Accelerator or Brake: Immune Regulators in Malaria

Abstract

Malaria is a life-threatening infectious disease, affecting over 250 million individuals worldwide each year, eradicating malaria has been one of the greatest challenges to public health for a century. Growing resistance to anti-parasitic therapies and lack of effective vaccines are major contributing factors in controlling this disease. However, the incomplete understanding of parasite interactions with host anti-malaria immunity hinders vaccine development efforts to date. Recent studies have been unveiling the complexity of immune responses and regulators against Plasmodium infection. Here, we summarize our current understanding of host immune responses against Plasmodium-derived components infection and mainly focus on the various regulatory mechanisms mediated by recent identified immune regulators orchestrating anti-malaria immunity.

Keywords: immune regulators; immune responses; malaria; protective immunity; signaling mechanisms; type I interferon.

Figure 1

Immune responses elicited by Plasmodium infection. During malaria infection, different PAMPs secreted from merozoites can be sensed by PRRs and activate the innate immunity (left panel). cDCs, macrophages, and pDCs are the crucial innate immune cells to defend malaria infection. Within the cytosol of these cells, pathogenic RNA interacts with MDA5 and recruits the adaptor protein MAVS, and Plasmodium gDNA can be detected by cGAS or other DNA sensors to activate adaptor protein STING. Both MAVS and STING could recruit serine/threonine-protein kinase TBK1 to phosphorylate IRF3 which translocate to nucleus and induce the expression of IFN-I. Furthermore, parasitic nucleic acid gDNA can also be sensed by inflammasome sensors AIM2, whereas haemozoin and uric acid activates NLRP3, leading to activation of inflammasomes and Caspase-1, which cleave pro-IL-1β and pro-IL-18 to form mature IL-1β and IL-18. Besides, parasite glycosylphosphatidylinositol (GPI) anchors to TLRs, including TLR2-TLR6 or TLR1-TLR2 heterodimers and TLR4 homodimers. TLRs signal transduces through MyD88, which finally causes the activation of NF-κB and MAPKs, and induces the secretion of pro-inflammatory cytokines, such as TNF-α and IL-6, as well as chemokines. Specifically, both CpG and hemozoin-combined gDNA can induce TLR9 translocation, and TLR7 can sense parasite RNA in the endosome of pDCs during the early infection stage, TLR9 as well as TLR7 recruit adaptor protein MyD88 and kinases TRAFs to phosphorylate IRF7 and induce the early robust production of IFN-I. After the innate immune responses, DC acts as a vital APC receiving stimulation via cytokines described upon, is activated and presents the antigens to naïve T cell through combination of MHC and TCR, which builds a bridge between innate and adaptive immunity. During adaptive immunity (right panel), naïve T cells differentiate into different subtypes with unique functions in anti-malaria immunity. Tfh, Th1, and Th17 could facilitate function of B cells, while Treg and IL-10⁺/IL-27⁺ CD4⁺ T cell can suppress B cell function; CD8⁺ T cells mainly express IFN-γ, and leaving function of Th2 is still uncertain. Activated DCs can also secrete IL-12 to promote the expression of IFN-γ from NK cell, which can enhance function of Th1 and macrophage thus help B cells to secrete antibody. Besides, IL-2 produced by Th1 can help NK cell to kill parasites. The diagram depicts a simplified version of indicated signaling pathway and immune cells involved in anti-malaria immunity. The abbreviations are defined in footnote.

Figure 2

Immune regulators in anti-malaria immunity. Anti-malaria immunity is tightly regulated by cytosolic and cell surface molecules at multiple levels. Negative regulators within cytosol. As a negative molecule binds to MyD88, SOCS-1 can not only suppress the NF-κB and MAPKs signaling, but also inhibits MyD88-mediated IFN-I signaling. MARCH1 can reduce IFN-I through increasing expression of SOCS-1. Besides, its target proteins, MAVS, STING, and TBK1, possibly are degraded through ubiquitination. FOSL1 inhibits the K63 ubiquitination of TRAF3 and TRIF and disrupts TBK1/TRAF3/TRIF complexes formation, which results in reduced phosphorylation of IRF3 and suppresses IFN-I production. RTP4 inhibits the expression of TBK1 and IRF3 and/or activation by binding with TBK1 to reduce IFN-I production. Negative regulators on the cell membrane. Binding of ICAM1 and PfEMP leads to static adhesion of parasite and evades immune clearance. LAG3 inhibits T cell responses and antibody secreting B cell responses. CTLA-4 expressed on activated T cells could suppress the CD4⁺ Th and humoral immune responses. TIM3 can inhibit T lymphocytes, NK cells, and macrophages responses. TIGIT proteins mainly suppress the function of T cell and NK cell. The activation of PD-1 pathway dramatically inhibits TCR-mediated proliferation and function of T cells. Positive regulators on the cell membrane. CD40 could compete with STING to bind TRAF2/3 and/or TRAF6 to reduce STING ubiquitination, which leads to increased expression of IFN-I. CD28 can enhance CD4⁺ T cell responses, but the CD28-B7 signals can also be inhibited by BTNL2. OX40 enhances Plasmodium specific CD4 T cell activity. B220 expressed on the surface of B and T cells can help promoting the maturation of both T and B cell.