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Association between RANTES/CCL5 levels with Plasmodium infections and malaria severity: a systematic review

Malaria Journal volume 23, Article number: 335 (2024) Cite this article

Abstract

Background

Malaria continues to be a significant global health concern, and developing effective therapeutic strategies requires an understanding of the immune response to the disease. This systematic review synthesized the current body of research on the role of regulated on activation, normal T cell expressed and secreted (RANTES)—in the pathogenesis and disease severity of malaria.

Methods

A systematic review protocol was registered with PROSPERO under the registration number CRD42024535822. The systematic review was conducted following PRISMA guidelines to identify studies examining RANTES levels in individuals infected with Plasmodium species. Searches were performed across multiple databases, including ProQuest, Journals@Ovid, Embase, Scopus, PubMed, and MEDLINE. Further searches were performed in Google Scholar. Quality assessment was done using the Joanna Briggs Institute (JBI) critical appraisal tools. Alterations in RANTES levels in patients with malaria were synthesized narratively.

Results

A comprehensive search of major databases identified 22 studies meeting inclusion criteria, predominantly focusing on Plasmodium falciparum and Plasmodium vivax infections. RANTES levels were found to vary significantly across different severities of malaria, with several studies reporting lower levels in severe cases compared to non-malarial controls. However, inconsistencies were observed in the alterations of RANTES levels between severe and non-severe malaria cases.

Conclusion

Taken together, the finding of this systematic review underscore the complex regulation of RANTES in malaria pathophysiology. Future research should focus on longitudinal assessments to elucidate the dynamic role of RANTES throughout the course of malaria and recovery, to potentially inform the design of novel therapeutic strategies.

Background

Malaria is a disease prevalent in tropical and subtropical regions of the world, with an estimated 249 million cases in 85 endemic countries and areas in 2022 [1]. It is caused by parasitic Plasmodium species, most commonly Plasmodium falciparum, and is transmitted through the bites of infected female Anopheles mosquitoes [2]. Besides P. falciparum, malaria can be caused by Plasmodium vivax, Plasmodium ovale wallikeri, Plasmodium ovale curtisi, Plasmodium malariae, and Plasmodium knowlesi [3,4,5]. The disease can range from mild acute febrile episodes to severe complications like cerebral malaria, which involves multi-organ damage and is particularly deadly [6, 7]. Globally, malaria caused an estimated 608,000 deaths in 2022, with most occurring in children under 5 years of age [1].

The immune response to malaria is complex and involves both innate and adaptive immunity [8, 9]. Upon infection, the body’s immediate defense mechanisms include the activation of macrophages and the release of pro-inflammatory cytokines, which help control the early stages of the parasite [10, 11]. Regulatory cytokines and chemokines, involved in leukocyte trafficking and activation, play a crucial role in controlling parasitemia and eliminating infection. Key cytokines and chemokines include interferon-gamma (IFN-γ), tumour necrosis factor (TNF), interleukin (IL)-10, IL-17, IL-4, and the regulated on activation, normal T cell expressed and secreted (RANTES) [12,13,14,15,16,17,18].

RANTES, also known as C–C motif chemokine ligand 5 (CCL5), is a 68-amino acid chemokine involved in orchestrating the immune response, playing a significant role in the recruitment and activation of various immune cells during an immune challenge [19]. RANTES facilitates the trafficking and homing of classical lymphoid cells by binding to its receptor [19]. This pro-inflammatory chemokine, predominantly generated by CD8 + T cells, fibroblasts, epithelial cells, and platelets, is a hallmark of inflammation. Increased RANTES expression has been linked to various inflammatory disorders and pathologies, including allogeneic transplant rejection, atherosclerosis, arthritis, atopic dermatitis, and other inflammatory conditions [20]. RANTES promote leukocyte migration by binding to receptors in the seven-transmembrane G protein-coupled receptor (GPCR) family, including C-C motif chemokine receptor (CCR) 1, CCR3, CCR4, and CCR5 [21]. It promotes the infiltration of leukocytes (such as T cells and monocytes, basophils, eosinophils, natural killer cells, dendritic cells, and mast cells) to sites of inflammation [20, 22].

Prior studies have shown that differences in the RANTES gene affect the synthesis of the RANTES protein and the host's ability to fight against different infections [23, 24]. In the context of malaria, low amounts of RANTES protein have been observed in cases of severe malaria, which may be related to thrombocytopenia brought on by malaria or monocytes acquiring Plasmodium haemozoin [15]. Children with cerebral malaria have a higher death rate when their RANTES levels are lower [25]. Although RANTES levels were reported to be lower in patients with malaria, the precise role of RANTES in Plasmodium infection in relation to severity remains unclear. This systematic review aims to collate evidence of RANTES levels in individuals infected with Plasmodium species. Understanding the differences in this key chemokine and the resulting immunomodulation may provide crucial insights into malaria pathology.

Methods

Protocol and registration

This systematic review protocol was registered with PROSPERO under the registration number CRD42024535822. The reports follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [26].

Search strategy

A systematic review was conducted to identify studies that examined the levels of RANTES in patients infected with Plasmodium species. The search involved several databases, including ProQuest, Journals@Ovid, Embase, Scopus, PubMed, and MEDLINE. The search terms used were: “(RANTES OR CCL5 OR “RANTES Protein” OR “T-Cell RANTES Protein” OR “CCL5 Chemokine”) AND (malaria OR plasmodium OR “Plasmodium Infection” OR “Remittent Fever” OR “Marsh Fever “ OR Paludism)” (Table S1). There were no restrictions on the language or publication date of the retrieved articles. Additionally, Google Scholar was searched to ensure all relevant articles were included.

Eligibility criteria

The inclusion criteria for the studies were as follows: studies involving human participants infected with Plasmodium species, studies measuring RANTES levels in plasma or serum, and studies comparing RANTES levels in malaria patients to non-malarial controls or between different severities of malaria. The exclusion criteria included animal or in vitro studies, conference abstracts without full-text articles, studies lacking relevant information on RANTES, or non-original articles.

Study selection and data extraction

Initially, records were retrieved and identified from databases and imported to EndNote software (Version 20, Clarivate Analytics, UK). After removing duplicates, the remaining records were screened based on predetermined inclusion and exclusion criteria, focusing on studies that investigated RANTES levels in infected and uninfected individuals and the association of RANTES with malaria severity. Study selection was independently performed by two authors (MK, AM), with discrepancies resolved by consensus.

The following data were extracted from each study: author and year of publication; continent and country; study design; year of experiments; number and characteristics of participants; Plasmodium species; age range; RANTES levels in patients infected with Plasmodium species (and also non-malarial controls); RANTES levels in quantitative values (mean ± standard deviation or median with range); parasite density; method for detection of Plasmodium parasites; and method for RANTES quantification. Data extraction was performed independently by two authors (MK, AM). Discrepancies were resolved by consensus or consultation with a third author (PK).

Risk of bias assessment and data syntheses

The risk of bias among the included studies was assessed using the Joanna Briggs Institute (JBI) tool, a critical appraisal tool for evaluating the methodological quality of various study designs, including case–control, cross-sectional, randomized controlled trials (RCTs), and cohort studies [27]. For case–control studies, the JBI tool evaluates factors like comparability of cases and controls, consistency in criteria application, exposure measurement reliability, and handling of confounding factors. For cross-sectional studies, it focuses on inclusion criteria clarity, subject description, measurement validity and reliability, and appropriate statistical analysis. For RCTs, the tool assesses randomization, blinding, follow-up completeness, and the rigour of outcome measurement. Lastly, for cohort studies, it examines the identification and management of confounding factors, follow-up completeness, exposure measurement validity, and the appropriateness of statistical methods used. A narrative synthesis using a thematic synthesis approach was applied to synthesize the findings of the reviewed studies [28]. A meta-analysis was not conducted due to the inadequate quantitative data on RANTES levels in participants with Plasmodium infections and comparison groups.

Results

Search results

Initially, 1,488 records were identified from main databases such as ProQuest, Journals@Ovid, Embase, Scopus, PubMed, and MEDLINE, with 382 duplicates removed. Of the remaining records, 996 were excluded for not meeting the criteria related to participants or outcomes. Consequently, 110 reports were sought for retrieval, but 1 report was not retrieved. A total of 109 reports were assessed for eligibility, with 91 being excluded for reasons such as being animal or in vitro studies, conference abstracts, or lacking relevant RANTES information. An additional 200 records were identified via Google Scholar. Of these records, 32 reports were sought, 2 were not retrieved, and 30 were assessed, leading to 26 exclusions for specific reasons that they did not meet the inclusion criteria. Finally, 22 studies were included in the review [11, 15, 29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48]: 18 from the main databases [11, 15, 30,31,32,33,34,35,36, 38,39,40,41,42,43, 46,47,48] and 4 from Google Scholar [29, 37, 44, 45] (Fig. 1).

Fig. 1
figure 1

Study flow diagram

Full size image

Characteristics of included studies

The included studies in the systematic review predominantly focus on P. falciparum infections, accounting for 86.36% of the studies, with a smaller portion (13.64%) examining P. vivax (Table 1). Most of these studies (54.55%) were published between 2010 and 2019, while 27.27% were published between 2000 and 2009, and 18.18% from 2020 to 2023. In terms of study design, the majority were case–control studies (40.91%), followed by cross-sectional (27.27%) and cohort studies (27.27%), with only one randomized controlled trial (4.55%). Geographically, the studies were primarily conducted in Africa (72.73%), notably in Ghana, Kenya, Mali and Uganda. Asia and South America also contributed to the dataset, with India and Brazil each accounting for 13.64% of the studies conducted. Participants were predominantly children (54.55%), with studies also including adults (18.18%), both children and adults (18.18%), and pregnant women (9.09%). Microscopy was the most common malaria detection method (50%), often supplemented by polymerase chain reaction (PCR) (18.18%) or rapid diagnostic tests (RDTs) (22.73%). For RANTES detection, bead-based assays were used in the majority of studies (72.73%), while ELISA was employed in 22.73% of the studies. With regards to the type of blood sample used, RANTES measurements were predominantly from plasma (86.36%), with a minority using serum (13.64%).

Table 1 Summary characteristics of included studies
Full size table

Risk of bias assessment

For cross-sectional studies included in the review, Aguilar et al. [29] and Noone et al. [40] demonstrated the lowest risk of bias, meeting all criteria, including clear inclusion criteria, detailed subject description, valid and reliable measurements, and appropriate statistical analysis. Boström et al. [32], Panda et al. [43], and Turner et al. [46] showed some risk of bias due to inadequate identification and management of confounding factors, despite meeting most other criteria. Were et al. [48] exhibited the highest risk of bias, with unclear aspects such as exposure measurement, use of objective criteria, and statistical analysis.

For case–control studies included in this review, most studies ensured group comparability and proper matching of cases and controls, consistently applied criteria for identification, and used reliable exposure measurement methods. However, Frimpong et al. [37] did not consistently apply criteria for identifying cases and controls, and several studies either did not address or unclearly addressed confounding factors. For cohort studies included in the review, there were variations in the identification and handling of confounding factors and completeness of follow-up. Boström et al. [33] and Suguitan et al. [45] addressed confounding factors adequately but had issues with incomplete follow-up. Bujarbaruah et al. [34] and Ochiel et al. [41] did not identify or address confounding factors and had follow-up issues. Reuterswärd et al. [44] and Vinhaes et al. [47] identified confounding factors but did not comprehensively report on follow-up strategies. All studies used valid and reliable exposure measurement methods and applied appropriate statistical analyses (Table S2).

RANTES levels in malaria compared to non-malaria patients

Table 2 presents details from the included studies, focusing on RANTES levels in patients with malaria. Seventeen studies reported comparisons of RANTES levels between patients with malaria and non-malarial controls [11, 15, 29,30,31,32,33,34,35, 37,38,39, 41, 44,45,46, 48]. Several studies consistently found significantly lower RANTES levels in severe malaria compared to non-malarial controls [15, 29, 31, 33, 34, 38, 41, 44, 48]. For instance, Boivin et al. observed lower RANTES levels in severe malaria compared to community controls in their randomized controlled trial [31], while Were et al. reported lower RANTES levels in severe malarial anaemia compared to healthy controls [48]. John et al. noted decreased RANTES levels in cerebral malaria compared to community controls [15], and Ochiel et al. found lower RANTES levels in children with both mild and severe malaria compared to healthy controls [41]. Bujarbaruah et al. reported significantly lower serum RANTES concentrations in severe malaria cases compared to control cases [34], and Frimpong et al. observed lower RANTES levels in children with malaria compared to children with sepsis but higher than febrile controls [37].

Table 2 Details of included studies
Full size table

Boström et al. showed significantly lower RANTES levels in infected Dogon populations compared to uninfected Dogon, but found no difference in RANTES levels between infected and uninfected Fulani [32]. Aguilar et al. [29], Boström et al. [33], and Reuterswärd et al. [44] similarly reported lower RANTES levels in infected individuals compared to uninfected individuals [29]. Hojo-Souza et al. demonstrated lower RANTES levels in individuals with P. vivax infection compared to endemic controls [38]. In contrast, several studies did not find significant differences in RANTES levels between infected individuals and uninfected controls [30, 35, 39, 45, 46]. For example, Turner et al. found no difference in RANTES levels between infected individuals and uninfected adults [46], Jain et al. observed no difference between different malaria groups and healthy controls [39], and Armah et al. reported no difference between children with malaria and non-malarial controls [30]. Cruz et al. [35, 45] found no significant difference in RANTES levels between symptomatic vivax patients and uninfected controls. Suguitan et al. [45] also found no significant difference in RANTES levels between P. falciparum-infected and uninfected individuals. Obeng-Aboagye et al. noted higher RANTES levels in severe malaria compared to febrile controls but no difference between uncomplicated malaria and febrile controls [11].

RANTES levels in patients with malaria in relation to disease severity

Eight studies examined RANTES levels in patients with malaria across different complications and severities [11, 30, 34, 39, 41,42,43, 48]. Some studies reported no significant differences in RANTES levels between various groups. For instance, Jain et al. found no difference in RANTES levels between cerebral malaria survivors, non-survivors, and mild malaria cases [39]. Armah et al. observed no difference in RANTES levels between children with cerebral malaria and severe malarial anaemia [30]. Ong’echa et al. similarly reported no differences among patients with severe malarial anaemia, non-severe malarial anaemia, and uncomplicated malaria [42]. Obeng-Aboagye et al. revealed no variation in RANTES levels between severe and uncomplicated malaria [11].

In contrast, other studies identified significant differences in RANTES levels based on malaria severity. Were et al. observed decreasing RANTES levels with increasing severity of malarial anaemia, with the severe malarial anaemia group showing lower circulating RANTES than children with moderate and mild malarial anaemia [48]. Ochiel et al. demonstrated significantly lower RANTES levels in children with severe malaria compared to those with mild malaria [41]. Panda et al. found significantly lower RANTES levels in severe malaria compared to non-complicated malaria [43]. Bujarbaruah et al. reported significantly lower serum RANTES concentrations in severe malaria cases (15,708.92 ng/L) compared to uncomplicated malaria cases (16,147.74 ng/L) [34].

Other findings about RANTES in patients with malaria

John et al. found that RANTES levels at 72 h after admission were significantly higher than those at the time of admission. These levels were comparable to those observed in children with uncomplicated malaria but still lower than those in community controls [15]. Hojo-Souza et al. demonstrated a significant increase in RANTES levels after treatment when following the same individuals [38]. Daveport et al. reported that RANTES levels were highest in co-infected individuals, high in individuals with malaria alone, and lowest in those exposed to both human immunodeficiency virus (HIV) and P. falciparum infections [36]. Vinhaes et al. showed significantly higher RANTES levels in symptomatic malaria compared to asymptomatic cases [47]. Noone et al. found no association between RANTES and P. falciparum parasitaemia [40]. Boivin et al. observed that severe malaria survivors with higher plasma RANTES levels showed better cognitive performance after receiving a computerized cognitive rehabilitation training (CCRT) intervention [31].

Discussion

The data from the included studies provide a comprehensive view of the role of RANTES in malaria pathogenesis and severity. Several studies highlighted lower RANTES levels in patients with severe malaria compared to non-malaria controls, suggesting a potential role of RANTES in the immune response against Plasmodium infection. For example, Were et al. [48] and John et al. [15] found decreased RANTES levels in severe malarial anaemia and cerebral malaria, respectively, suggesting that reduced RANTES may be associated with severe disease outcomes. Conversely, studies by Jain et al. [39] and Armah et al. [30] did not find significant differences in RANTES levels between malaria patients and non-malarial controls, indicating the complexity of RANTES regulation across different patient populations and malaria presentations.

The variation in RANTES levels among different ethnic groups, as shown in studies by Boström et al., suggests that genetic or environmental factors might influence RANTES expression. Moreover, the differential RANTES response to treatment, as demonstrated by Hojo-Souza et al. [38], underscores the dynamic nature of RANTES during the course of the disease and recovery. A key observation from the synthesis is the potential protective role of RANTES in uncomplicated malaria, where higher RANTES levels might contribute to better clinical outcomes and recovery, as indicated by the improved cognitive performance in severe malaria survivors with higher RANTES levels undergoing rehabilitation [31]. However, the association of low RANTES levels with thrombocytopenia, a common condition in severe malaria, points to the intricate link between platelet counts and RANTES levels. This link is supported by studies such as that of Frimpong et al. [37], which found significant differences in RANTES levels among children with sepsis, malaria, and febrile controls, suggesting that RANTES could serve as a biomarker for differentiating these conditions.

The immunomodulatory role of RANTES in reducing malaria pathogenesis aligns with observations that RANTES levels are lower during periods of lower malaria transmission intensity [29]. Previous studies have shown that neither serum nor cerebrospinal fluid (CSF) levels of RANTES are predictive of cerebral malaria mortality [30]. According to RCTs, individuals who survived severe malaria and had higher plasma and CSF RANTES levels after receiving rehabilitation training outperformed those who did not in terms of cognitive performance [31], implying that lower RANTES levels during acute illness are generally associated with more adverse clinical outcomes.

Low levels of RANTES in malaria patients may be explained by reduced platelet counts during acute Plasmodium infections [32, 49, 50]. Additionally, decreased RANTES levels could be attributed to the reduction of CD8 + T cells during Plasmodium infections [51, 52]. In pregnant women with acute P. falciparum infection, decreased RANTES levels have been reported, which is potentially associated with pregnancy-related stress [33]. According to a prior study, pregnant women with acute, uncomplicated malaria are more thrombocytopenic than non-pregnant women [53]. Studies have suggested that RANTES concentrations could differentiate between children with sepsis, clinical malaria, and febrile controls [37]. Lower RANTES levels in children with cerebral malaria have been linked to higher mortality in cases of severe malaria, even after controlling for other cytokine levels [15]. Thrombocytopenia has also been associated with decreased RANTES levels, while normal platelet counts have been found to correlate with normal RANTES levels [15]. Previous studies have suggested that RANTES concentrations directly mediate protection from severity and aid recovery in uncomplicated malaria cases by controlling the expression and modulation of monocytes, which in turn regulate the downstream effector cytokine TNF [34]. Elevated TNF levels have been correlated with disease severity [54, 55].

The mechanism linking RANTES to cerebral malaria may involve its role in mediating Plasmodium infection control, with impaired RANTES production potentially leading to severe malaria and increased mortality in children with cerebral malaria [15]. RANTES production occurs in both the brain and peripheral circulation, including lymphocytes, monocytes, and platelets [19]. Therefore, RANTES may have varying effects in these areas, primarily influencing regions where sequestration occurs (the brain) and having less impact in peripheral circulation, where local inflammatory mediators and cell concentrations may be less pronounced. Studies have shown decreased mRNA and protein levels of RANTES in children with severe malaria, suggesting that higher RANTES levels may offer protection against severe disease [41].

This study has some limitations. Firstly, the quantitative data from the included studies were insufficient to conduct a meta-analysis, precluding comparison of pooled mean differences in RANTES levels between participant groups. Secondly, other chemokines or cytokines involved in malaria pathogenesis may also influence RANTES levels in malaria patients. Therefore, further research on RANTES in conjunction with these molecules could provide a clearer understanding of how RANTES modulation might be leveraged for therapeutic interventions in malaria.

Conclusion

The literature demonstrates that RANTES levels tend to be lower in infected participants compared to non-malarial controls. However, whether RANTES levels correlate with malaria severity and patient outcomes still requires further investigation, as individual studies have shown mixed results—some indicating that RANTES levels decrease with increasing malaria severity, while others show no significant difference among different severities. Future studies should prioritize longitudinal assessments of RANTES levels throughout the disease progression and recovery phases. This approach could provide a clearer understanding of how RANTES modulation might be leveraged for therapeutic interventions in malaria.

Availability of data and materials

All relevant data are within the manuscript and its Supporting Information files.

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Authors and Affiliations

  1. Medical Technology, School of Allied Health Sciences, Walailak University, Tha Sala, Nakhon Si Thammarat, Thailand

    Pattamaporn Kwankaew

  2. Department of Protozoology, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand

    Aongart Mahittikorn

  3. Medical Technology Program, Faculty of Science, Nakhon Phanom University, Nakhon Phanom, Thailand

    Wanida Mala, Kwuntida Uthaisar Kotepui & Manas Kotepui

  4. Department of Biochemistry & Molecular Medicine, School of Medicine, University for Development Studies, Tamale, Ghana

    Nsoh Godwin Anabire

  5. West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell & Molecular Biology, University of Ghana, Accra, Ghana

    Nsoh Godwin Anabire

  6. Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

    Polrat Wilairatana

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  1. Pattamaporn Kwankaew
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Contributions

MK and PK carried out the study design, study selection, data extraction, and statistical analysis. PK and MK drafted the manuscript. NGA, WM, KUK, AM, and PW reviewed and critically edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Manas Kotepui.

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Kwankaew, P., Mahittikorn, A., Mala, W. et al. Association between RANTES/CCL5 levels with Plasmodium infections and malaria severity: a systematic review. Malar J 23, 335 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12936-024-05152-1

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12936-024-05152-1

Keywords

Malaria Journal

ISSN: 1475-2875

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