Publication Database

Human genetic polymorphisms influencing the risk and manifestation of malaria in India and Africa (2020)

Art

Hochschulschrift

Autor

Gai, Prabhanjan (WE 7)

Quelle

Berlin, 2020 — VII, 116 Seiten

Sprache

Englisch

Verweise

URL (Volltext): https://refubium.fu-berlin.de/handle/fub188/27359

Kontakt

Institut für Mikrobiologie und Tierseuchen

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51843 / 66949
mikrobiologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Malaria is one of the most relevant parasitic diseases and caused by infection with Plasmodium parasites. More than 3 billion people are at risk of Plasmodium infection worldwide. Populations in malaria endemic areas are subject to evolutionary selection of genetic polymorphisms conferring relative protection against the disease. Primarily, those genetic variants affect host erythrocytes. In addition, polymorphisms in genes related to molecules regulating the immune system also influence susceptibility to malaria as well as its pathophysiology. The available knowledge with respect to malaria-related traits is more extensive as regards falciparum malaria than vivax malaria. Moreover, P. vivax, traditionally thought to be benign, is increasingly reported to cause severe malaria, particularly in India. However, the available data are scarce and ambiguous. Similar limitations apply to the extent and spread of antimalarial drug resistance. In Mangaluru, southern India, firstly, we assessed the manifestation pattern of malaria and in particular of P. vivax infection. This study shows that in Mangaluru malaria is mostly uncomplicated and affects predominantly young men from a low-socio-economic background, who are majorly migrant workers from other parts of India. Severe vivax malaria occurs at a rate slightly lower than in falciparum malaria but its low prevalence contrasts with considerably higher figures reported from other parts of the country. Secondly, in a case-control study, we examined the association of polymorphisms in the Duffy antigen receptor for chemokines (DARC) with malaria. DARC is a central component in P. vivax invasion into the red blood cells. DARC 298A carriage increased the odds of malaria per se and more prominently of P. vivax infection. Interestingly, FYB carriage appeared to confer protection against severe falciparum malaria. We also expanded the existing knowledge on host genetic associations with falciparum malaria in Africa, in particularly among pregnant women and children in Africa. The O blood group was observed to confer protection against falciparum malaria in primiparous Ghanaian women, whereas a common polymorphism in miRNA 146a, rs2910164 G > C was associated with increased odds of malaria in pregnancy. In addition, we examined the association of a common TP53 polymorphism previously suggested to be malaria protective. However, this variant was not associated with falciparum malaria among Ghanaian primiparae or Rwandan children. As to antimalarial drug resistance, we assessed associated molecular markers in Plasmodium isolates from Africa and India. The present work observed an infrequent occurrence of Kelch 13 gene variants in P. falciparum isolates from Rwanda but detected two mutations (P574L and A675V) associated with artemisinin resistance in Southeast Asia. Among the P. falciparum isolates from India, no K13 variants were present. Sulfadoxine-pyrimethamine (SP) plus artesunate is the current first-line antimalarial in India. Based on the antifolate resistance allele distribution, we assume that SP resistance in the study area is pronounced but not yet intense, thereby limiting the useful therapeutic lifespan of artesunate-SP. Moreover, the near fixation of the pfmdr1 allele combination N86-184F-D1246 suggests that artemether-lumefantrine, introduced in the northeastern parts of this country, is not a promising alternative in the study area. Chloroquine (CQ) is primarily used to treat vivax malaria and pvmdr1 variants have been associated with CQ resistance. However, the virtual absence of such variants among the P. vivax isolates as well as almost complete parasite clearance within 2-3 days suggest that CQ is still effective. Overall, the present thesis provides new insights or expands the present knowledge on the roles of host genetic variation in various study settings which, in turn, may contribute to a better understanding of malaria pathophysiology. Moreover, this study improves the remarkably limited characterisation of the manifestation of malaria in India. Most lastly, the data show the threat of the effectiveness of the first-line antimalarials in India and Rwanda.