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Review
. 2023 Jan 4:13:1091961.
doi: 10.3389/fimmu.2022.1091961. eCollection 2022.

Host-parasite interactions during Plasmodium infection: Implications for immunotherapies

Pankaj Chandley  1 , Ravikant Ranjan  1 , Sudhir Kumar  2 , Soma Rohatgi  1
Affiliations
Review

Host-parasite interactions during Plasmodium infection: Implications for immunotherapies

Pankaj Chandley et al. Front Immunol. .

Abstract

Malaria is a global infectious disease that remains a leading cause of morbidity and mortality in the developing world. Multiple environmental and host and parasite factors govern the clinical outcomes of malaria. The host immune response against the Plasmodium parasite is heterogenous and stage-specific both in the human host and mosquito vector. The Plasmodium parasite virulence is predominantly associated with its ability to evade the host's immune response. Despite the availability of drug-based therapies, Plasmodium parasites can acquire drug resistance due to high antigenic variations and allelic polymorphisms. The lack of licensed vaccines against Plasmodium infection necessitates the development of effective, safe and successful therapeutics. To design an effective vaccine, it is important to study the immune evasion strategies and stage-specific Plasmodium proteins, which are targets of the host immune response. This review provides an overview of the host immune defense mechanisms and parasite immune evasion strategies during Plasmodium infection. Furthermore, we also summarize and discuss the current progress in various anti-malarial vaccine approaches, along with antibody-based therapy involving monoclonal antibodies, and research advancements in host-directed therapy, which can together open new avenues for developing novel immunotherapies against malaria infection and transmission.

Keywords: Plasmodium; antibody therapy; host-directed therapy; immune evasion; immunotherapeutics; vaccine candidates.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of malaria vaccine candidates during different developmental stages. (A) Pre-erythrocytic candidates (RTS,S/AS01, PfTRAP, PbCSP-TRAP, R21, AAV8-PfCSP, RAS, cryopreserved RAS-7DW85, RPL6, PfGAP3KO, PfSPZ-CVac (CQ), PfLARC GAP, PbVac). (B) Erythrocytic candidates MSP1, MSP2, GMZ2, MSP3-LSP, MSP8, MSP9, RAP-1, MSP119, PfEMP1, PfAMA1, PbAMA-1, PfCyRPA). (C), Sexual stage candidates (Pfs230, Pfs230D1-EPA, Pfs230p, Pfs25, Pfs25-EPA, Pfs48/45, Pfs48/45-6C, Pfs47, PfHAP2, PfHAP2p, PbHAP2, Pf77, PfMDV-1). (D) Mosquito stage candidates PM4, CHT1, CHT2, Pfs25, Pfs28, Pvs25, Pvs28, PfCelTOS, PbPSOP7, PbPSOP25, PbPSOP26, AnAPN1). Steps 1-14 show the malaria parasite life cycle which completes in four stages; pre-erythrocytic, erythrocytic, sexual, and mosquito stages. During the pre-erythrocytic stage, sporozoites are injected by an infected mosquito into the human host which then migrates to the liver and infects hepatocytes. Sporozoites start pre-erythrocytic schizogony by forming schizonts. Schizonts rupture and release merozoites into blood circulation. Merozoites invade erythrocytes which initiates the erythrocytic stage. Merozoites differentiate into different forms such as ring, trophozoite and schizont forms. Schizonts rupture and release either merozoites or gametocytes. Merozoites start the intraerythrocytic cycle while gametocytes undergo further development in the bone marrow. While inside bone marrow, the gametocytes differentiate into sequential gametocyte stages (Stage I-V). Stage V gametocytes move to peripheral circulation and are then picked up by the mosquito. Gametocytes develop in the mosquito midgut and differentiate into microgametes (male gametes) and macrogametes (female gametes). Fertilization takes place in the mosquito midgut which forms a short-lived zygote which transforms into a motile zygote, ookinete. The ookinete develops into an oocyst and sporozoite development starts within the oocyst. The oocyst ruptures and releases the sporozoites, which then invade the salivary glands of the mosquito. The life cycle of the malaria parasite restarts when the mosquitoes bite another human host. Created with BioRender.com.
Figure 2
Figure 2
Multiple antibody effector functions involved in immunity to malaria: (A) Antibodies to sporozoites can function through phagocytosis, complement activation, inhibition of sporozoite motility, inhibition of hepatocyte traversal and inhibition of hepatocyte invasion. (B) Antibodies to merozoites can function through phagocytosis, complement activation, promoting neutrophil respiratory burst, agglutination and inhibition of erythrocyte invasion. (C) Antibodies against infected erythrocytes function through phagocytosis, NK-cell mediated antibody-dependent cellular cytotoxicity (ADCC), agglutination, inhibition of endothelial invasion, inhibition of rosette formation, and schizont egress. (D) Antibodies during parasite sexual stages function through phagocytosis, complement activation, promoting TBA by blocking fertilization, inhibition of midgut invasion and inhibition of parasite development in the mosquito. Created with BioRender.com.
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