Cerebral Malaria (CM) is an often fatal complication of Plasmodium falciparum infection. CM has a characteristic cerebral vascular pathology. Post-mortem analysis of CM patients show microvascular sequestration of platelets, infected red blood cells (iRBCs) as well as leukocytes. CM has thus been viewed by some as a mechano-obstructive pathology and by others, the result of prolonged immune stimulation leading to a pro-inflammatory state. Platelets have both vascular obstructive and pro-inflammatory effects and can thus bridge these seemingly opposing views of CM pathology. Previous studies have shown that platelets are directly activated by iRBCs and may contribute adversely to CM pathogenesis by promoting a pro-inflammatory environment within the cerebral microvasculature. Recently, platelets have been described as having the capacity in uncomplicated malaria to kill intraerythrocytic Plasmodium parasites. These somewhat conflicting roles for platelets in malaria infections provide further impetus to study the contributions of platelets to CM pathogenesis. In particular it is of great interest to study the potentially diametric functions of platelets during the course of disease progression and to demonstrate the capacity of platelets to act as innate immune cells. This application thus has two aims: 1) To demonstrate that iRBCs activate platelets and these activated platelets subsequently induce an early innate immune response and 2) to determine the specific mechanisms through which this occurs.
Significance: Cerebral Malaria (CM) is an often fatal complication of Plasmodium infection for children in endemic countries as well as adults from non-endemic areas travelling or working in endemic areas. There has been a major funding emphasis on vaccine development over the past two decades and while this effort is vital, there is also a need to develop alternative therapies, such as cell based therapies, in conjunction with pharmaceutical therapies that can fill the treatment void as vaccine efforts continue. Platelet directed therapies may be a vital part of this effort, increasing the need to study their role in C.