…”

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

“…Differences in parasite virulence may also account for some of the observed differences. We avoid using parasites passaged more than 3 times without recirculation through a mosquito, as repeated passage of murine strains of malaria has been demonstrated to increase virulence and substantially alter the host response (80).…”

“…To examine antigen-specific CD4 + T cells responding to infection, P. yoelii were generated that constitutively express the Lymphocytic choriomeningitis virus-derived (LCMV-derived) glycoprotein (GP) epitope (GP [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] ). This allows for the identification and analysis of antigen-specific CD4 + T cells using previously described GP66:I-A B tetramer enrichment strategies (16).…”