A linkage between presence of Sickle Haemoglobin (HbS) and protection from
malaria infection and clinical manifestations in certain areas was suspected from early observations and progressively elucidated by more recent studies. Research has confirmed the abovementioned connection, but also clarified how such protection may be abolished by coexistence of
sickle cell trait (HbS trait) and
alpha thalassemia, which may explain the relatively low incidence of HbS trait in the Mediterranean. The mechanisms of such protective effect are now being investigated: factors of genetic, molecular and immunological nature are prominent. As for genetic factors attention is given to the role of the red blood cell (RBC) membrane
complement regulatory
proteins as polymorphisms of these components seem to be associated with resistance to severe
malaria; genetic
ligands like the Duffy
group blood antigen, necessary for erythrocytic invasion, and human
protein CD36, a major receptor for P. falciparum-infected RBC's, are also under scrutiny: attention is focused also on plasmodium erythrocyte-binding
antigens, which bind to RBC surface components. Genome-wide linkage and association studies are now carried out too, in order to identify genes associated with
malaria resistance. Only a minor role is attributed to intravascular sickling, phagocytosis and
haemolysis, while specific molecular mechanisms are the object of intensive research: among these a decisive role is played by a biochemical sequence, involving activation of haeme
oxygenase (HMO-1), whose effect appears mediated by
carbon monoxide (CO). A central role in protection from
malaria is also played by
immunological factors, which may stimulate antibody production to plasmodium
antigens in the early years of life; the role of agents like pathogenic CD8 T-cells has been suggested while the effects of molecular actions on the immunity mechanism are presently investigated. It thus appears that protection from
malaria can be explained by interaction of different factors: the elucidation of such mechanisms may prove valuable for the prevention and treatment strategy of a disease which still affects large parts of the world.