# Fetal hemoglobin enables malaria parasite growth in sickle cells but augments production of transmission stage parasites

## TL;DR

Fetal hemoglobin protects individuals from malaria and sickle cell disease but increases the production of malaria parasites that can be transmitted to mosquitoes.

## Contribution

This study reveals that fetal hemoglobin enables parasite persistence and gametocyte maturation in sickle cells, increasing malaria transmissibility.

## Key findings

- Higher fetal hemoglobin levels protect against malaria disease but increase gametocyte production.
- Fetal hemoglobin allows Plasmodium falciparum to persist and mature in sickled red blood cells.
- Individuals with elevated fetal hemoglobin may act as a reservoir for malaria transmission.

## Abstract

Sickle cell trait is the quintessential example of the human evolutionary response to malaria, providing protection against severe disease, but leading to sickle cell disease (SCD) in the homozygous state. Fetal Hemoglobin (HbF) reduces the pathology of SCD and several mutations lead to the prolonged production of HbF into childhood and adult life. HbF has been suggested to contribute to protection against malaria. Two long-term cohorts were genotyped for three quantitative trait loci associated with HbF production and analyzed for HbF titers, malaria clinical episodes and the production of parasite stages infectious to mosquitoes, gametocytes, in asymptomatic infections. Plasmodium falciparum parasites were also grown in vitro in HbSS cells with measured levels of HbF. The genetic determinants of prolonged HbF production were associated with increased HbF titers and that increased HbF afforded protection from malaria disease but increased the production of gametocytes. The presence of HbF in sickled red cells was also shown in in vitro culture to enable parasite persistence in conditions otherwise deleterious for the parasite and enabled complete maturation of gametocytes. The beneficial personal effect of HbF, whether through protection against malaria or alleviating effects of SCD, is seemingly offset by increased parasite transmissibility and potential disease burden for the community. These individuals represent a potentially important reservoir of infection and could be targeted in elimination strategies.