CD8 T cell mediated blood-brain barrier disruption promotes vascular leakage and edema in vital brain regions during experimental cerebral malaria

Abstract

Abstract Human cerebral malaria (HCM) is a serious lethal complication of Plasmodium falciparum infection. The most severe outcomes for patients include coma, permanent neurological deficits, and death. Recently, a large-scale MRI study in humans identified brain swelling as the most prominent indicator of fatal HCM. In this study, we sought to define the mechanism causing edema during cerebral malaria by utilizing the murine experimental cerebral malaria model (ECM). We determined that areas of blood-brain barrier (BBB) permeability colocalized with the disorganization of the tight junction proteins claudin-5 and occludin. Furthermore, we put together a magnetic resonance imagine (MRI) platform to analyze the murine brain. Through gadolinium enhanced T1-weighted MRI analysis we discovered that vascular permeability is not homogeneous, but rather confined to specific regions of the brain. Our findings show BBB permeability localized within the brain stem of Plasmodium berghei ANKA (PbA) infected C57BL/6 mice. This could explain hallmark symptoms of ECM such as strained respiration and impaired balance. Concurrently with the initiation of vascular permeability, T2 weighted MRI analysis shows edema and brain swelling during PbA infection. This correlates with the human disease and solidifies the ECM model as a useful system for mechanistic insight into HCM. Interestingly, mice lacking perforin are fully protected from vascular permeability and edema. We propose that CD8 T cells initiate BBB breakdown during ECM through disruption of tight junctions. In turn, vascular leakage into the brain parenchyma causes brain swelling and edema. This results in a breakdown of homeostatic maintenance that likely contributes ECM pathology.