Unravelling disease tolerance and host resistance in afebrile P. falciparum infections: a prospective study in Mozambican adults residing in Manhiça District (ASINTMAL)

Asymptomatic Plasmodium falciparum (Pf) infections debilitate the health of the affected population while representing a hidden source of parasite transmission that can compromise elimination efforts. The lack of consensus on the best strategy to deal with this asymptomatic reservoir is partly due to the poor knowledge on the biological mechanisms underlying these subclinical infections.

We hypothesize that these four main trajectories are driven by antibodies against Pf variant antigens, codified by the var gene family and expressed on the surface of infected erythrocytes, which would clear the infection unless the parasites develop immune evasion mechanisms, and by tolerance factors that minimize parasite-induced pathology and sustains host homeostasis.

With the overarching goal of identifying key biological factors sustaining afebrile malaria infections, this project will establish a cohort of afebrile Mozambican adults followed during one month to identify subjects who can reduce pathogen load and eventually clear the infection, those who maintain infections at high-density and afebrile levels (tolerant), and those who fail to establish disease tolerance and progress to fever.

We will quantify circulating and overall parasite biomass, and identify new infections during follow-up using next-generation sequencing. Clinical samples from individuals with low and high parasite densities will be used to test whether parasitological trajectories of afebrile Pf infections correlate with host antibody immunity against Pf and the transcription of Pf var genes. Cytometry by time of flight and global mass spectrometry will be applied to identify leukocyte populations and metabolic pathways involved in the regulation of inflammation, tissue damage and normoglycemia that support host-parasite relationships at afebrile levels.

The project will allow us to identify key molecular drivers of afebrile Pf infections for a better understanding of the relevance of these infections as well as for the development of new tools to achieve sterilizing immunity and enhance disease tolerance.

ISGlobal - project detailsNIH - Grant details

Asymptomatic Reservoir

Jun 2020 — May 2025

$129,470

Mozambique