Perforin Expression by CD8 T Cells Is Sufficient To Cause Fatal Brain Edema during Experimental Cerebral Malaria

Abstract

Human cerebral malaria (HCM) is a serious complication of Plasmodium falciparum infection. The most severe outcomes for patients include coma, permanent neurological deficits, and death. Recently, a large-scale magnetic resonance imaging (MRI) study in humans identified brain swelling as the most prominent predictor of fatal HCM. Therefore, in this study, we sought to define the mechanism controlling brain edema through the use of the murine experimental cerebral malaria (ECM) model. Specifically, we investigated the ability of CD8 T cells to initiate brain edema during ECM. We determined that areas of blood-brain barrier (BBB) permeability colocalized with a reduction of the cerebral endothelial cell tight-junction proteins claudin-5 and occludin. Furthermore, through small-animal MRI, we analyzed edema and vascular leakage. Using gadolinium-enhanced T1-weighted MRI, we determined that vascular permeability is not homogeneous but rather confined to specific regions of the brain. Our findings show that BBB permeability was localized within the brainstem, olfactory bulb, and lateral ventricle. Concurrently with the initiation of vascular permeability, T2-weighted MRI revealed edema and brain swelling. Importantly, ablation of the cytolytic effector molecule perforin fully protected against vascular permeability and edema. Furthermore, perforin production specifically by CD8 T cells was required to cause fatal edema during ECM. We propose that CD8 T cells initiate BBB breakdown through perforin-mediated disruption of tight junctions. In turn, leakage from the vasculature into the parenchyma causes brain swelling and edema. This results in a breakdown of homeostatic maintenance that likely contributes to ECM pathology. Approximately 70% of fatal malaria cases occur in children less than 5 years old (1). While uncomplicated Plasmodium falciparum infection is highly treatable, the most severe complication, cerebral malaria, presents a significant problem for patients. Human cerebral malaria (HCM) is characterized by disruption of the blood-brain barrier (BBB), coma, seizures, and death (2, 3). Patients that survive HCM are prone to persisting cognitive and neurological deficits after they have recovered from the infection (4, 5). While antimalarial drugs have shown efficacy in killing parasites, treatments to improve the outcome of HCM are lacking (6). Furthermore, the cellular mechanisms regulating

Erg mediates downregulation of claudin‐5 in the brain endothelium of a murine experimental model of cerebral malaria

“…The reduction in claudin-5 contributes to an increased permeability of BBB during the progression of CM [7]. Our results provide further evidence that mRNA and protein levels of claudin-5 are reduced in in vivo and in vitro models of mouse ECM.…”

“…An elevated intracranial hypertension was observed in 75–80% of African children with CM, who either died or survived with neurological sequelae . The high intracranial pressure in CM is partially caused by increased vascular permeability and brain edema . During progression of CM, accumulation of infected red blood cells (iRBCs) and immune cells in cerebral vessels induces malfunction of the blood–brain barrier (BBB) , leading to a fatal outcome .…”

Microglia in neuropathology caused by protozoan parasites

“…In vivo in mice it was shown that parasite-specific CD8 + T cells interact with endothelial cells in an interferon-gamma (IFN-γ ) dependent manner, and that this was responsible for activating endothelial cells in the brain microvasculature (Swanson et al, 2016). Moreover, CD8 + T cells expressing perforin were responsible for vascular permeability breakdown inducing brain swelling and oedema (Huggins et al, 2017). Therefore, although cerebral malaria is primarily a problem of a disrupted blood supply to the brain, the CNS can be affected in a broader sense and is likely to be protected by its defense machinery, including the microglia.…”

Severe and multifaceted systemic immunosuppression caused by experimental cancers of the central nervous system requires release of non-steroid soluble mediators

“…Next, we assessed thymi during TMEV infection in C57BL/6 mice. C57BL/6 mice clear TMEV infection within 21-45 days post infection (15,16,20,48). Because C57BL/6 mice mount an effective antiviral CD8 T cell response, this model allows us to determine whether thymic involution is reversible upon viral clearance (20,74).…”