Open access peer-reviewed chapter

The Submicroscopic Plasmodium falciparum Malaria in Sub-Saharan Africa – Current Understanding of the Host Immune System and New Perspectives

Written By

Kwame Kumi Asare

Submitted: 25 April 2022 Reviewed: 28 April 2022 Published: 26 May 2022

DOI: 10.5772/intechopen.105086

From the Edited Volume

Malaria - Recent Advances and New Perspectives

Edited by Pier Paolo Piccaluga

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Abstract

The bottlenecks in malaria infections affect malaria control and eradication programs. The gaps in the relationships between stages specific parasites molecules and their effects in the various stages of malaria development are unknown. The challenge hampers the wholesome understanding of policies and programs implemented to control and eliminate malaria infections in the endemic areas. Submicroscopic malaria and its transmission dynamisms are of interest in malaria control programs. The role of various stages of natural protective immunity in submicroscopic malaria infections and the insight into the collaborative role of antibodies from antigens for maintaining lower and submicroscopic malaria could provide a relevant guideline for vaccine developments. The chapter discusses the roles of mosquito and malaria antibodies in maintaining submicroscopic P. falciparum infection and its transmission potentials in malaria-endemic areas and the new perspectives on the inter-relatedness of stage-specific antibodies to improve malaria control programs in Sub-Saharan Africa.

Keywords

  • Malaria
  • Plasmodium falciparum
  • Anopheles gambiae
  • stage specific immunity
  • Submicroscopic infection
  • gSG6-P1
  • PfCSP
  • PfEBA175
  • Pfs230

1. Introduction

Malaria is a protozoan disease of global health importance. Malaria affects about 241 million people with 627,000 deaths [1, 2, 3]. The majority of malaria cases and deaths occur in Sub-Saharan Africa [4]. The malaria eradication campaign has marked reductions in malaria morbidity and mortality [2, 5]. The eradication is challenged by the recent stall gains achieved in malaria control programs [6, 7].

Malaria infection is initiated and transmitted during a blood meal by an infected female Anopheles mosquito [8]. The mosquito injects saliva containing sporozoites for liver invasion and liver-stage merozoites development and subsequent rapturing and infection of the red blood cells (RBCs) [9, 10]. The blood-stage merozoites undergo several rounds of replication and reinvasion of RBCs; a small proportion of the merozoites form the sexual stage gametocytes (male and female gametocytes) are required for malaria transmission from humans to mosquitoes to complete the parasite life cycle (Figure 1) [11, 12, 13, 14, 15].

Figure 1.

Life cycle of malaria parasite. In the pre-erythrocytic stage: Plasmodium falciparum-infected Anopheles mosquito bites a human and transmits sporozoites into the bloodstream. Sporozoites migrate through the dermis and bloodstream to invade hepatocytes; divide to form multinucleated schizonts. Erythrocytic phase: The liver stage schizonts rupture and release merozoites into the circulation and subsequent invasion into red blood cells. The merozoites mature from ring forms to trophozoites to multinucleated schizonts. Some merozoites differentiate into male or female gametocytes. Anopheles mosquito ingests gametocytes into the midgut, where it develops into sporozoites.

The malaria parasites employ several parasite antigens (parasite proteins) for initial recognition and reversible attachment, reorientation and irreversible attachment, and final tissue or cell invasion and development [16, 17, 18]. The circumsporozoite protein (CSP), erythrocyte membrane protein 1 (PfEMP-1), repetitive interspersed family proteins (RIFINs) and ookinete surface antigen (Pfs230) are exposed to the host immune system to induce complex immune response at each stage of the parasite development [19, 20, 21]. Other factors such as malaria control strategies (treatment, vector control strategies), malaria distribution, epidemiological factors and chronic malaria infections account for low parasite density and submicroscopic malaria infections in malaria-endemic populations [22, 23, 24, 25, 26, 27].

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2. The submicroscopic Plasmodium falciparum malaria

Submicroscopic malaria is Plasmodium parasite infections below the detection limit of microscopy [28]. Large numbers of falciparum malaria go undetected by the current point-of-care diagnostic (POC) techniques due to the low sensitivity of microscopy and rapid diagnostic test (RDTs) [28, 29, 30].

Human malaria, Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale and Plasmodium knowlesi; Plasmodium falciparum malaria is the most virulent species that subvert the host physiology, results in severe complications such as cerebral malaria, severe anaemia, and respiratory distress and causes most deaths [31]. However, estimating the malaria burden and transmission intensity caused by P. falciparum in highly endemic Sub-Saharan Africa is essential for malaria control and eradication efforts [32, 33].

The undetected malaria infections serve as a reservoir and prominent contributor to malaria transmission [34, 35]. The underlying mechanisms for residual submicroscopic parasitaemia or gametocytaemia and its transmission dynamics are poorly understood. Thus, submicroscopic P. falciparum gametocyte densities could result in mosquito infections and maintain malaria transmission in the endemic communities [35]. A recent study showed that diagnosed and treated malaria-infected individuals had higher submicroscopic prevalence 30 days after treatment [36]. The low P. falciparum malaria infections in endemic Sub-Saharan Africa are associated with partial humoral immunity in the population [37, 38, 39].

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3. Humoral antibody immunity to malaria

Acquisition of antibodies in P. falciparum malaria infection reduces parasitaemia and the risk of severe and mild malaria cases [40, 41]. The mechanisms such as antibody-dependent cellular inhibition (ADCI) and antibody-dependent cellular cytotoxicity (ADCC) play a role in malaria infection [42]. The hyperimmune immunoglobulin G (IgG) and the predominant isotypes (IgG1, IgG2 and IgG3) in malaria-endemic areas have lower parasitaemia and lower risk of malaria attack [43, 44, 45]. The natural immunity to malaria develops gradually and is hyper-polymorphic [44]. The functionality of parasite antigen and antibodies interactions determines the quality of protection against malaria [46]. The robust immune response elicited at the various developmental stages of P. falciparum is poorly understood. Several of the parasite variant antigens are vaccine candidates. Thus, the IgG antibodies reduce parasitaemia and clinical symptoms in malaria-endemic communities. The insight into the collaborative role of antibodies from various antigens for maintaining lower and submicroscopic malaria could provide a relevant guideline for vaccine developments (Figure 2).

Figure 2.

Stage-specific development of IgG antibodies in P. falciparum malaria and their functional roles.

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4. Pre-erythrocytic antibodies in P. falciparum endemic areas

4.1 An. gambiae salivary gland protein-6 peptide 1 (gSG6-P1) antibody

The active micro-components in Anopheles saliva prevent blood coagulation, induce complement activation, elicit and modify the immune response to influence the vector-malaria transmission [47]. An. gambiae salivary gland protein 6 (gSG6) has recently attracted scientific interest as a biomarker to estimate the intensity of exposure to mosquito bites and the risk of malaria infection [48, 49, 50]. The IgG immune antibody against gSG6-P1 has high sensitivity and specificity to determine the entomological inoculation rate (EIR) and overcome some of the challenges associated with EIR [51, 52]. The IgG antibody is an essential estimation of the risk of malaria transmission in the endemic areas [53]. Aside using gSG6-P1 IgG antibodies to estimate the risk of infection or vector-malaria transmission, does gSG6-P1 play any role in Plasmodium falciparum invasion and development? A question that will prove vital to the control efforts of malaria if rightly answered.

4.2 The circumsporozoite protein (CSP) antibody

The female Anopheles mosquito inoculates saliva containing sporozoites which migrate from the dermis into the hepatocytes [53, 54]. P. falciparum sporozoites are highly susceptible to the induced antibody against the most abundant sporozoite surface protein, the CSP [55, 56, 57]. The prolonged exposure of anti-CSP against sporozoites severely affects the development of the liver stage infections, thus reducing the chances of successful blood-stage of P. falciparum infections [56]. Currently, CSP based RTS, S anti-malaria vaccine is the only malaria vaccine that has been rolled out with efficacy of approximately 78% [58, 59]. These favourable safety profiles and protection-inducing immunity do not interfere with the general immune response mechanisms in a paediatric population. Although the RTS, S malaria vaccine has achieved a milestone, it is not without several concerns in high parasitaemia levels (>5000 parasites/ul) among subjects considered to be protected [60]. The inexplicable variations in the protection-induced immune response by CSP antibody in asymptomatic and symptomatic malaria require further understanding.

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5. The erythrocytic stage antibodies in P. falciparum endemic areas

5.1 P. falciparum erythrocyte binding antigen-175

The merozoites invade red blood cells through parasite ligands-host receptors interactions to facilitate initial attachment, apical reorientation, tight junction formation and final entry into the red blood cells [61]. The exposed parasite ligands to the host immune system induce antibodies against parasite ligands [62, 63, 64]. Naturally acquired PfEBA-175 antibodies bind P. falciparum erythrocyte binding antigen-175 (PfEBA-175) to prevent red blood cell invasion [65, 66]. The PfEBA-175 engagement with Glycophorin A (GPA) remains one of the major pathways for red blood cells invasion and establishment of clinical disease in malaria [67, 68]. Therefore, blocking this critical pathway of parasite invasion into RBCs has become an approach to controlling malaria. The PfEBA-175-RII IgG-mediated antibody offers protection by binding to the functional R217 loop region of the PfEBA-175 inhibiting P. falciparum invasion of RBCs [69, 70]. Although the malaria parasite uses PfEBA-175-GPA invasion pathway, it can also adopt alternative ways to invade the PfEBA-175 antibody RBCs invasion blockage [71]. The high levels of PfEBA-175 antibody among the population in malaria-endemic areas and high-level submicroscopic malaria infection suggest a role of the PfEBA-175-GPA pathway in malaria infections [66, 72]. This is backed by the high relative avidity of IgG antibodies against EBA175RIII-V in low malaria-endemic communities [66, 73, 74].

5.2 Pfs230 gametocyte antibody

The sustained reservoirs of submicroscopic or asymptomatic malaria infections are not well understood [75, 76, 77]. The P. falciparum mature stage gametocytes could persist at submicroscopic levels for effective transmission to the mosquito [78, 79]. The exposure of gametocyte antigen Pfs230 expressed on the mature gametocyte surface and the gamete surface induces an antibody response in the human host [80, 81, 82]. There is a natural antibody response against the Pfs230 in malaria-endemic populations [83, 84]. The Pfs230 antibody blocks the fusion of gametes in the mosquito and prevents transmission [85, 86]. The anti-gametocytes IgG antibodies against Pfs230 reduce oocyst intensity by 55–70% and up to 44% reduction in proportions of infected mosquitoes [87]. The Pfs230 antibody has been associated with recent and concurrent high-density gametocyte exposure and impacts the dynamism of transmission by significantly reducing the infectiousness of high gametocyte density infections.

5.3 The missing links and the inter-relationships between stage-specific P. falciparum antibodies

There are several missing links in the association between the effects of various stage-specific antibodies and how they subsequently affect the development of the other parasites’ stages [88]. For instance, there are several unknown points in the sexual stage immunity which could aid in the reduction of transmission to mosquitoes and elimination of malaria; such as how the Pfs230 antibody develops in either microscopic or submicroscopic gametocyte carriage, and the subsequent impacts on parasite development in mosquitoes and reinfection of the human host is still obscure. The current knowledge of the functionality of the Pfs230 antibody has shown to be dependent on density [89, 90, 91, 92]. Also, factors that reduce or prevent blood-stage parasitaemia development have the potential to reduce gametocyte development and reduce malaria transmission [93, 94]. Other immune factors such as antibodies against Anopheles salivary proteins and their relationship to the development of the liver-stage malaria parasites, erythrocytic phase development or sexual stage development are poorly understood.

However, current study has revealed a strong negative correlation between IgG antibodies of PfCSP and gSG6-P1. There is no evidence of an association between IgG antibodies of gSG6-P1, PfEBA175, Pfs230 or IgG antibodies of PfEBA175 and IgG antibodies of Pfs230 (Figure 3). Although the exact role of gSG6-P1 is unknown, this finding suggests either gSG6-P1 is involved in sporozoites invasion or the liver stage development.

Figure 3.

A strong negative correlation between PfCSP IgG antibody and anopheles gSG6-P1 IgG antibody. A. Correlation between IgG antibodies concentration of PfCSP and gSG6-P1. B. Correlation between IgG antibodies concentration of Pfs230 and gSG6-P1. C. Correlation between IgG antibodies concentration of PfEBA-175 and gSG6-P1. D. Correlation between IgG antibodies concentration of PfEBA-175 and Pfs230. The statistical analysis was performed using spearman correlation. The IgG antibody concentration of PfCSP and IgG antibody concentration of anopheles gSG6-P1 showed a significant negative correction r = −0.1571 (−0.2704 to −0.03944), p = 0.0073. The observed strong negative correlation between IgG antibodies of PfCSP and gSG6-P1 is an indication that salivary gland proteins may play a role in the invasion and development of malaria sporozoites in the liver. Further studies are required to ascertain the specific role of gSG6-P1 in liver-stage malaria infection.

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6. The new perspectives

The salivary gland molecules may play a role in sporozoite survival and invasion of hepatocytes. However, there is no identified role of salivary gland molecules on sporozoite migration through the skin to the liver or development in the liver.

Previous studies have reported a putative mucin-like protein, the anti-platelet protein, the long-form D7 salivary protein, the putative gVAG protein precursor, the D7-related 3.2 protein, gSG7 salivary proteins, and the gSG6 protein may be involved in sporozoite maturation and transmission [95]. The authors of this study could not establish the direct association or role of the individual salivary gland proteins in the development of malaria parasites.

Also, the salivary gland molecules and underlying mechanisms for sporozoites recognition and invasion of the mosquito salivary gland are poorly understood. Until recently, the unique sporozoite ligand-salivary gland receptor interaction and molecules involved in triggering the mosquito salivary gland invasion were unknown. The discovery of Anopheles salivary gland protein, the CSP-binding protein (CSPBP) and its role in the mosquito salivary glands invasion has opened a new understanding of the invasion mechanism of sporozoites [96]. The antibodies raised against the CSPBP reduced sporozoites load by 25% and 90% in 14 and 18 days after the infected blood meal by mosquitoes, respectively [96].

In the hepatocyte invasion, region II of the C-terminal region of the sporozoite CSP attaches to the liver cells through the heparan sulfates proteoglycans (HSPG) [97, 98]. The conformations of CSP play a role in the sporozoite migration through different tissues in mosquito and human hosts [99]. However, factors involved in the sporozoite migration, invasion and development in hepatocytes remain largely unknown. The mosquitoes’ gamma interferon-inducible thiol reductase (mosGILT) negatively influences sporozoite speed and cell traversal movement in the host [100, 101, 102]. Thus, the mosquito salivary gland proteins could either enhance or reduce the transmission of malaria parasites. The interaction of the PfCSP and gSG6-P1 proteins may play an essential role in sporozoites development in the human host. This finding is new information that requires further research into the role of gSG6-P1 in the development of pre-erythrocytic phase parasites.

In conclusion, submicroscopic malaria infection and transmission is one of the bottlenecks in malaria control and elimination strategy in malaria-endemic areas. The inoculation of the female Anopheles salivary gland content and sporozoites initiate the entire malaria human host developmental process. However, there are several missing links to how vector and parasite molecules influence the development and establishment of malaria infection. The observed strong negative correlation between IgG antibodies of PfCSP and gSG6-P1 is an indication that salivary gland proteins may play a role in the invasion and development of malaria sporozoites in the liver. Further studies are required to ascertain the specific role of gSG6-P1 in liver-stage malaria infection.

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Written By

Kwame Kumi Asare

Submitted: 25 April 2022 Reviewed: 28 April 2022 Published: 26 May 2022