Figure 2.

The role of innate immune cells during African trypanosomiasis. During early trypanosome infection, a strong Th₁ immune response is initiated by the host. In the skin, neutrophils and NK cells are the first to respond to trypanosomal pathogen-associated molecular patterns (PAMPs), such as VSG and CpG DNA. Neutrophils are heavily involved in repairing the initial wound caused by the tsetse fly bite and also produce pro-inflammatory IL-1β and IL-6. NK cells produce pro-inflammatory TNF and IFN-γ that results in the classical activation of pro-inflammatory macrophages (Mθ) via iNOS activation. Macrophages can also be activated through interactions with trypanosomal PAMPs. Classically activated macrophages produce further pro-inflammatory molecules, including TNF, nitric oxide (NO), and reactive nitrogen intermediates (RNIs) and reactive oxygen intermediates (ROIs). These chemicals can directly kill trypanosomes in extravascular spaces and tissues and allows for parasite control. Macrophage secretion of TNF can also recruit and activate T cells which self-renew via autocrine IL-2 secretion. T cells produce IFN-γ to further activate macrophages and IL-4 to activate B cells. Macrophages and dendritic cells (DCs) will further activate B cells during a Th₁ response, via IL-6, IL-12, and IFN-γ, to promote the production of antibodies that can target the VSG trypanosomes, inducing waves of parasite clearance in the bloodstream. However, antigenic variation hinders the effective clearance of trypanosome populations. Macrophages can also become alternatively activated, resulting in a Th2 immunosuppressive response. Cytokines such as IL-10, IL-4, and TGF-β initiate this type of response by promoting arginase activation in macrophages. As a result, alternatively activated macrophages produce immunosuppressive IL-10 and suppress production of trypanostatic NO and IFN-γ. This promotes parasite growth and survival, leading to a chronic infection.