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.
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
Submitter: Ya ZHAO | zhaoya@fmmu.edu.cn
Authors: Ya ZHAO, Jun WANG, and Yan SHEN
Department of Medical Microbiology and Parasitology, Fourth Military Medical University, Xi'an, China
Published January 14, 2021
Riggle et al. characterized cerebrovascular immune cells in brain sections from 34 children who died of CM. Their findings illuminated the potential mechanism that CD8+ T cells play an essential role in the development of CM, as evidenced by the similarities between the distribution of CD8+ T cells in the brains of children CM and that of mice ECM. (1-3). Virtually, we also administered PDL1 fusion protein targeting overactivated CD8+ T cells to ECM mice and prolonged their survival time significantly(4).
It is accepted that the amount of CD8+ T cells infiltrated into the brain parenchyma is one of the hallmarks of BBB disruption during ECM. The evidence derived merely from the multiplex immunohistochemistry in the brain slices may be slightly insufficient to illustrate the real distribution and engagement of CD8+ T cells, especially when it comes to the spatial relationship with cerebral vessels. Hence, we suggest that the author try continuous thin slices scanning combined with digital 3D reconstruction technology to examine whether the CD8+ T cells infiltrate into the abluminal of cerebrovasculature or not.
Moreover, the author claimed that HIV co-infection promoted CD8+ T cells “shift” from intravascular luminal to abluminal in the brain. The “shift” ability suggested that CD8+ T cells activity was enhanced after HIV infection. It seemed to be contradictory with the conventional cognition that HIV destroys the host immune responses. Interestingly, a lot of evidence indicated that human immune system might presented a status called “abnormal activation” which featured the upregulation of many biomarkers related to immune cell activation after HIV infection. Research demonstrated that the abnormal activation of human immune system was closely positive correlation with the patients’ viral load(5-7). Additionally, some research indicated that HIV infection led to the exhaustion of the immune system(8, 9). Therefore, we speculate that the increase of abluminal CD8+ T cells in the brain of children CM patients co-infected with HIV could be considered as some kind of “exhausted-like” overactivation status of T cells. Maybe the “seemingly contradictory” phenomenon could be better explained by confirming the more specific period of the patient HIV infection and the activity status of their CD8+ T cells at that time.
In summary, we are pleased to find that our previous research results of ECM model have been verified by this article. Applying PDL1 fusion protein to repress the overactivated CD8+ T cell may become a promising adjunctive therapy for CM.
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