Adhesion ofPlasmodium falciparum-infected erythrocytes to human cells: molecular mechanisms and therapeutic implications

Abstract

Severe malaria has a high mortality rate (15–20%) despite treatment with effective antimalarial drugs. Adjunctive therapies for severe malaria that target the underlying disease process are therefore urgently required. Adhesion of erythrocytes infected with Plasmodium falciparum to human cells has a key role in the pathogenesis of life-threatening malaria and could be targeted with antiadhesion therapy. Parasite adhesion interactions include binding to endothelial cells (cytoadherence), rosetting with uninfected erythrocytes and platelet-mediated clumping of infected erythrocytes. Recent research has started to define the molecular mechanisms of parasite adhesion, and antiadhesion therapies are being explored. However, many fundamental questions regarding the role of parasite adhesion in severe malaria remain unanswered. There is strong evidence that rosetting contributes to severe malaria in sub-Saharan Africa; however, the identity of other parasite adhesion phenotypes that are implicated in disease pathogenesis remains unclear. In addition, the possibility of geographic variation in adhesion phenotypes causing severe malaria, linked to differences in malaria transmission levels and host immunity, has been neglected. Further research is needed to realise the untapped potential of antiadhesion adjunctive therapies, which could revolutionise the treatment of severe malaria and reduce the high mortality rate of the disease.

Sickle cell trait is associated with controlled levels of haem and mild proinflammatory response during acute malaria infection

“…Evidence from previous studies have shown that haem, the substrate of HO‐1, is also its major inducer 15, 16, 17, 20, 33, and when cells are exposed to haem there is an increased expression of HO‐1 to catabolize haem and prevent its cytotoxicity 33. As patients with the HbAS genotype have higher levels of haem compared with HbAA genotype at convalescence, we investigated the possibility of a corresponding induction of HO‐1 in both genotypes.…”

Pathogenic mechanisms in Plasmodium falciparum malaria

“…Los receptores más importantes son la glucoproteína CD36 y la molécula 1 de adhesión intercelular (Intercellular Adhesion Molecule 1, ICAM-1) en el endotelio y el sulfato A de condroitina (Chondroitin Sulfate A, CSA) en placenta. Otros receptores incluyen la molécula 1 de adhesión vascular (Vascular Cell Adhesion Molecule 1, VCAM-1) y la E-selectina en endotelio, las proteínas PCAM-1/ CD31 en plaquetas y endotelio, el sistema de antígenos ABO, el sulfato de heparán y el receptor 1 del complemento (CR1) en eritrocitos no parasitados (8). Bajo condiciones fisiológicas, el secuestro puede obedecer a una interacción con múltiples receptores y en parásitos aislados se han observado fenotipos multiadhesivos que se asocian con enfermedad grave (3,8,9).…”

“…La unión a este receptor es común en parásitos aislados en diferentes países de África (9,11,12), Thailandia (13,14) y Brasil (10). La relación entre el CD36 y la gravedad clínica es controversial; en general, se asocia este receptor con enfermedad no complicada (8,9,11,13 …”

“…La unión a ICAM-1 se ha observado en el 80 % de los parásitos aislados en África y es común en Tailandia y Brasil (8)(9)(10)(11)13,14). La interacción con la ICAM-1 se asocia con enfermedad grave, en particular con malaria cerebral (11,13).…”

“…Representan fenotipos adherentes menos frecuentes en aislamientos de P. falciparum (8,14). La unión a PCAM-1 se encontró en 50 % de los parásitos aislados en Kenia.…”