Simultaneous adjunctive treatment of malaria and its co-evolved genetic disorder sickle cell anaemia

Abstract

Effective treatments for genetic disorders that co-evolved with pathogens require simultaneous betterment of both conditions. Hydroxyurea (HU) offers safe and efficacious treatment for sickle cell anemia (SCA) by reducing clinical complications, transfusions, and death. Despite concerns that HU-treatment for SCA would increase infection risk by the human malaria Plasmodium falciparum, (the genetic driver of the sickle mutation), HU instead reduced clinical malaria. We show that at physiologically relevant exposures, HU (and other ribonucleotide reductase inhibitors) have significant, intrinsic killing activity in vitro against blood stages of P. falciparum, with low risk of eliciting stably resistant parasites or compromising potency of current antimalarial drugs. Additive activity devoid of antagonism by HU was observed with a wide spectrum of commonly used antimalarial treatments. These data endorse broad, safe, long-term use of HU for SCA in malaria endemic countries and provide a novel biological model for simultaneous, adjunct therapy of a life-threatening infection and concomitant management of a co-evolved genetic disorder. SignificanceGenetic disorders are increasingly being treated in global health settings. Hydroxyurea (HU; a ribonucleotide reductase inhibitor) is safe and efficacious for treating sickle cell anemia (SCA). Since the sickle mutation co-evolved with the human malaria parasite Plasmodium falciparum, HU-treatment may potentially have increased malarial infection in SCA patients. However, HU reduced clinical malaria, but why this occurred was not understood. We discovered that in doses used in patients, HU kills P. falciparum and shows strong potential for safe, adjunctive use with current antimalarial drugs. Our findings endorse, long-term use of HU for SCA in malaria-endemic countries and a novel model for simultaneous, adjunct treatment of a life-threatening infection like malaria with concomitant management of multiple genetic hematological disorders of global proportions.