The influence of host genetics on erythrocytes and malaria infection: is there therapeutic potential?

Abstract

As parasites, Plasmodium species depend upon their host for survival. During the blood stage of their life-cycle parasites invade and reside within erythrocytes, commandeering host proteins and resources towards their own ends, and dramatically transforming the host cell. Parasites aptly avoid immune detection by minimizing the exposure of parasite proteins and removing themselves from circulation through cytoadherence. Erythrocytic disorders brought on by host genetic mutations can interfere with one or more of these processes, thereby providing a measure of protection against malaria to the host. This review summarizes recent findings regarding the mechanistic aspects of this protection, as mediated through the parasites interaction with abnormal erythrocytes. These novel findings include the reliance of the parasite on the host enzyme ferrochelatase, and the discovery of basigin and CD55 as obligate erythrocyte receptors for parasite invasion. The elucidation of these naturally occurring malaria resistance mechanisms is increasing the understanding of the host-parasite interaction, and as discussed below, is providing new insights into the development of therapies to prevent this disease.

OK/basigin expression on red blood cells varies between blood donors and correlates with binding of recombinant Plasmodium falciparum reticulocyte‐binding protein homolog 5

“…Therefore, new therapies and preventive measures against malaria should be developed. Moreover, in the blood stage life cycle of the parasite, the process of merozoite invasion is directly exposed to the host humoral immune system and considered an attractive vaccine target . Nevertheless, the P. falciparum merozoite infection of RBCs is a complex process.…”

“…Moreover, in the blood stage life cycle of the parasite, the process of merozoite invasion is directly exposed to the host humoral immune system and considered an attractive vaccine target. 10,11 Nevertheless, the P. falciparum merozoite infection of RBCs is a complex process. Although more than 50 proteins are estimated to be present on the surface of the merozoite and most of them might have receptors on RBCs, only a few ligandreceptor pairs have been confirmed.…”

Adenosine monophosphate deaminase 3 activation shortens erythrocyte half-life and provides malaria resistance in mice

“…In each case, a number of mechanisms have been proposed for the observed resistance, including decreased invasion, decreased parasite growth, and increased RBC senescence. 10 Although all processes may contribute to resistance, Ampd3…”

“…In most cases, cells show signs of increased senescence, including increased oxidative stress and phosphatidylserine (PS) exposure. 2,[7][8][9] Intriguingly, many of these diseases are also associated with protection from severe malaria, 10,11 which has led some authors to propose a role for RBC senescence and clearance in malaria resistance. [12][13][14] RBC lifespan may be critically regulated by changes in intracellular adenosine nucleotide (adenosine triphosphate [ATP], adenosine 59-diphosphate [ADP], and adenosine 59-monophosphate [AMP]) levels.…”

Possible selection of host folate pathway gene polymorphisms in patients with malaria from a malaria endemic region in North East India

“…29 Host factors also play an important role in this selection process. For instance, erythrocytes are protected from increased infection by the malarial parasite through the up regulation of a hormone, i.e., hepcidin.…”