Immune Receptors Interaction and Plasmodium falciparum.
Phagocytic assembly mechanisms contribute significantly to host-immune interactions with Plasmodium falciparum . The effective roles of antigen-presenting cells (DCs, MQs) rapidly occur after sensing P. falciparum sporozoites (SPZ) and cells boosting the expression markers of phagocytic activities [18]. The importance of Plasmodium falciparum proteins or molecules is represented in the efficient contribution in remodelling the host cells and malaria pathogenesis, and P. falciparum infection alters innate immune cell response mechanisms, including modulation of DCs, monocytes, and macrophages, impacting the proinflammatory response [19,20].
Plasmodium falciparum triggers innate immune cell responses through specific immune sensation receptor interactions by Plasmodium antigens that promote cellular hyperresponsiveness immune regulation, which involves epigenetic modifications, signalling pathways, and pro-inflammatory cytokine production [21,22]. Plasmodium falciparum GPI anchors and hemozoin stimulate innate immune responses via the TLR family to activate pro-inflammatory pathways in host macrophages and DCs through MyD88-dependent signalling [23]. PfEMP1 in Plasmodium falciparum -infected erythrocytes plays a significant role in immune sensation and recognition, contributing to host innate immunity against malaria [24]. The recognition of infected RBCs (IEs) by P. falciparum and malaria molecules occurs through phagocytic cells and induces a hyper-responsive state characterized by the activation of the promoter gene (H3K4me3) [25].
Plasmodium falciparum -infected red blood cells (IEs) have been investigated and the interaction process was noticed to take place through the lipid phosphatidylserine (PS) on the surface of IEs and CD36 binding receptor on the phagocytes [26]. Research has demonstrated that IEs or P. falciparum hemozoin stimulates peripheral blood mononuclear cells (PBMCs) to be hyperresponsive to Toll-like receptor (TLR) interactions (Figure 1 ), which can recognize IEs and P. falciparum through cyclic GMP-AMP synthase (cGAS) [27]. Other in vitro experiments have clarified that phagocytes recognize IEs through neoantigens inserted during P. falciparum advancement, expanding phagocytic activities, particularly with the contribution of Fc receptors [28]. The parasite also stimulates the production of autoantibodies and activation of complement system molecules (C3) for better identification of plasmodium pathogens [29]. Phagocyte recognition mechanisms may take a different approach but share a common purpose.
The interactions of Phagocytic cells with infected erythrocytes (IEs) and parasite particles take place in a particular form during malaria infection. Phagocytic cells such as monocytes and macrophages interact with infected erythrocytes and parasite particles via opsonic and non-opsonic phagocytosis, which aids in parasite clearance and immune response regulation. Studies have shown that opsonic antibodies bind to late-stage Plasmodium falciparum-infected erythrocytes, promoting their phagocytic uptake through Fcγ receptors, followed by IEs ingestion and destruction within phagolysosomes and by producing nitric oxide and oxygen radicals [16,30,31]. In addition, Phagocytic cells interact with non-opsonic infected erythrocytes through CD36 receptor, implicating scavenger receptors in the clearance of ring-stage Plasmodium falciparum, highlighting innate defense against malaria [32]. Phagocytic cells in the spleen interact with infected erythrocytes by preferentially phagocytosing immature parasite forms, demonstrating splenic trapping, pitting, and destruction of both infected and noninfected erythrocytes [33,34]. These findings highlight the complex interaction between phagocytic cells and infected erythrocytes or parasite particles, providing insight into immunity and pathogenesis.
Phagocytosis-induced signalling in P. falciparum infection involves the activation of host cell signalling pathways, including PKC, RAS-ERK, Ca+2, NF-κB signalling, at different parasite stages, hemozoin, immune complexes, and IEs [22]. These signalling events are induced by several receptor-mediated phagocytic processes, such as TLR, CD36, FcγR, CR3 (Table 1 ), and mannose receptors[35]. There are important integrated receptors for the phagocytic process; however, their roles in P. falciparum infection are still not well understood.
The Phagocyte engulfment of Plasmodium falciparum -infected erythrocytes (IEs) and parasite molecules involves complex dynamic immune mechanisms and critical components of the innate immune response. The engulfment process is influenced by the presence of curved membrane-bound protein complexes (CMC) and actin polymerization, which aid in reducing the bending energy cost and promoting quicker engulfment [36]. Plasmodium-infected erythrocytes undergo oxidative changes, leading to hemichrome formation, band 3 aggregation, complement and IgG deposition, enhancing phagocytosis [37]. Opsonization of infected erythrocytes interacts with Fc receptor-mediated phagocytosis, enhancing inflammasome activation and pro-inflammatory cytokine secretion, while later parasite forms are recognized by non-opsonic receptors, such as CD36 [38]. This process aids in maintaining low parasitemia and preventing malaria complications. The phagocytosis process of IEs aims to eliminate these cells and utilize the nutrient components of the host cell, in which macrophages (MQs) are mainly responsible for parasitemia reduction and enhanced survival [39]. A critical step in Malaria pathogenesis and cerebral malaria development involves the interaction between intercellular adhesion molecule 1 (ICAM-1) and endothelial protein C receptor (EPCR) mediates binding of Plasmodium falciparum-infected erythrocytes to endothelial cells [40]. Phagocytic responses to Plasmodium falciparum involve intricate immunomodulatory mechanisms. Studies have shown that phagocyte-specific subpopulations, parasite ligands, and opsonin-like antibodies modulate the effective phagocytic response against IEs [41].
Vital phagocyte cells in Plasmodium falciparum infection.
Distinct immune cells play an important role in the phagocytosis of infected erythrocytes (IEs) by P. falciparum or blood-stage merozoites. Circulatory heterogeneous monocytes can be classified into three subclasses: classical (CD14+CD16), intermediate (CD14+CD16+), and non-classical monocytes (CD14dimCD16+) [54,55] (Figure 2) . In contrast, the roles of intermediate and non-classical monocytes have been recognized to be more efficient for the antibody-dependent phagocytosis of IEs by Plasmodium falciparum, which was attributed to the expression levels of CD36, TLR 2, and TLR4 in these cells [56,57]. An investigation has indicated that monocytes (CD14+CD16-) and neutrophils play important roles as dominant phagocytic cells involved in the opsonic phagocytosis (OP) process. Neutrophil cells take the main phagocytic activities for blood-stage merozoites with FcγRIIIB acting synergistically with FcγRIIA at high anti-malarial antibody concentrations, and the protection from febrile malaria is also connected with the opsonic phagocytic activity of neutrophils [25]. At low antibody levels, CD14+CD16 monocytes are the most dominant phagocytic cells involved in opsonic phagocytosis with FcγRIIA [58,59]. The heterogeneity of neutrophil cell populations has also been identified, as well as other phagocytic cells, and their roles have been stated in phagocytic mechanisms against IEs, hemozoin and antibody-opsonized merozoites, but are still not well understood [41].
Data characterizing the roles of the tissue macrophage subclasses (M1, M2) in the phagocytic mechanism of IEs by P. falciparum remain unexplained. A few cases underwent an investigation of macrophage phenotyping in complicated malaria infection, and in dead patients with pulmonary oedema, researchers have reported M1 (CD68+CD40+), indicating an active phagocytic role in the lung tissues, and the reset studies provided indirect signs about the phagocytic potential activity of M1 in P. falciparum infection by studying proinflammatory cytokines (IFN-γ, IL-6, TNF, and IL-10) [60]. Additionally, macrophages generated from murine bone marrow have been shown to exhibit remarkable phagocytic activity against early and late stages of gametocytes, accompanied by the induction of inflammatory mediators [61]. Overall, the findings of these studies provide clear evidence of the importance of these cells in the phagocytosis of IEs and Plasmodium falciparum blood-stage pathogens.
Host factors influencing phagocytosis.
The complement system is involved in phagocytosis through secreted proteins, which may strengthen the phagocytosis of IEs [62]. The role of C3 fragments has been recognized in opsonizing infected and uninfected erythrocytes, causing severe malarial anemia (SMA) by erythrocyte phagocytosis. Defects in complement regulatory proteins, such as (CR1) and age-related decreases in protein expression contribute to the augmentation of complement deposition on cells and phagocytosis [63,64]. Additionally, other plasma proteins have been reported to significantly contribute to phagocytosis. Antibody-dependent phagocytosis of IEs and non-infected erythrocytes has been shown to play an efficient role in the protection and elimination of malaria pathogens [65]. IgG, a potent naturally occurring antibody, has been shown to have a unique implication and correlates with opsonic phagocytic activity, and has been shown to promote distinct phagocytic and opsonizing effects due to the specification features toward the infected erythrocytes and Plasmodium falciparum antigens[66] (Figure 1 (B )). Furthermore, antibodies with antigenic specificity toward merozoite antigens have been identified to have an explicit connection with increased phagocytosis activity against IEs [67].
Plasma proteins take a crucial function in the phagocytic mechanism ofPlasmodium falciparum and infected erythrocytes and are involved in the acute inflammatory response. Studies have shown that certain plasma proteins can promote antibody-dependent phagocytosis ofPlasmodium falciparum -infected erythrocytes, aiding malaria protection by targeting merozoite antigens on ring-stage parasites [65]. In addition, the role of fibrinogen and platelets has been demonstrated in preventing the removal of plasmodium hemozoin by neutrophils and strengthening phagocytic activities [68]. Additionally, active phase proteins such as mannan-binding lectin (MBL) in the innate immune system involve glycosylated parasite-derived proteins and contribute to the identification of Plasmodium falciparum proteins and phagocytosis induction, aiding in defense against infections [69]. These findings suggest that a combination of different factors targeting various parasite antigens contributes to the phagocytic activity of P. falciparum-infected erythrocytes.
Immune Evasion strategies and phagocytosis.
Plasmodium falciparum and infected erythrocytes employ diverse evasion tactics to evade phagocytosis and the human immune system. One of the key mechanisms is the recruitment of complement regulatory molecules, such as factor H (FH), to IEs or parasite surfaces to inhibit complement activation and subsequent lysis, highlighting the dual role of the complement system in parasite infection [70,71] (Figure 3) . Additionally, at late infection stages, P. falciparum utilizes surface proteins such as SERA5 and SE36 to interact with host proteins such as vitronectin (VTN), thereby preventing phagocytosis of the parasite and IEs [72]. Plasmodium falciparum -infected erythrocytes (IEs) have been found to express surface antigens such as RIFIN, interact with inhibitory immune receptors, suppress host immune cell activation, and utilize multiple immune evasion mechanisms [52]. Furthermore,Plasmodium falciparum evades phagocytosis through VAR2CSA-mediated interactions with host cells and immune components, ensuring its survival and persistence during placental malaria [73]. Additionally, Plasmodium falciparum evades phagocytosis by inducing Kupffer cell apoptosis in the pre-erythrocytic stage and interfering with macrophage phagocytic functions using hemozoin in the erythrocytic stage [74,75]. These collective strategies aid in evading the phagocytosis process through antigenic variation, sequestration, and blocking of antibodies, which contributes to the parasite’s ability to evade phagocytosis and survive within the host.
Therapeutic potential of phagocytosis in P. falciparum infection.
The phagocytic mechanisms and responses in vaccine development for P. falciparum infection have substantially improved. Studies have highlighted the importance of DNA vaccination against PfRH5-inducingPlasmodium falciparum -specific neutralizing antibodies and T-cell responses, highlighting a promising strategy for vaccine development targeting phagocytic responses [76]. Vaccines targeting merozoite proteins on ring-infected and uninfected erythrocytes can enhance phagocytic responses, aiming to control parasitemia and prevent clinical malaria in P. falciparum infections [65]. Additionally, acceleratedPlasmodium falciparum sporozoite chemoprophylaxis regimens induce strong T-cell and antibody responses, potentially enhancing vaccine efficacy by targeting phagocytic responses against malaria infection [77]. Studies have indicated that vaccine development by focusing on phagocytic responses to Plasmodium falciparum infection can be supported through the use of a topical adjuvant with a TLR7 agonist, such as imiquimod, to enhance humoral immunity [78]. A liposomal adjuvant system, which induces robust antibody and CD8+ T-cell responses against Plasmodium falciparum, also highlights the potential role of phagocytic responses in malaria vaccine progress [79]. Furthermore, the approach of phagocytic response stimulation in vaccine development aims to induce protective immunity by neutralizing parasite infectivity and has been investigated using a synthetic vaccine against Plasmodium falciparum targeting the dominant epitope (NANP)3 [80]. These advancements underscore the need to investigate the phagocytic approach required for successful vaccine development against P. falciparum infections.
A complete understanding of the phagocytic mechanisms against infected erythrocytes and Plasmodium falciparum molecules, the role of phagocyte cells, and the autophagy process in Plasmodium survival is crucial for malaria treatment and includes several challenges and limitations. Phagocytosis of infected and uninfected erythrocytes is essential, but discriminating between them and staining the early ring stages represents a great challenge for selective phagocytic activity [28,65]. Moreover, the limited efficacy of conventional anti-malarial drugs, resistance development, inhibitory effects, and potential toxicities hinder effective macrophage-specific drug delivery[81,82]. Overall, the complexity of phagocytic interactions need for precise targeting, and limitations in studying these processes pose significant obstacles in leveraging phagocytic activities for effective malaria treatment[16,41,83].
This work focuses on enhancing the understanding of phagocytosis in malaria immunity by discussing the recent and previous findings with targeted investigations exploring the impact of effective cells, host factors, and opsonin-like antibodies on parasite clearance. In addition, The role of phagocyte subpopulations, specifically monocytes in detecting and clearing infected erythrocytes (IEs) or parasite molecules. Subsequent research should explore in more detail the phagocytic mechanism on advanced cellular and molecular levels by providing deeper insights into its protective and potentially harmful effects. Additionally, the impact of merozoite antigens on the phagocytic process can be stated by shedding light on potential targets for controlling parasitemia and preventing clinical malaria. Understanding the molecular pathways that influence the balance between protection and pathology is crucial for developing novel antimalarial therapies and informing vaccine designs.
The review article results may have a substantial influence on clinical trials and subsequent research on malaria since it offers collective findings on the relationship between the malaria parasite and the phagocytic mechanism. The data generated may help create new treatment approaches and vaccine designs that target certain immune evasion pathways or enhance phagocytic activity by clarifying how P. falciparum evades phagocytosis and the ensuing immunological response. This might lead to more effective treatments and preventive measures, which could enhance clinical trial results and hasten the fight to eradicate malaria.
Conclusion
Exploring Phagocytic complex activities in P. falciparum infection involves understanding the roles of different phagocytic cells, interrelated factors, and their interactions with infected erythrocytes (IEs) and parasite particles. The impact of phagocytosis on the overall host protective immune response contributes substantially to the elimination of infected cells and control of malaria infection. Quite a perception of phagocytic immunomodulation and evasion strategies and previous treatment implications is essential, and it can potentially lead to the design of innovative therapeutic approaches to enhance phagocytic activities and strengthen outcomes in malaria infections.
It is imperative to understand the immunological pathways and factors affecting phagocytosis, including opsonins, distinct phagocyte subpopulations, and inhibitory molecules, which represent a great scientific and immunological challenge. Thus far, there is a need for more comprehensive studies to address the complete spectrum of phagocytic mechanisms involved in P. falciparum infections.