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Molecular Research on Plasmodium Infection and Immunity

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 15335

Special Issue Editors


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Guest Editor
Unit of Experimental Medicine, de Duve Institute, Université Catholique de Louvain, SSS/DDUV – ICP, Av. Hippocrate 75, bte B1.75.02, 1200 Brussels, Belgium
Interests: research in development; infectious diseases; viruses; parasites; immune microenvironment; hygiene hypothesis; cytokines; immune regulatory mechanisms; immunopathology; autoimmune diseases
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Guest Editor
Center for Infection and Immunity of Lille-CIIL, Institut Pasteur de Lille, CNRS UMR 9017-Inserm U1019, University Lille, 59019 Lille, France
Interests: plasmodium; immunity; infections

Special Issue Information

Dear Colleagues,

Malaria still affects millions of people around the world and kills hundreds of thousands, mostly children, every year. Although the first vaccine has been approved for children in moderate to high endemic areas, eradication of the most pathogenic strain of the parasite, P. falciparum, targeted for 2030, is far from acquired. More knowledge on malaria immunity is needed that will inform further vaccine, drug, and diagnostic development efforts.

Immune control of infection by Plasmodium parasites involves mostly CD4+ and CD8+ lymphocytes, antibodies, and cytokines such as gamma-interferon. However, this immune control is impaired by the complexity of the Plasmodium biological cycle and antigen variation, the emergence of parasite variants, and the modulation of immune responses by the pathogen and/or environmental factors. Nevertheless, the nature and intensity of the host immune response determine the clinical presentation of malaria, from asymptomatic to severe, and the level of parasitemia. In addition, immunomodulation by Plasmodium parasites through a bystander effect may affect the course of diseases concomitant with malaria.

The purpose of this Special Issue will be to report both in patients and in animal models, through regular research papers and/or reviews of the literature, on:

  • The cellular and molecular immune mechanisms involved in Plasmodium control;
  • The modulations of anti-Plasmodium immune responses by host genetic factors;
  • The regulation of anti-Plasmodium immune responses by environmental factors;
  • The interactions between Plasmodium infection and unrelated pathogens during co-infections;
  • The consequences of Plasmodium infection on the host global immunity and on concomitant diseases.

Prof. Dr. Jean-Paul Coutelier
Dr. Sylviane Pied
Guest Editors

Manuscript Submission Information

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Keywords

  • malaria
  • Plasmodium
  • genetic factors
  • environmental factors
  • coinfections
  • bystander effect
  • immune microenvironment
  • vaccine

Published Papers (10 papers)

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Editorial

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3 pages, 177 KiB  
Editorial
Molecular Research on Plasmodium Infection and Immunity
by Jean-Paul Coutelier and Sylviane Pied
Int. J. Mol. Sci. 2024, 25(7), 4133; https://doi.org/10.3390/ijms25074133 - 8 Apr 2024
Viewed by 773
Abstract
The WHO’s global strategy for malaria targets a reduction of at least 90% of both incidence and mortality rates for 2030 [...] Full article
(This article belongs to the Special Issue Molecular Research on Plasmodium Infection and Immunity)

Research

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21 pages, 3881 KiB  
Article
DHEA Induces Sex-Associated Differential Patterns in Cytokine and Antibody Levels in Mice Infected with Plasmodium berghei ANKA
by Fidel Orlando Buendía-González, Luis Antonio Cervantes-Candelas, Jesús Aguilar-Castro, Omar Fernández-Rivera, Teresita de Jesús Nolasco-Pérez, Monserrat Sofía López-Padilla, David Roberto Chavira-Ramírez, Armando Cervantes-Sandoval and Martha Legorreta-Herrera
Int. J. Mol. Sci. 2023, 24(16), 12549; https://doi.org/10.3390/ijms241612549 - 8 Aug 2023
Cited by 1 | Viewed by 1224
Abstract
Malaria is the most lethal parasitic disease worldwide; the severity of symptoms and mortality are higher in men than in women, exhibiting an evident sexual dimorphism in the immune response; therefore, the contribution of 17β-estradiol and testosterone to this phenomenon has been studied. [...] Read more.
Malaria is the most lethal parasitic disease worldwide; the severity of symptoms and mortality are higher in men than in women, exhibiting an evident sexual dimorphism in the immune response; therefore, the contribution of 17β-estradiol and testosterone to this phenomenon has been studied. Both hormones differentially affect several aspects of innate and adaptive immunity. Dehydroepiandrosterone (DHEA) is the precursor of both hormones and is the sexual steroid in higher concentrations in humans, with immunomodulatory properties in different parasitic diseases; however, the involvement of DHEA in this sexual dimorphism has not been studied. In the case of malaria, the only information is that higher levels of DHEA are associated with reduced Plasmodium falciparum parasitemia. Therefore, this work aims to analyze the DHEA contribution to the sexual dimorphism of the immune response in malaria. We assessed the effect of modifying the concentration of DHEA on parasitemia, the number of immune cells in the spleen, cytokines, and antibody levels in plasma of CBA/Ca mice infected with Plasmodium berghei ANKA (P. berghei ANKA). DHEA differentially affected the immune response in males and females: it decreased IFN-γ, IL-2 and IL-4 concentrations only in females, whereas in gonadectomized males, it increased IgG2a and IgG3 antibodies. The results presented here show that DHEA modulates the immune response against Plasmodium differently in each sex, which helps to explain the sexual dimorphism present in malaria. Full article
(This article belongs to the Special Issue Molecular Research on Plasmodium Infection and Immunity)
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20 pages, 4092 KiB  
Article
Construction, Expression, and Evaluation of the Naturally Acquired Humoral Immune Response against Plasmodium vivax RMC-1, a Multistage Chimeric Protein
by Ada da Silva Matos, Isabela Ferreira Soares, Barbara de Oliveira Baptista, Hugo Amorim dos Santos de Souza, Lana Bitencourt Chaves, Daiana de Souza Perce-da-Silva, Evelyn Kety Pratt Riccio, Letusa Albrecht, Paulo Renato Rivas Totino, Rodrigo Nunes Rodrigues-da-Silva, Cláudio Tadeu Daniel-Ribeiro, Lilian Rose Pratt-Riccio and Josué da Costa Lima-Junior
Int. J. Mol. Sci. 2023, 24(14), 11571; https://doi.org/10.3390/ijms241411571 - 18 Jul 2023
Cited by 1 | Viewed by 1285
Abstract
The PvCelTOS, PvCyRPA, and Pvs25 proteins play important roles during the three stages of the P. vivax lifecycle. In this study, we designed and expressed a P. vivax recombinant modular chimeric protein (PvRMC-1) composed of the main antigenic regions of these vaccine candidates. [...] Read more.
The PvCelTOS, PvCyRPA, and Pvs25 proteins play important roles during the three stages of the P. vivax lifecycle. In this study, we designed and expressed a P. vivax recombinant modular chimeric protein (PvRMC-1) composed of the main antigenic regions of these vaccine candidates. After structure modelling by prediction, the chimeric protein was expressed, and the antigenicity was assessed by IgM and IgG (total and subclass) ELISA in 301 naturally exposed individuals from the Brazilian Amazon. The recombinant protein was recognized by IgG (54%) and IgM (40%) antibodies in the studied individuals, confirming the natural immunogenicity of the epitopes that composed PvRMC-1 as its maintenance in the chimeric structure. Among responders, a predominant cytophilic response mediated by IgG1 (70%) and IgG3 (69%) was observed. IgM levels were inversely correlated with age and time of residence in endemic areas (p < 0.01). By contrast, the IgG and IgM reactivity indexes were positively correlated with each other, and both were inversely correlated with the time of the last malaria episode. Conclusions: The study demonstrates that PvRMC-1 was successfully expressed and targeted by natural antibodies, providing important insights into the construction of a multistage chimeric recombinant protein and the use of naturally acquired antibodies to validate the construction. Full article
(This article belongs to the Special Issue Molecular Research on Plasmodium Infection and Immunity)
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12 pages, 1442 KiB  
Communication
Increased Neutrophil Percentage and Neutrophil–T Cell Ratio Precedes Clinical Onset of Experimental Cerebral Malaria
by Lucas Freire-Antunes, Uyla Ornellas-Garcia, Marcos Vinicius Rangel-Ferreira, Mônica Lucas Ribeiro-Almeida, Carina Heusner Gonçalves de Sousa, Leonardo José de Moura Carvalho, Cláudio Tadeu Daniel-Ribeiro and Flávia Lima Ribeiro-Gomes
Int. J. Mol. Sci. 2023, 24(14), 11332; https://doi.org/10.3390/ijms241411332 - 12 Jul 2023
Cited by 2 | Viewed by 1184
Abstract
Newly emerging data suggest that several neutrophil defense mechanisms may play a role in both aggravating and protecting against malaria. These exciting findings suggest that the balance of these cells in the host body may have an impact on the pathogenesis of malaria. [...] Read more.
Newly emerging data suggest that several neutrophil defense mechanisms may play a role in both aggravating and protecting against malaria. These exciting findings suggest that the balance of these cells in the host body may have an impact on the pathogenesis of malaria. To fully understand the role of neutrophils in severe forms of malaria, such as cerebral malaria (CM), it is critical to gain a comprehensive understanding of their behavior and functions. This study investigated the dynamics of neutrophil and T cell responses in C57BL/6 and BALB/c mice infected with Plasmodium berghei ANKA, murine models of experimental cerebral malaria (ECM) and non-cerebral experimental malaria, respectively. The results demonstrated an increase in neutrophil percentage and neutrophil–T cell ratios in the spleen and blood before the development of clinical signs of ECM, which is a phenomenon not observed in the non-susceptible model of cerebral malaria. Furthermore, despite the development of distinct forms of malaria in the two strains of infected animals, parasitemia levels showed equivalent increases throughout the infection period evaluated. These findings suggest that the neutrophil percentage and neutrophil–T cell ratios may be valuable predictive tools for assessing the dynamics and composition of immune responses involved in the determinism of ECM development, thus contributing to the advancing of our understanding of its pathogenesis. Full article
(This article belongs to the Special Issue Molecular Research on Plasmodium Infection and Immunity)
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11 pages, 1420 KiB  
Article
Integrated Analysis of Cytokine Profiles in Malaria Patients Discloses Selective Upregulation of TGF-β1, β3, and IL-9 in Mild Clinical Presentation
by Ella Larissa Ndoricyimpaye, Jacques Van Snick, Jean de Dieu Niyoyita, Philbert Kanimba, Jean Bosco Mbonimpa, Robert Rutayisire, Réverien Rutayisire, Vedaste Ndahindwa, Paméla Cheou, Jean Paul Coutelier and Nadine Rujeni
Int. J. Mol. Sci. 2022, 23(20), 12665; https://doi.org/10.3390/ijms232012665 - 21 Oct 2022
Cited by 4 | Viewed by 1698
Abstract
The proper control of Plasmodium infection requires a finely balanced immune response. Here, we evaluated the implication of TGF-β1 and TGF-β3 in this process using novel monoclonal antibodies to measure their plasma concentrations in comparison with other cytokines and the expression of FOXP3 [...] Read more.
The proper control of Plasmodium infection requires a finely balanced immune response. Here, we evaluated the implication of TGF-β1 and TGF-β3 in this process using novel monoclonal antibodies to measure their plasma concentrations in comparison with other cytokines and the expression of FOXP3 mRNA. Plasma cytokine levels were measured in 80 patients with severe anaemic malaria and 186 with a mild presentation using ELISA, and rtPCR was used to measure FOXP3 mRNA expression. While no mature TGF-β isoforms were detected in the plasma, the latent TGF-β1 and TGF-β3 were strongly upregulated in patients with mild malaria and nearly undetected in patients with severe disease. Similar selective upregulation in mild patients was observed for IL-9 and FOXP3 mRNA, while IL-7, IL-10, IL-17, and IL-27, although higher in mild cases, were also detected in severe disease. In contrast, a clearly skewed trend of severe cases towards higher pro-inflammatory (IL-6, IL-13, TNF-α) and Th1 (IFN-γ) responses was observed, which was associated with a higher level of parasitaemia as well as lower IgG and higher IgM responses. Together, these results suggest that the stimulation of regulatory T cells through TGF-β1/TGF-β3 and IL-9 is paramount to an effective and balanced protective immunity in natural human malaria infection. Full article
(This article belongs to the Special Issue Molecular Research on Plasmodium Infection and Immunity)
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12 pages, 621 KiB  
Article
Metagenomic Sequencing for the Diagnosis of Plasmodium spp. with Different Levels of Parasitemia in EDTA Blood of Malaria Patients—A Proof-of-Principle Assessment
by Hagen Frickmann, Felix Weinreich, Ulrike Loderstädt, Sven Poppert, Egbert Tannich, Jana Bull, Bernd Kreikemeyer and Israel Barrantes
Int. J. Mol. Sci. 2022, 23(19), 11150; https://doi.org/10.3390/ijms231911150 - 22 Sep 2022
Cited by 5 | Viewed by 1649
Abstract
Molecular diagnostic approaches are increasingly included in the diagnostic workup and even in the primary diagnosis of malaria in non-endemic settings, where it is difficult to maintain skillful microscopic malaria detection due to the rarity of the disease. Pathogen-specific nucleic acid amplification, however, [...] Read more.
Molecular diagnostic approaches are increasingly included in the diagnostic workup and even in the primary diagnosis of malaria in non-endemic settings, where it is difficult to maintain skillful microscopic malaria detection due to the rarity of the disease. Pathogen-specific nucleic acid amplification, however, bears the risk of overlooking other pathogens associated with febrile illness in returnees from the tropics. Here, we assessed the discriminatory potential of metagenomic sequencing for the identification of different Plasmodium species with various parasitemia in EDTA blood of malaria patients. Overall, the proportion of Plasmodium spp.-specific sequence reads in the assessed samples showed a robust positive correlation with parasitemia (Spearman r = 0.7307, p = 0.0001) and a robust negative correlation with cycle threshold (Ct) values of genus-specific real-time PCR (Spearman r = −0.8626, p ≤ 0.0001). Depending on the applied bioinformatic algorithm, discrimination on species level was successful in 50% (11/22) to 63.6% (14/22) instances. Limiting factors for the discrimination on species level were very low parasitemia, species-depending lacking availability of reliable reference genomes, and mixed infections with high variance of the proportion of the infecting species. In summary, metagenomic sequencing as performed in this study is suitable for the detection of malaria in human blood samples, but the diagnostic detection limit for a reliable discrimination on species level remains higher than for competing diagnostic approaches like microscopy and PCR. Full article
(This article belongs to the Special Issue Molecular Research on Plasmodium Infection and Immunity)
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10 pages, 9017 KiB  
Article
Assemblages of Plasmodium and Related Parasites in Birds with Different Migration Statuses
by Xi Huang, Zelin Chen, Guocheng Yang, Canwei Xia, Qiujin Luo, Xiang Gao and Lu Dong
Int. J. Mol. Sci. 2022, 23(18), 10277; https://doi.org/10.3390/ijms231810277 - 7 Sep 2022
Cited by 5 | Viewed by 1431
Abstract
Migratory birds spend several months in their breeding grounds in sympatry with local resident birds and relatively shorter periods of time at stopover sites. During migration, parasites may be transmitted between migratory and resident birds. However, to what extent they share these parasites [...] Read more.
Migratory birds spend several months in their breeding grounds in sympatry with local resident birds and relatively shorter periods of time at stopover sites. During migration, parasites may be transmitted between migratory and resident birds. However, to what extent they share these parasites remains unclear. In this study, we compared the assemblages of haemosporidian parasites in migratory, resident, and passing birds, as well as the correlations between parasite assemblages and host phylogeny. Compared with passing birds, migratory birds were more likely to share parasites with resident birds. Shared lineages showed significantly higher prevalence rates than other lineages, indicating that common parasites are more likely to spill over from the current host to other birds. For shared lineages, the prevalence was significantly higher in resident birds than in migratory birds, suggesting that migratory birds pick up parasites at their breeding ground. Among the shared lineages, almost two-thirds presented no phylogenetic signal in their prevalence, indicating that parasite transmission among host species is weakly or not correlated with host phylogeny. Moreover, similarities between parasite assemblages are not correlated with either migration status or the phylogeny of hosts. Our results show that the prevalence, rather than host phylogeny, plays a central role in parasite transmission between migratory and resident birds in breeding grounds. Full article
(This article belongs to the Special Issue Molecular Research on Plasmodium Infection and Immunity)
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Review

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21 pages, 2467 KiB  
Review
The Laboratory Diagnosis of Malaria: A Focus on the Diagnostic Assays in Non-Endemic Areas
by Adriana Calderaro, Giovanna Piccolo and Carlo Chezzi
Int. J. Mol. Sci. 2024, 25(2), 695; https://doi.org/10.3390/ijms25020695 - 5 Jan 2024
Cited by 2 | Viewed by 1601
Abstract
Even if malaria is rare in Europe, it is a medical emergency and programs for its control should ensure both an early diagnosis and a prompt treatment within 24–48 h from the onset of the symptoms. The increasing number of imported malaria cases [...] Read more.
Even if malaria is rare in Europe, it is a medical emergency and programs for its control should ensure both an early diagnosis and a prompt treatment within 24–48 h from the onset of the symptoms. The increasing number of imported malaria cases as well as the risk of the reintroduction of autochthonous cases encouraged laboratories in non-endemic countries to adopt diagnostic methods/algorithms. Microscopy remains the gold standard, but with limitations. Rapid diagnostic tests have greatly expanded the ability to diagnose malaria for rapid results due to simplicity and low cost, but they lack sensitivity and specificity. PCR-based assays provide more relevant information but need well-trained technicians. As reported in the World Health Organization Global Technical Strategy for Malaria 2016–2030, the development of point-of-care testing is important for the improvement of diagnosis with beneficial consequences for prompt/accurate treatment and for preventing the spread of the disease. Despite their limitations, diagnostic methods contribute to the decline of malaria mortality. Recently, evidence suggested that artificial intelligence could be utilized for assisting pathologists in malaria diagnosis. Full article
(This article belongs to the Special Issue Molecular Research on Plasmodium Infection and Immunity)
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14 pages, 1731 KiB  
Review
The IL-33/ST2 Pathway in Cerebral Malaria
by Corine Glineur, Inès Leleu and Sylviane Pied
Int. J. Mol. Sci. 2022, 23(21), 13457; https://doi.org/10.3390/ijms232113457 - 3 Nov 2022
Cited by 4 | Viewed by 2597
Abstract
Interleukin-33 (IL-33) is an immunomodulatory cytokine which plays critical roles in tissue function and immune-mediated diseases. IL-33 is abundant within the brain and spinal cord tissues where it acts as a key cytokine to coordinate the exchange between the immune and central nervous [...] Read more.
Interleukin-33 (IL-33) is an immunomodulatory cytokine which plays critical roles in tissue function and immune-mediated diseases. IL-33 is abundant within the brain and spinal cord tissues where it acts as a key cytokine to coordinate the exchange between the immune and central nervous system (CNS). In this review, we report the recent advances to our knowledge regarding the role of IL-33 and of its receptor ST2 in cerebral malaria, and in particular, we highlight the pivotal role that IL-33/ST2 signaling pathway could play in brain and cerebrospinal barriers permeability. IL-33 serum levels are significantly higher in children with severe Plasmodium falciparum malaria than children without complications or noninfected children. IL-33 levels are correlated with parasite load and strongly decrease with parasite clearance. We postulate that sequestration of infected erythrocytes or merozoites liberation from schizonts could amplify IL-33 production in endothelial cells, contributing either to malaria pathogenesis or recovery. Full article
(This article belongs to the Special Issue Molecular Research on Plasmodium Infection and Immunity)
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Other

8 pages, 1956 KiB  
Brief Report
Enhanced Mouse Susceptibility to Endotoxin Shock after Plasmodium yoelii Infection Is Correlated with Increased Serum Levels of Lipopolysaccharide Soluble Receptors
by Pyone Pyone Soe and Jean-Paul Coutelier
Int. J. Mol. Sci. 2023, 24(10), 8851; https://doi.org/10.3390/ijms24108851 - 16 May 2023
Cited by 1 | Viewed by 977
Abstract
Sepsis is a common disease in sub-Saharan Africa and Asia, where malaria is also prevalent. To determine whether Plasmodium infection might enhance susceptibility to endotoxin shock, we used a mouse model of lipopolysaccharide (LPS) administration. Our results indicated that Plasmodium yoelii infection in [...] Read more.
Sepsis is a common disease in sub-Saharan Africa and Asia, where malaria is also prevalent. To determine whether Plasmodium infection might enhance susceptibility to endotoxin shock, we used a mouse model of lipopolysaccharide (LPS) administration. Our results indicated that Plasmodium yoelii infection in mice strongly enhanced the susceptibility of the host to develop endotoxin shock. This increased susceptibility to endotoxin shock was correlated with a synergistic effect of Plasmodium and LPS on the secretion of Tumor Necrosis Factor (TNF). TNF contributed mostly to lethality after the dual challenge since neutralization with an anti-TNF antibody provided protection from death. Plasmodium infection also induced an enhancement of the serum levels of LPS soluble ligands, sCD14 and Lipopolysaccharide Binding Protein. In this regard, our data confirm that Plasmodium infection can profoundly modify responses to secondary bacteria challenges, resulting in dysregulated cytokine expression and pathological effects. If confirmed in humans, LPS soluble receptors might serve as markers of susceptibility to septic shock. Full article
(This article belongs to the Special Issue Molecular Research on Plasmodium Infection and Immunity)
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