Platelet depletion by anti-CD41 (αIIb) mAb injection early but not late in the course of disease protects against Plasmodium berghei pathogenesis by altering the levels of pathogenic cytokines

Abstract

Accumulating evidence indicates that platelets play a critical role in the pathogenesis of experimental severe malaria (ESM) elicited by infection with Plasmodium berghei. Mice injected on day 1 of P berghei infection (early) with either anti-CD41 or anti-CD61 monoclonal antibodies (mAbs) exhibited significantly (P < .001) increased survival from ESM compared with infection controls, indicating that platelets function early in the disease. In contrast, groups of mice treated on days 4, 5, and 6 (late) with anti-CD41 mAb exhibited similar mortality as controls.Because platelet depletion by anti-CD41 mAb on day 4 of infection did not protect mice, and platelet adherence occurs on day 6, platelet adherence to endothelium is not required to mediate malarial pathogenesis. Few platelet microparticles were detected in the blood during the course of malaria, but large numbers of erythrocyte vesicles, microparticles, and debris were detected. The protective effect of early anti-CD41 mAb treatment was independent of the number of platelets, platelet microparticles, erythrocyte-platelet conjugates, and erythrocyte vesicles. Mice IntroductionOne of the hallmarks of cerebral malaria, which is caused by infection with Plasmodium falciparum, is petechial hemorrhaging into the brain, indicating that platelets may play a crucial role in malarial pathogenesis. 1 Clinical studies of patients with P falciparum indicate a marked procoagulant state with consumption of clotting factors, the presence of fibrin dimers, and decreased levels of the anticoagulants protein C and S 2-4 ; the procoagulant state correlates with the development of severe malaria. Grau and colleagues 5 have proposed that platelet activation and adherence contributes to the development of severe malaria. Patients with severe falciparum malaria exhibit profound thrombocytopenia, and platelet accumulation in the brains of children who have succumbed to severe falciparum malaria is significantly higher than platelet accumulation in the brains of patients who died from other coma complications. [6][7][8][9] These clinical results in humans with malaria provide the impetus for parallel mechanistic studies in animal models. Extrapolation of results from mouse models of severe malaria must be cautious because the P falciparum species of the malarial parasite cannot be used in rodent models of severe malaria because they do not replicate in mouse erythrocytes, and there are also differences between rodents and humans. Nevertheless, direct evidence for the importance of platelets in malarial pathogenesis has come from the P berghei model of severe malaria. 10,11 CD41/CD61 (␣IIb/␤3 integrin heterodimer, also known as gpIIb/IIIa) is an important molecule in platelet biology and its major function is contributing to expansion of clot formation and platelet adhesion to the microvasculature. 12-14 Our previous studies indicate that platelet adhesion during experimental severe malaria (ESM) occurs primarily in venules within the pial microvasculature and that CD41 plays an imp...

Platelet power: sticky problems for sticky parasites?

“…For example, mice with significantly compromised platelet function (CXCL4 or CXCR3 deficient) have been shown to survive longer than their wild-type counterparts [4]. By contrast, platelet depletion by anti-CD41 monoclonal antibody injection early, but not late, in the course of disease is known to protect C57BL6 mice from Plasmodium berghei ANKA-induced severe experimental cerebral malaria (ECM) by altering levels of pathogenic cytokines [5]. Unfortunately, the study by McMorran et al used P. chabaudi, a rodent malaria thatalthough capable of sequestering to a number of organs -is not known to develop ECM.…”

Thrombocytopenia in malaria: who cares?

“…In mice infected with P. berghei ANKA, mice deficient of tissue and uroquinase plasminogen activators demonstrated less capillary sequestration of platelets and less severe malaria (Piguet et al 2000). Blocking GPIIb with anti-CD41 monoclonal antibodies in the first day of murine infection with P. berghei also led to higher production of interleukin (IL)-10, IL-1α, IL-6, interferon-α and TNF and less mortality among mice, suggesting that platelets may act as cofactors of severe malaria (Sun et al 2003, van der Heyde et al 2005. There was also an inverse correlation between platelet count and TNF in patients with vivax infection and no association between specific mutation G→A in the position 308 in the TNF gene (a polymorphism whose functional effect upon severe disease is hypothesised) and platelet count was observed.…”

Plasmodium falciparum malaria, bilateral sixth cranial nerve palsy and delayed cerebellar ataxia

“…The inflammatory cytokines (IL-1, IL-2, IFN-ϒ, and TNF-α) are all required for the development of experimental severe malaria (ESM). A marked elevation of serum TNF-α, IL-6, and IL-2 was demonstrated in DCA [19,20]. CD4+ T-cell activation leads to the production of proinflammatory cytokines, which up-regulate a variety of macrophage functions, one of which is the release of TNF-α in response to malaria antigens [21].…”

“…At physiological concentrations, recombinant TNF-α is antiparasitic, synergizing with IFN-ϒ to induce production of nitric oxide and other toxic radicals [22]. Differences in resistance and susceptibility to ESM in different strains of mice correlate with the development of inflammatory versus anti-inflammatory cytokines [20].…”