Unravelling disease tolerance and host resistance in afebrile P. falciparum infections: a prospective study in Mozambican adults

ABSTRACT
Asymptomatic Plasmodium falciparum (Pf) infections debilitate the health of 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. Preliminary results in Mozambique
show that afebrile adults with a Pf infection detected by rapid diagnostic tests can progress to fever (10%),
clear the infection (20%) and stabilize at low-density (50%) or high-density (20%) parasitemias. 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 erythrocyte
surface antigens and the transcription of Pf var genes involved in cytoadhesion and immune evasion (Aim
1). Cytometry by time of flight and global mass spectrometry will be applied on clinical samples from afebrile
individuals with high parasite densities (tolerant) and those progressing to fever (non-tolerant) 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 (Aim 2). We will validate these
results using an independent set of samples obtained from a Ugandan cohort of children and adults with
longitudinal measurement of malaria incidence and parasite prevalence. This project will contribute to
develop scientific capacity at the Manhiça Health Research Center and create a sample repository for future
investigations on host and parasite interactions during afebrile malaria infections (Aim 3). The expected
outcome of this project is the identification of key molecular drivers of afebrile Pf infections for a better
understanding of the relevance of these infections in different transmission setting which may require
context-specific control approaches, as well as for the development of new tools to achieve sterilizing
immunity and enhance disease tolerance.

Grant Number: 5R01AI150521-05
NIH Institute/Center: NIH
Principal Investigator: Pedro AIDE