CD8+ T cells target cerebrovasculature in children with cerebral malaria
Brittany A. Riggle, Monica Manglani, Dragan Maric, Kory R. Johnson, Myoung-Hwa Lee, Osorio Lopes Abath Neto, Terrie E. Taylor, Karl B. Seydel, Avindra Nath, Louis H. Miller, Dorian B. McGavern, Susan K. Pierce
Brittany A. Riggle, Monica Manglani, Dragan Maric, Kory R. Johnson, Myoung-Hwa Lee, Osorio Lopes Abath Neto, Terrie E. Taylor, Karl B. Seydel, Avindra Nath, Louis H. Miller, Dorian B. McGavern, Susan K. Pierce
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Clinical Research and Public Health Infectious disease Neuroscience

CD8+ T cells target cerebrovasculature in children with cerebral malaria

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 CD8+ T 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 (Seqhi, Seqlo, Seq0) 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 (Seqhi > Seqlo, 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, CD3+CD8+ T cells are highly promising targets for CM adjunctive therapy, opening new avenues for the treatment of this deadly disease.FUNDING This research was supported by the Intramural Research Program of the National Institutes of Health.

Authors

Brittany A. Riggle, Monica Manglani, Dragan Maric, Kory R. Johnson, Myoung-Hwa Lee, Osorio Lopes Abath Neto, Terrie E. Taylor, Karl B. Seydel, Avindra Nath, Louis H. Miller, Dorian B. McGavern, Susan K. Pierce

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Figure 6

Activated CD68+IBA1+ monocytes/macrophages in the venous cerebrovasculature.

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Activated CD68+IBA1+ monocytes/macrophages in the venous cerebrovasculat...
Representative images of brain sections from CM+ Seqhi HIV–, CM+ Seqlo HIV–, and CM– Seq0 HIV– (A) patients and CM+ Seqhi HIV+, CM+ Seqhi HIV–, and CM– Seq0 HIV+ (E) patients. Images show the distribution of IBA1+ (green), CD68+ (red) monocytes/macrophages in relation to CD31+ (white) cerebrovasculature and DAPI-stained cell nuclei (blue). Yellow asterisks denote the vascular lumen. Scale bars: 20 μm. Normalized counts of luminal, abluminal, and total CD68+IBA1+ inflammatory monocytes/macrophages/vessel area (log2((number of cells/μm2/104) + 2) in the same ROIs used previously are given in B–D and F–H. Each symbol represents the number of CD68+IBA1+ cells/vessel area for each of the 20 vessels examined per child. There were significantly more activated monocytes/macrophages luminally in CM+ (n = 8) versus CM– (n = 7) children (B, FDR P < 0.0001). CM+ Seqlo HIV– in B–D, n = 5. This is also reflected when comparing total cell numbers between both groups (D, FDR P < 0.030). Comparison of CM patients with (n = 8) and without (n = 8) HIV shows that CM alone promotes recruitment of activated monocytes/macrophages on the luminal aspect of cerebrovasculature (F, FDR P < 0.006). This observation is also evident when comparing CM+ Seqhi HIV– and CM– Seq0 HIV+ (n = 4) patients (F, FDR P < 0.002). P values were obtained via post hoc analysis using the difflsmeans function under FDR correction conditions following mixed-effects modeling with the lmer function. Significant differences remained so under bootstrap conditions 100% of the time when any single vessel normalized cell count was removed or when all vessels for any 1 child were removed. Error bars: mean ± SD. Asterisks denote statistical significance: FDR *P ≤ 0.05; **P ≤ 0.01; ****P < 0.0001.