Balancing in a black box: Potential immunomodulatory roles for TGF-β signaling during blood-stage malaria

ABSTRACT

Malarial disease caused by Plasmodium parasites challenges the mammalian immune system with a delicate balancing act. Robust inflammatory responses are required to control parasite replication within red blood cells, which if unchecked, can lead to severe anemia and fatality. However, the same inflammatory response that controls parasite replication is also associated with immunopathology and severe disease, as is exemplified by cerebral malaria. A robust literature has identified critical roles for innate, cellular, and humoral immune responses orchestrated by IFN-γ and T_H1 type responses in controlling blood stage malarial disease. In contrast, TGF-β and IL-10 have been identified as important anti–inflammatory immunomodulators that help to limit inflammation and pathology during malaria. TGF-β is a pleiotropic cytokine, with the ability to exert a wide variety of context-dependent immunomodulatory roles.

The specific mechanisms that allow TGF-β to protect against malarial pathology remain essentially unexplored and offer a promising avenue to dissect the most critical elements of immunomodulation in avoiding severe malaria. Here we discuss potential immunomodulatory roles for TGF-β during malaria in light of recent advances in our understanding of the role of Tregs during blood-stage malaria.

KEYWORDS:

• Malaria
• TGF-β
• inflammation

Acknowledgments

We apologize to all authors whose relevant work could not be cited due to space limitations. Work in the JTH lab is supported by NIH/NIAID grants AI42767, AI85515, AI100527 and AI114543. LLD is supported by T32AI007260.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the National Institutes of Health [AI42767]; National Institutes of Health [AI85515]; National Institutes of Health [AI007260]; National Institutes of Health [AI114543]; National Institutes of Health [AI100527].