Publication Database

Human genetics affecting malaria susceptibility and manifestation, and P. falciparum genetics affecting antimalarial drug resistance (2022)

Art

Hochschulschrift

Autor

van Loon, Welmoed (WE 13)

Quelle

Berlin: Mensch und Buch Verlag, 2022 — vi, 133 Seiten

Sprache

Englisch

Verweise

URL (Volltext): https://refubium.fu-berlin.de/handle/fub188/38024

Kontakt

Institut für Parasitologie und Tropenveterinärmedizin

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 62310
parasitologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Genetic traits in both the human host and the malaria parasite affect malaria epidemiologically and on an individual level. This thesis combines these topics: host genetics interfering with malaria, and parasite genetics interfering with malaria outcome. By putting our epidemiological and experimental observations in context, we aim to contribute to improved design and interpretation of malaria interventions. We investigated how different Duffy antigen alleles, known for their crucial role in vivax malaria susceptibility, affect malaria susceptibility and manifestation in a case control study among 909 malaria patients and 909 healthy community controls in India. We observed that the FYB allele associated with protection against hospitalized falciparum malaria and that the DARC 298A allele associated with increased risk of malaria per se (adjusted odds ratio [aOR], 1.5; 95% confidence interval [CI], 1.1–2.0) and particularly of P. vivax infection (aOR, 1.6; 95% CI, 1.1–2.2). Since the P. vivax Duffy Binding Protein (PvDBP) is a major vaccine target, deciphering the differential antimalarial immunity properties of the Duffy antigen alleles is crucial. We studied how a common variant in an innate immune regulator, microRNA-146a, affects malaria susceptibility and manifestation in two different host populations. Among 509 pregnant women in Ghana, homozygosity for the genetic variant significantly increased the odds for infection (aOR, 2.3; 95% CI, 1.3–4.0), particularly in primigravidae (aOR, 5.8; 95% CI, 1.6–26.0). A similar effect was observed in 296 delivering primiparae (aOR, 5.9; 95% CI, 2.1–18.0). However, no such effect was seen in the case-control study in India. The first observation suggests of a role of microRNA-146a in the innate immune response to malaria, since primiparae constitute a relatively non-immune group in this endemic setting. Our somewhat conflicting, second observation underlines the complexities of malaria immunity on different genetic background, parasite species and clinical setting. Possibly, the microRNA-146a molecule has a major role in pregnancy-related malaria, and less in uncomplicated non-pregnancy related malaria. Due to the emerging interest in employing miRNAs as biomarker or therapeutic target for diseases, including malaria, a thorough understanding of their role in different malaria entities is required. We screened for markers of antimalarial drug resistance in 288 P. falciparum isolates from Rwanda (2010-2019) and main findings were i) an increase in PfK13 (the central gene in artemisinin resistance) diversity over the last decade, ii) the presence of a validated marker of artemisinin resistance (PfK13 R561H) in 4.5% in 2019, and in vitro confirmation of artemisinin resistance in Rwandan patient isolates from 2019. In addition, we observed a shift in the pattern of PfMDR1 haplotypes (known to interfere with sensitivity to various antimalarials) associated with increased artemether-lumefantrine tolerance. These data contribute to the recent and compelling evidence that artemisinin resistance is emerging in East Africa. As observed in South-East Asia, this facilitates the development of artemisinin combination therapy partner drug resistance, which has reached alarming levels there. Such developments would have disastrous consequences on the African continent. Surveillance for markers of artemisinin resistance urgently needs to be improved methodologically and expanded, since this will be a cornerstone of preventing further dissemination.