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.