Interferon Gamma in African Trypanosome Infections: Friends or Foes?

Abstract

African trypanosomes cause fatal infections in both humans and livestock. Interferon gamma (IFN-γ) plays an essential role in resistance to African trypanosomes. However, increasing evidence suggests that IFN-γ, when excessively synthesized, also induces immunopathology, enhancing susceptibility to the infection. Thus, production of IFN-γ must be tightly regulated during infections with African trypanosomes to ensure that a robust immune response is elicited without tissue destruction. Early studies have shown that secretion of IFN-γ is downregulated by interleukin 10 (IL-10). More recently, IL-27 has been identified as a negative regulator of IFN-γ production during African trypanosome infections. In this review, we discuss the current state of our understanding of the role of IFN-γ in African trypanosome infections. We have focused on the cellular source of IFN-γ, its beneficial and detrimental effects, and mechanisms involved in regulation of its production, highlighting some recent advances and offering some perspectives on future directions.

Keywords: Trypanosoma brucei; Trypanosoma congolense; immunopathology; interferon gamma; protection.

Figure 1

Role and regulation of interferon gamma (IFN-γ) during infection with African trypanosomes. Regulation: CD4⁺ T cells (, , –24), CD8⁺ T cells (–20), NK cells (18), and NKT cells (18) produce IFN-γ during infection with African trypanosomes. African trypanosomes activate mononuclear phagocytes to secrete IL-12 through TLR9 and MyD88 signaling (25). IL-12 stimulates CD4⁺ T cells to produce IFN-γ via activation of STAT4 signaling (26), whereas IL-27 inhibits CD4⁺ T cells to secrete IFN-γ (24). Interleukin 10, mainly synthesized by CD4⁺ (22, 23, 27) and myeloid cells (28), inhibits IFN-γ production through downregulation of the secretion of IL-12 by direct modulation of mononuclear phagocytes (2). Protective role: IFN-γ enhances Kupffer cell phagocytosis of trypanosomes circulating in the bloodstream (12, 13). IFN-γ also promotes M1 myeloid cells to produce TNF-α and nitric oxide, which mediate parasite lysis (, –31). Detrimental effects: excessive secretions of IFN-γ lead to liver pathology (12, 24, 26, 32) and activation of erythrophagocytic myeloid cells, resulting in anemia (18).