Cerebral malaria pathogenesis: Dissecting the role of CD4⁺ and CD8⁺ T-cells as major effectors in disease pathology

Abstract

Cerebral malaria (CM) is a severe complication of Plasmodium falciparum (P. falciparum) infection, with complex pathogenesis involving multiple factors, including the host’s immunological response. T lymphocytes, specifically CD4+ T helper cells and CD8+ cytotoxic T cells, are crucial in controlling parasite growth and activating cells for parasite clearance via cytokine secretion. Contrary to this, reports also suggest the pathogenic nature of T lymphocytes as they are often involved in disease progression and severity. CD8+ cytotoxic T cells migrate to the host’s brain vasculature, disrupting the blood-brain barrier and causing neurological manifestations. CD4+ T helper cells on the other hand play a variety of functions as they differentiate into different subtypes which may function as pro-inflammatory or anti-inflammatory. The excessive pro-inflammatory response in CM can lead to multi-organ failure, necessitating a check mechanism to maintain immune homeostasis. This is achieved by regulatory T cells and their characteristic cytokines, which counterbalance the pro-inflammatory immune response. Maintaining a critical balance between pro and anti-inflammatory responses is crucial for determining disease outcomes in CM. A slight change in this balance may contribute to a disease severity owing to an extreme inflammatory response or unrestricted parasite growth, a potential target for designing immunotherapeutic treatment approaches. The review briefly discusses the pathogenesis of CM and various mechanisms responsible for the disruption of the blood-brain barrier. It also highlights the role of different T cell subsets during infection and emphasizes the importance of balance between pro and anti-inflammatory T cells that ultimately decides the outcome of the disease.

SUMMARY

CM is potentially fatal complication of P. falciparum infection that presents with high mortality and morbidity. Vaccines are extensively being developed against the Plasmodium parasite but very few of them are effective. Artemisinin Combination Therapy (ACT) is a major treatment for malaria, but its effectiveness is declining due to Plasmodium sp. developing resistance to it, necessitating the need for development of new drugs and treatments. During infection, the parasite is responsible for causing infected red blood cell (RBC) sequestration and cytoadherence in brain vasculature and extreme pro-inflammatory response that ultimately causes endothelial dysfunction and bloodbrain barrier (BBB) disruption. The host initiates a pro-inflammatory response against the parasite which includes activation of cells of both innate and adaptive immune response. These cells control the parasite growth and aid in parasite clearance from host’s body. The inflammatory response generally targets foreign pathogens and provides protection against possible infection but can also cause harm to the self when left unchecked. It has been reported that activated immune cells, mainly T-lymphocytes often migrate to brain vasculature and ultimately results in neuronal damage characteristic CM. To counteract the overwhelming pro-inflammatory response, the host immune system deploys an anti-inflammatory response, which often involves regulatory cells and cytokines that help the body maintain immunological homeostasis. The review briefly highlights the necessity of balancing the pro- and anti-inflammatory responses for successful parasite clearance without the deleterious effects to the host that might increase disease severity in CM.

Graphical Abstract

Keywords:

• Blood-brain barrier (BBB)
• CD4+ T- cells and CD8+ T-cells
• cerebral malaria (CM)
• immunopathogenesis
• parasitized RBCs (pRBCs)

Acknowledgements

We are thankful to ICMR National Institute of Malaria Research (ICMR-NIMR) for infrastructural support. Indu Sharma is recipient of junior research fellowship from Department of Biotechnology (DBT) Govt. of India. Poonam Kataria is recipient of junior research fellowship from university grant commission (UGC) Govt. of India. We also thank to all lab members for their generous support during this work.

Authors’ contributions

IS and JD designed the original idea and developed it in detail, reviewed the literature and wrote the manuscript. IS generated all the figures and arranged references. PK provided valuable feedback, and helped to revise and edit the manuscript.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.