Parasite Recognition and Signaling Mechanisms in Innate Immune Responses to Malaria

Abstract

Malaria caused by the Plasmodium family of parasites, especially P.falciparum and P. vivax, is a major health problem in many countries in the tropical and subtropical regions of the world. The disease presents a wide array of systemic clinical conditions and several life-threatening organ pathologies, including the dreaded cerebral malaria. Like many other infectious diseases, malaria is an inflammatory response-driven disease, and positive outcomes to infection depend on finely tuned regulation of immune responses that efficiently clear parasites and allow protective immunity to develop. Immune responses initiated by the innate immune system in response to parasites play key roles both in protective immunity development and pathogenesis. Initial pro-inflammatory responses are essential for clearing infection by promoting appropriate cell-mediated and humoral immunity. However, elevated and prolonged pro-inflammatory responses owing to inappropriate cellular programming contribute to disease conditions. A comprehensive knowledge of the molecular and cellular mechanisms that initiate immune responses and how these responses contribute to protective immunity development or pathogenesis is important for developing effective therapeutics and/or a vaccine. Historically, in efforts to develop a vaccine, immunity to malaria was extensively studied in the context of identifying protective humoral responses, targeting proteins involved in parasite invasion or clearance. The innate immune response was thought to be non-specific. However, during the past two decades, there has been a significant progress in understanding the molecular and cellular mechanisms of host-parasite interactions and the associated signaling in immune responses to malaria. Malaria infection occurs at two stages, initially in the liver through the bite of a mosquito, carrying sporozoites, and subsequently, in the blood through the invasion of red blood cells by merozoites released from the infected hepatocytes. Soon after infection, both the liver and blood stage parasites are sensed by various receptors of the host innate immune system resulting in the activation of signaling pathways and production of cytokines and chemokines. These immune responses play crucial roles in clearing parasites and regulating adaptive immunity. Here, we summarize the knowledge on molecular mechanisms that underlie the innate immune responses to malaria infection.

Keywords: host receptors; immunostimulatory factors; innate immune responses; malaria; pathogenesis; protective immunity; signaling mechanisms.

Figure 1

PAMP-PRR interaction-induced signaling pathways. (A) RNA of the liver stage parasites growing inside hepatocytes is recognized by MDA5 leading to the activation of MAVS-TBK1-IRF3/IRF7 signaling and downstream production of type I IFNs. (B) At the blood stage infection, parasite DNA, RNA and GPI interact with, respectively, TLR9, TLR7, and TLR2, leading to the activation of primarily MAPK and NF-κB signaling pathways and downstream cytokine and chemokine responses. In the cytosol, similar to the liver stage parasite RNA, the blood stage parasite RNA is sensed by MDA5 leading to the activation of MAVS-TBK1-IRF3/IRF7 signaling (see A). However, this signaling seems induce the expression of SOCS1, which downregulate RNA-TLR7-induced type I IFN production (81). Parasite DNA in the cytosol is sensed by cGAS, resulting in the activation of STING-TBK1-IRF3 signaling and type I IFN response. Parasite DNA also activates AIM2 inflammasome, which cleaves pro-caspase 1 to activate caspase 1. Hemozoin (Hz) and uric acid (UA) induce danger signaling, activating NLRP3 inflammasome and the cleavage of pro-caspase 1 to activate caspase 1. Parasites have also been reported to activate NLRP12 inflammasome through unidentified interaction, leading to the cleavage of pro-caspase 1 to activate caspase 1 (44, 82). It appears that microparticles released from IRBCs and heme produced during infection activate TLR4 signaling (83, 84). Ligands bind to TLR4 homodimer through the cooperation of accessory proteins CD14 and MD2, leading to MAPK, NF-κB and TRIF-TBK1-IRF3 signaling. Note: the diagram depicts a simplified version of indicated signaling pathways and additional details can be found in review articles (, –70). The abbreviations are defined in footnote in page 1.

Figure 2

Illustration of predicted pathways activated by the binding of PfEMP 1 expressed on the IRBC surface to CD36 (A), ICAM-1 (B) and EPCR (C). (A) Interaction of PfEMP1 on the surface of IRBC with CD36 on the surface of macrophages. SFK, Src family of protein tyrosine kinases; Syk, spleen tyrosine kinase; Fyn, proto-oncogene tyrosine protein kinase Fyn; MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal-regulated kinase 1 and 2; JNK, c-Jun N-terminal kinase; Vav1/Vav2, Vav family of guanine nucleotide exchange factors; PLCγ2, phospholipase Cγ2 (151). (B) Interaction of PfEMP1 on the surface of IRBC with ICAM-1 on the surface of endothelial cells surface. PKC, protein kinase C; Src, proto-oncogene tyrosine-protein kinase Src; PI3K, Phosphatidyl inositol 3-kinase; Akt, RAC-alpha serine/threonine-protein kinase (152). (C) Interaction of EPCR on the surface of endothelial cells with PfEMP1 on the surface of IRBCs (–155). EPCR, endothelial protein C receptor; TM, thrombomodulin; T, thrombin; APC, Activated protein C; PAR1, protease-activated receptor 1; RhoA, Ras homolog gene family, member A GTAase.