Duffy, M. F. | bioRxiv Science

bioRxiv2023

Malaria parasite resistance to azithromycin is not readily transmitted by mosquitoes

Antimalarials are now used in combination with partner drugs to stem parasite drug resistance. Partners are often older, safe, cheap drugs, but resistance is already circulating for many, which raises the risk of selecting for multidrug resistance. If the partner drug(s) could be refractory to the spread of resistance, better resistance control could be implemented. We tested whether resistance to the antibiotic azithromycin, which kills malaria parasites by perturbing prokaryote-like protein synthesis in the apicoplast (relict plastid), had fitness costs to the spread of parasites via mosquitoes where parasites are not under drug pressure. Azithromycin resistance mutations in both rodent and human malaria parasites had a negative impact on the ability of resistant parasites to transmit from one vertebrate host to another via mosquitoes. Azithromycin resistance will therefore be less likely to spread geographically, making it an attractive option as a perennial partner compound to protect appropriate frontline antimalarials.

molecular biology↗

bioRxiv2020

Common virulence gene expression in naive and severe malaria cases

Sequestration of Plasmodium falciparum-infected erythrocytes to host endothelium through the parasite-derived PfEMP1 adhesion proteins is central to the development of malaria pathogenesis. PfEMP1 proteins have diversified and expanded to encompass many sequence variants conferring each parasite a similar array of human endothelial receptor binding phenotypes. Here, we analyzed RNA-seq profiles of parasites isolated from 32 P. falciparum infected adult travelers returning to Germany. Patients were categorized into either malaria naive (n=15) or pre-exposed (n=17), and into severe (n=8) or non-severe (n=24) cases. For differential expression analysis of PfEMP1-encoding var gene transcripts were de novo assembled from RNA-seq data and, in parallel, var expressed sequence tags were analyzed and used to predict the encoded domain composition of the transcripts. Both approaches showed in concordance that severe malaria was associated with PfEMP1 containing the endothelial protein C receptor (EPCR)-binding CIDR1 domain, whereas CD36-binding PfEMP1 was linked to non-severe malaria outcomes. First-time infected adults were more likely to develop severe symptoms and tended to be infected for a longer period. Thus, parasites with more pathogenic PfEMP1 variants are more common in patients with a naive immune status and/or adverse inflammatory host responses to first infections favors growth of EPCR-binding parasites.

molecular biology↗