The most severe clinical complication of Plasmodium falciparum infection is cerebral malaria (CM) which has high morbidity despite treatment. The spread of malaria is becoming increasingly more serious as Plasmodium falciparum develops resistance to traditional drugs used to treat the condition. For the above reasons, understanding the etiology of CM is critical to treat this highly significant global issue. Recently, more rigorous large scale MRI studies have been conducted on CM patients. As previously hypothesized, disruption of the blood-brain barrier (BBB), extensive edema, and brain swelling are associated with fatal human CM. Given the above observations in human CM, the mechanism of BBB disruption and vascular permeability needs to be defined. Plasmodium berghei ANKA (PbA) infection of mice is an established model of human CM. Considerable CNS pathology associated with PbA infection is driven by an acute CD8 T cell response which induces disruption of BBB tight junction proteins and CNS vascular permeability. Using our novel MHC class I conditional knockout mice, we have determined that macrophages and dendritic cells prime non-equivalent CD8 T cell responses in response to PbA infection. While both antigen presenting cells prime CD8 T cell response that infiltrate the brain, only CD8 T cells raised by dendritic cells induce lethal blood-brain barrier disruption. Our central hypothesis is that specific APC subsets, namely macrophages, microglia, and dendritic cells, contribute to the generation distinct brain infiltrating CD8 T cell responses against PbA infection. These distinct CD8 T cell responses have differential ability to induce fatal BBB disruption. We plan to test this central hypothesis through execution of the following specific aims:
Specific Aim #1 ? Define the brain infiltrating CD8 T cell repertoire raised by LysM+ and CD11c+ APCs during acute PbA infection.
Specific Aim #2 ? Identify the CD11c+ APC required for CD8 T cell mediated BBB disruption.
Specific Aim #3 ? Determine the capacity of CD8 T cell populations primed by distinct antigen presenting cell types to inflict BBB disruption during the effector phase of PbA infection. The proposed work is innovative because it capitalizes on our unique transgenic mouse models, novel imaging methodology, and new core facilities available to our research program at Mayo Clinic. Our goal is to define mechanistically the contribution of inflammation to BBB disruption in experimental human CM through knowledge gained using a leading experimental model. Beyond the innovative methodology employed, the concept that antigen presenting cells raise differential CD8 T cell responses is a highly novel finding which warrants further investigation to a mechanism which is therapeutically targetable. This is especially important if one form of CD8 T cell priming in vivo is initiating lethal neurological disease.

Public Health Relevance

Blood-brain barrier disruption, brain swelling and edema were recently defined as biomarkers of disease severity in the first clinical studies using MRI in patients suffering from cerebral malaria. In this proposal, we use novel transgenic mice to present evidence that CD8 T cell induced lethal blood-brain barrier disruption is initiated through priming by discrete antigen presenting cell types. In this proposal, we will this ?nature verses nurture? hypothesis pertaining to how CD8 T cells induce BBB disruption in vivo using the Plasmodium berghei ANKA (PbA) model of experimental cerebral malaria.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Wong, May
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Mayo Clinic, Rochester
United States
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Willenbring, Robin C; Ikeda, Yasuhiro; Pease, Larry R et al. (2018) Human perforin gene variation is geographically distributed. Mol Genet Genomic Med 6:44-55
Malo, Courtney S; Huggins, Matthew A; Goddery, Emma N et al. (2018) Non-equivalent antigen presenting capabilities of dendritic cells and macrophages in generating brain-infiltrating CD8 + T cell responses. Nat Commun 9:633
Willenbring, Robin C; Johnson, Aaron J (2017) Finding a Balance between Protection and Pathology: The Dual Role of Perforin in Human Disease. Int J Mol Sci 18: