1. Introduction
Malaria, a human parasite infectious disease, has been a cause of mortality and morbidity across the world. Significant advancements toward the vaccine development have been made, yet half of the world’s population survives under the threat of malaria infection, particularly young children residing in South East Asia (SEA) and Sub-Saharan Africa. As per the latest World Malaria Report 2022, 247 million cases of malaria were registered in 2021, slightly higher as compared to 245 million in 2020. Additionally, malaria death increased by 10% and reached an estimated number of 6,25,000 [1]. Malaria occurs due to the bite of female
The tens of millions of non-immunes from areas where malaria is not transmitted visit malaria-endemic areas, and face risks of malaria infection. The two major weapons against malaria are vector control and chemoprophylaxis/chemotherapy. Unfortunately, attempts to eradicate the disease based on these methods have had only limited success due to widespread development of drug resistance by the parasite and insecticide resistance by the mosquito vector [3]. Therefore, there is an urgent need to develop newer drugs and therapeutic approaches. There is no single effective malaria vaccine available due to the complex life cycle of malaria parasite; a number of approaches to malaria vaccine development based on attenuated sporozoite, synthetic and recombinant immunogenic peptide is available. However, these approaches suffer from the drawbacks of safety and short-lived species & stage-specific immunity [3].
There are antimalarial drug(s) available to treat human malaria infection, but continuous drug pressure to clear
Malaria life cycle begins with the bite of
2. Modulation of host immune system
The malaria life cycle in the human host initiates in the liver followed by symptomatic blood stage infection. Different experimental studies of humans and mice have confirmed the role of immune system to fight against the infection [2]. Further, studies have shown the importance of T cells, mainly IFN-γ producing CD8+ T cells which have a prominent role in providing sterile protection during the infectious challenge. Moreover, other cells such as IFN-γ producing CD4+ T cells and follicular helper T cells (Tfh) also play an important role in killing iRBCs and generation of antibody-producing B cells, respectively [2]. Additionally, different immune cells of innate immunity also support augmenting the immune response to the malaria infection [2]. It has been well-established that among the different immune cells, distinct mononuclear phagocytic cells known as dendritic cells (DCs) are consider as professional antigen-presenting cells (APCs). DCs have been well-known APCs to identify antigens, capturing, processing, and presentation to the T cells as well as activating B cells directly [6]. Furthermore, it also stimulates the innate immune system (activation of NK cells). The role of DCs is well-defined. These cells work in coordination with other immune cells and bridge the gap between adaptive and non-adaptive immunity (Figure 2).
They are classified into different subsets and majority of them are divided according to the expression of certain defined phenotypic markers and location [6]. They reside in lymphoid and non-lymphoid organs and mainly classified as conventional/myeloid dendritic cells (cDCs/mDCs) (CD3−CD14−CD19−CD20−CD56−HLA-DR+DC11c+) and plasmacytoid dendritic cells (pDCs) (CD3−CD14−CD19−CD20−CD56−HLA-DR+DC11c+CD303(BDCA2)+CD304(BDCA4)+). These mDCs in blood and lymphoid tissues can be further divided into two more subsets which express CD1c (BDCA1) or CD141 (BDCA3). pDCs are the major reservoir for antiviral immune response (IFN-α) which consist of 0.35% of PBMC whereas cDCs have a captive role in priming of T cells and account for 0.65% of PBMCs [7].
It has been established that protection against the malaria infection (liver/blood stage infection) is initiated when the DCs or macrophages capture the malaria antigen followed by processing and presenting them to T cells through MHC-I or II pathway. During the antigen presentation, several signaling mechanisms resulted in the secretion of pro-inflammatory cytokines such as IFN-γ, IL-12, and TNF-α. It further activates/stimulates the other immune cells and results in the direct/indirect killing of infected cells. Experimental studies have confirmed that DCs play a dual role by producing cytokines against the respective pathogen and creating tolerogenic conditions [6, 7].
2.1 Functional DCs during malaria infection
Role of DCs during malaria infection has been recently reviewed showing contradictory outcomes. However, it could be reasoned due to the use of different species and a subset of DCs. Therefore, our main focus is on understanding the mechanism of
DCs have a different role to play based on location specificity. The liver resident DCs are less mature and express lower costimulatory molecules compared to the blood DCs which accounts for their poor antigen presentation [9]. Additionally, their allogenic T cell response is also lower compared to their blood counterpart which results in less T cell-based response against the subsequent stimulation [10]. Whereas liver DCs are prominent IL-10-producing cells which favor the survival of sporozoites in the liver and hence fail to generate sterile immunity against natural infection [9]. Thus, after successfully invading the immune system by marginally around 30% of sporozoites, the tolerogenic nature of liver DCs is the first step for the development of malaria infection which could further progress and develop immunopathology. In this context, developed humanized mice may be a valuable tool to explore and study the role of DCs in liver-stage malaria infection [11].
Once the malaria infection reaches to blood stage, it allows the host immune system to activate and respond accordingly as a range of innate and toll-like receptors (TLRs) get activated.
Role of DCs in human malaria infection has been studied mainly in two ways. One in which peripheral DCs of infected or pre-and-post infection DCs and in another way
2.1.1 DCs and P. falciparum interaction
Studies conducted on DCs role in pregnant women have shown contradictory results. Out of four studies, two studies have shown the overall decrease in DCs population in
Human studies confirmed that functional impairment of DCs in malaria is common. The endemic and higher transmission showed the parasite load and higher chances of re-infection. Furthermore, studies of co-infection with two
2.1.2 P. falciparum modulates TLRs present on DCs
The study conducted by Loharungsikul and colleagues has detailed the role of
2.1.3 In vitro modulation of DCs
Earlier studies have shown the role of TLRs during malaria infection. To study more in detail, isolated peripheral blood mononuclear cells (PBMCs) of pregnant women (naturally exposed to
Only fewer studies have been carried out using the
2.1.4 Modulation of DCs from controlled human malaria infection (CHMI) studies
The controlled human malaria infection model (CHMI) is one of the successful models developed for understanding host-pathogen interaction. This has provided us with significant insights into antimalarial immunity. Woodberry and colleagues carried out a study to understand the role of DCs in malaria by inoculating the ultra-low or low numbers of
In this direction, another two studies were done to study more about BDCA-1+ cDC2 activation [33] and the function of pDC [34]. The results of both studies were found to be similar. Moreover, elevated apoptosis in DCs with a reduction in number and its decreased phagocytic activity was found only in the higher-dose group. Additionally, Loughland
2.1.5 Interaction between DCs and parasite-generated metabolic products
Parasite progresses inside the human host and mainly relies on the nutrient available in the vicinity. Hemoglobin, the major target of the parasite, is the key product as it metabolite and results into the formation of heme which is further neutralized by parasites and converted into hemozoin [35]. It plays a dual role in the activation and suppression of DCs. Later on, it has been confirmed that hemozoin serves as a carrier for
3. Conclusions
The role of DCs in malaria infection failed to understand the immunopathology due to several factors in-and-out of experiments. Similarly, the studies which had a focus on direct interaction between
Acknowledgments
Rajeev K. Tyagi would like to express his gratitude to DBT, New Delhi, Ramalingaswami Re-entry Fellowship Project (No. BT/RLF/Re-entry/27/2018) and Indian Council of Medical Research (ICMR), New Delhi extramural grant (35/1/2020-Nano/BMS) for generously supporting this study. Rajeev K. Tyagi would like to express his thanks to the central MIL facility of CSIR-IMTECH, Chandigarh. Nikunj Tandel would like to thank the Nirma University and the Indian Council of Medical Research (ICMR) for providing the fellowship to carry out his research (ICMR award letter No.: 2020-7623/CMB-BMS).
Abbreviations
ACT | artemisinin-based combination therapy |
APC | antigen-presenting cells |
cDCs/mDCs | conventional/myeloid dendritic cells |
CHMI | controlled human malaria infection model |
DCs | dendritic cells |
Flt3-L | Fms-like tyrosine kinase receptor 3 ligand |
iRBCs | infected red blood cells |
MHC | major histocompatibility complex |
pRBC | parasitized red blood |
PPR | pattern recognition receptors |
RBCs | red blood cells |
SEA | South-East Asia |
TLRs | toll-like receptors |
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