Unraveling the mechanisms by which CD8+ T cells and platelets contribute to cerebral malaria immunopathology Open Access
Darling, Thayer (Spring 2020)
Abstract
Malaria is a severe disease caused by infection with Plasmodium parasites. Despite continuing control efforts, reported malaria cases have increased in recent years. Cerebral malaria (CM) and malaria-associated acute lung injury/acute respiratory distress syndrome (MA-ALI/ARDS) are among the most severe complications of Plasmodium falciparum infection, yet the mechanisms underlying these diseases remain poorly understood. While these disease manifestations are complex and multifactorial, both CD8+ T cells and platelets have been described to play a role in the development of CM and MA-ALI/ARDS in mice as well as humans. However, the mechanisms by which CD8+ T cells and platelets contribute to exacerbation of organ pathology in the immune response to severe malaria have yet to be fully elucidated. Therefore, we were particularly interested in identifying molecular factors that may contribute to blood-brain barrier breakdown and increased lung vascular permeability in the development of these severe malaria syndromes.
Using a mouse model of experimental cerebral malaria (ECM), a disease which recapitulates key features of human CM including blood-brain barrier (BBB) dysfunction, we have identified a receptor tyrosine kinase, EphA2, essential for ECM development. EphA2 is upregulated in brains of Plasmodium berghei ANKA (PbA)-infected mice immediately prior to the onset of ECM symptoms, and EphA2-/- mice are protected from ECM. Interestingly, EphA2 upregulation uniquely occurs in brains of mice infected with PbA but not PbNK65, a highly similar strain of Plasmodium that does not cause ECM. Furthermore, CD8+ T cells, which are required for ECM development, are not found in brains of PbA-infected EphA2-/- mice. This reduction in brain CD8+ T cells is associated with enhanced endothelial cell junction integrity and reduced blood-brain barrier breakdown. These results indicate EphA2 may play a key role in ECM and could represent a distinguishing factor in the disparate disease phenotypes observed between these two malaria models.
In addition to CD8+ T cells, we address the role of platelets in the development of severe malaria using three different murine models of platelet dysfunction/depletion. We show that platelets are not required for control of blood-stage Plasmodium growth. On the contrary, platelet alpha-granules (a-granules) enhance parasite organ sequestration. In the absence of functional platelets, mice are protected from Plasmodium-associated lung and brain damage and death during ECM suggesting a key role for platelets and platelet a-granules, in particular, in mediating organ pathology during severe malaria.
Our findings reveal a key role for the receptor EphA2 and platelet a-granules in mediating CD8+T cell and platelet pathology in severe malaria. Given the increased incidence of malaria worldwide and paucity of CM and MA-ALI/ARDS treatment options, these observations could provide avenues into exploring novel therapeutics for this formidable disease.
Table of Contents
CHAPTER I Introduction..................................................................................................…….……….1-41
CHAPTER II EphA2 contributes to disruption of the blood-brain barrier in cerebral malaria…………........42-110
CHAPTER III Platelet a-granules contribute to organ-specific pathologies in a mouse model of severe malaria. 111-136
CHAPTER IV Discussion and Perspectives.…………………………...............................................................137-151
CHAPTER V Bibliography.………………………………..............................................................................152-200
APPENDIX Unpublished data…………................................................................................................201-209
Interferon-gamma: The Jekyll and Hyde of Malaria……......................................................210-216
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