Malaria is caused by Plasmodium parasites and is commonly thought of as a disease resulting from the cyclic infection and destruction of red blood cells. However, a subset of infected individuals will develop “cerebral malaria”—a pathogenic neuroinflammation, presumably caused by parasitized red blood cells sequestering in the brain. Those affected, usually children under the age of five, can die or suffer permanent cognitive impairment long after successful treatment of infection. The exact causes of cerebral malaria are poorly understood, but mouse models of experimental cerebral malaria have identified CD8+ T cells as key players in the development of this debilitating condition.

In this issue, Kennedy et al. used an unbiased genome-wide screen of ENU-mutagenized mice to identify a novel gene, Ccdc88b, that influences T cell activation and function and that is associated with resistance to cerebral malaria following infection with the mouse malaria parasite Plasmodium berghei. They found Ccdc88b to be expressed in T cells and myeloid cells. T cells from Ccdc88b−/− knockout mice were impaired in their ability to become activated and to secrete effector cytokines in response to stimulation via their T cell receptor. Importantly, unlike T cells from wild-type mice, adoptive transfer of T cells from knockout mice did not confer cerebral malaria to recipient mice.

With over 300 million malaria infections each year, cerebral malaria causes substantial mortality. Understanding the molecular and cellular etiology of cerebral malaria will lead to better identification and treatment of those most at risk. Furthermore, CD8+ T cells have a duplicitous role in malaria infection—both helping to clear the parasite from the liver and blood and in orchestrating the damaging neuroinflammation seen in cerebral malaria. Understanding the events leading to a pathogenic T cell response could also help inform the design of malaria vaccines that eliminate, but do not exacerbate, disease.

The authors’ work also extends beyond models of malaria, as a region in the human genome that contains Ccdc88b has been implicated in autoimmune disorders such as inflammatory bowel disease, multiple sclerosis, and Crohn’s disease. This further supports the idea that Ccdc88b is a novel and important regulator of immune function. It will be fascinating to confirm the role of Ccdc88b in other immune disease models and to determine whether this pathway could be manipulated to quell overzealous T cells in malaria pathogenesis and beyond.

References

Kennedy
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J.M.
, et al
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2014
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J. Exp. Med.
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