Cytokine gene polymorphisms implicated in the pathogenesis of Plasmodium falciparum infection outcome

Abstract

Cytokines play a critical role in the immune mechanisms involved in fighting infections including malaria. Polymorphisms in cytokine genes may affect immune responses during an infection with Plasmodium parasites and immunization outcomes during routine administration of malaria vaccines. These polymorphisms can increase or reduce susceptibility to this deadly infection, and this may affect the physiologically needed balance between anti-inflammatory and pro-inflammatory cytokines. The purpose of this review is to present an overview of the effect of selected cytokine gene polymorphisms on immune responses against malaria.

Keywords: cytokines; gene polymorphisms; immune response; pathogenesis; plasmodium.

Figure 1

Immune response mechanisms to malaria parasites at different stages in the host. (A1) Antibodies bind to inoculated sporozoites and prevent them from entering the blood circulation. (A2) Phagocytes present in the dermis recognise and phagocytose sporozoites. (A3) Antibodies against free sporozoites bind and neutralise proteins required for cell traversal and invasion such as CSP. The binding of these antibodies also activates complement fixation, phagocytosis, and lysis by cytotoxic cells. (B1) NK cells, Kupffer cells, and CD4+ dependent CD8+ T cells that produce interferon-γ upon parasite recognition, kill intrahepatic parasites through an antibody-dependent cell-mediated mechanism. (C1) Proinflammatory cytokines produced by CD4+ T helper cells activate macrophages, B cell clones and T cells. Macrophages differentiate into pro-inflammatory and anti-inflammatory M1 and M2 phenotypes respectively. These activated macrophages produced cytokines; pro-inflammatory cytokines kill malaria parasites directly. Together, the pro and anti-inflammatory cytokines activate T cells and specific B cell clones. (C2, C3) Antibodies bind to and coat the surface of infected erythrocytes and merozoites. This prevents their adhesion to the endothelium and the uptake and invasion of erythrocytes. It also enhances their phagocytosis and clearance. (C4) Interferon-gamma, perforins, and granzyme B produced by NK cells kill parasites in infected erythrocytes. (C5) Antibodies neutralize parasite toxins to reduce excessive inflammation. (C6) Antibodies bind to gametocytes which are killed through complement-mediated lysis and this prevents sequestration and maturation of gametocytes in the host. ,CSP, circumsporozoite protein; NK, Natural Killer. Created with BioRender.com.

Figure 2

Role of cytokines in the pathogenesis of malaria. Cells of the innate and adaptive immune system produce cytokines, where some have autocrine function. (A) IFN-γ produced by T cells activate macrophages that in-turn activate B cells to differentiate to plasma cells through the help of IL-6. Plasma cells then produce immunoglobulins which can switch classes with the help of IL-4. (E) The immunoglobulins then inhibit parasite growth. (B) Unique functional polymorphisms in cytokine genes of TNF-α, IL-4, IL-10, IL-13, IL-18 and CXCL8 increases susceptibility to malaria parasite development (F). (C) Normal plasma cytokines levels which are deemed to be protective, inhibit parasite development (G). (D) Functional polymorphisms in TNF-α, TGF-β, IL-1β, IL-6, IL-10, IL-13, IL-17 and IL-22 either cause increased or decreased production of these cytokines. (H) This may account for some of the pathologies and complications associated with malaria. Created with BioRender.com.