Biological Mechanisms in Afebrile P. Falciparum Malaria
Condition: Falciparum Malaria
MeSH terms: Malaria; Malaria, Falciparum
Study type: Observational

Summary: 
      This project aims to disentangle the role of host immune resistance and disease tolerance in
      afebrile malaria infections, with the goal of guiding context-adapted tactics to target this
      hidden reservoir, as well as to develop new approaches to clear malaria infection and reduce
      its severity through host-directed therapies.
    

Detailed description: 
      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. The study hypothesis is 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. Circulating and overall parasite biomass will be quantified,
      and new infections will be identified 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. 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. 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.
    

Intervention name(s): No intervention
Intervention type(s): Other
Intervention description(s): No intervention
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Healthy individuals (temperature below 37.5ºC) with a P. falciprum infection confirmed by
        RDT and microscopy
      
Keywords: afebrile; resistance; tolerance