Journal article
CD8(+) T cells target cerebrovasculature in children with cerebral malaria
The Journal of clinical investigation, Vol.130(3), pp.1128-1138
03/02/2020
DOI: 10.1172/JCI133474
PMCID: PMC7269583
PMID: 31821175
Abstract
BACKGROUND. Cerebral malaria (CM) accounts for nearly 400,000 deaths annually in African children. Current dogma suggests that CM results from infected RBC (iRBC) sequestration in the brain microvasculature and resulting sequelae. Therapies targeting these events have been unsuccessful; findings in experimental models suggest that CDEVT cells drive disease pathogenesis. However, these data have largely been ignored because corroborating evidence in humans is lacking. This work fills a critical gap in our understanding of CM pathogenesis that is impeding development of therapeutics.
METHODS. Using multiplex immunohistochemistry, we characterized cerebrovascular immune cells in brain sections from 34 children who died from CM or other causes. Children were grouped by clinical diagnosis (CM+ or CM-), iRBC sequestration (Seq(hi), Seq(lo), Seq(0)) and HIV status (HIV+ or HIV-).
RESULTS. We identified effector CD3(+)CD8(+)T cells engaged on the cerebrovasculature in 69% of CM+ HIV- children. The number of intravascular CD3(+)CD8(+)T cells was influenced by CM status (CM+ > CM- , P. 0.004) and sequestration level (Seq(hi) > Seq(lo), P = 0.010). HIV coinfection significantly increased T cell numbers (P = 0.017) and shifted cells from an intravascular (P = 0.004) to perivascular (P < 0.0001) distribution.
CONCLUSION. Within the studied cohort, CM is associated with cerebrovascular engagement of CD3(+)CD8(+)T cells, which is exacerbated by HIV coinfection. Thus, CO3(+)CD8(+)T cells are highly promising targets for CM adjunctive therapy, opening new avenues for the treatment of this deadly disease.
Details
- Title: Subtitle
- CD8(+) T cells target cerebrovasculature in children with cerebral malaria
- Creators
- Brittany A. Riggle - National Institute of Allergy and Infectious DiseasesMonica Manglani - Penn State Milton S. Hershey Medical CenterDragan Maric - National Institutes of HealthKory R. Johnson - Information Technology Program, Division of Intramural Research, and.Myoung-Hwa Lee - National Institute of Neurological Disorders and StrokeOsorio Lopes Abath Neto - NCI, Lab Pathol, NIH, Bethesda, MD 20892 USATerrie E. Taylor - University of MalawiKarl B. Seydel - University of MalawiAvindra Nath - National Institute of Neurological Disorders and StrokeLouis H. Miller - National Institute of Allergy and Infectious DiseasesDorian B. McGavern - National Institute of Neurological Disorders and StrokeSusan K. Pierce - National Institute of Allergy and Infectious Diseases
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.130(3), pp.1128-1138
- Publisher
- Amer Soc Clinical Investigation Inc
- DOI
- 10.1172/JCI133474
- PMID
- 31821175
- PMCID
- PMC7269583
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Number of pages
- 11
- Grant note
- Intramural Research Program of the National Institute of Allergy and Infectious Diseases, Laboratory of Immunogenetics National Institute of Neurological Disorders and Stroke of the National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS)
- Language
- English
- Date published
- 03/02/2020
- Academic Unit
- Pathology
- Record Identifier
- 9984277266302771
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