Chemokines responses to Plasmodium falciparum malaria and co-infections among rural Cameroonians

October 3, 2017 | Autor: Clement Isaac | Categoria: Parasitology, Immunology
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Parasitology International 64 (2015) 139–144

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Chemokines responses to Plasmodium falciparum malaria and co-infections among rural Cameroonians Jane Nchangnwi Che a,b, Onyebiguwa Patrick Goddey Nmorsi a, Baleguel Pierre Nkot b, Clement Isaac a,⁎, Browne Chukwudi Okonkwo c a b c

Tropical Disease Research Unit, Department of Zoology, Ambrose Alli University, Ekpoma, Nigeria Centre for the Diagnosis and Control of Tropical Disease, Nkolbisson, Yaounde, Cameroon Department of Internal Medicine, Central Hospital, Agbor, Nigeria

a r t i c l e

i n f o

Article history: Received 4 August 2014 Received in revised form 10 October 2014 Accepted 6 November 2014 Available online 16 November 2014 Keywords: Uncomplicated malaria Chemokines Co-infections Symptoms Cameroon

a b s t r a c t Malaria remains the major cause of disease morbidity and mortality in sub-Saharan Africa with complex immune responses associated with disease outcomes. Symptoms associated with severe malaria have generally shown chemokine upregulation but little is known of responses to uncomplicated malaria. Eight villages in central Cameroon of 1045 volunteers were screened. Among these, malaria-positive individuals with some healthy controls were selected for chemokine analysis using Enzyme-Linked Immunosorbent Assay (ELISA) kits. Depressed serum levels of CXCL5 and raised CCL28 were observed in malarial positives when compared with healthy controls. The mean concentration of CXCL11 was higher in symptomatic than asymptomatic group, while CCL28 was lower in symptomatic individuals. Lower chemokine levels were associated with symptoms of uncomplicated malaria except for CXCL11 which was upregulated among fever-positive group. The mean CXCL5 level was higher in malaria sole infection than co-infections with HIV and Loa loa. Also, there was a raised mean level of malaria + HIV co-infection for CXCL9. This study hypothesises a situation where depressed chemokines in the face of clinical presentations could indicate an attempt by the immune system in preventing a progression process from uncomplicated to complicated outcomes with CXCL11 being identified as possible biomarker for malarial fever. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction An estimated two billion people live in areas at risk of malaria with blood stage of the parasite responsible for malaria-associated pathology [1]. In malaria-endemic regions, uncomplicated and severe malaria exists with the former being highly prevalent. Parasite load of more than 100,000 parasites/μL of blood are commonly regarded as indicators of risk of severe malaria in a low-transmission setting [2]. Symptoms of uncomplicated malaria may include fever, althralgia, headache, pallor, liver enlargement (mild hepatomegaly) and spleen enlargement (mild splenomegaly); and any of these could present at any stage of infection. However, since the aforementioned symptoms are non-specific for malaria, WHO recommends that malaria parasite confirmation in blood film through microscopy should be mandatory especially in endemic regions where these symptoms are mostly perceived to be solely caused by malaria and thereby given to arbitrariness and self medication [3]. Most times, among malarial-infected population, symptomatic and asymptomatic individuals are represented with the later largely due to the protective effect of the immune system following a repertoire of infection [4]. ⁎ Corresponding author. E-mail address: [email protected] (C. Isaac). 1383-5769/© 2014 Elsevier Ireland Ltd. All rights reserved.

Immunity to malaria is dependent on both the innate and adaptive (both cell- and antibody mediated) arms of the immune system [5]. Chemokines are chemotactic cytokines that play important roles in bridging the innate and the adaptive immune system [6]. Being classified into subfamilies, CC, CXC, CX3C and C, chemokines share a significant degree of sequence homology [7] and play key roles in protozoan parasite infections by mediating cell trafficking and immune cells recruitment for the development of protective responses. Generally, during infection, leucocytes could cause a shift from constitutive to inflammatory chemokines with polarisation of CD4+ T cells to TH1 and TH2 subsets orchestrated by the upregulation of distinct set of chemokines and their chemokine receptors [8,9]. Typically, TH1 and TH2 cells are predominantly characterised by known chemokine receptors' expressions, but the association of T-helper phenotypes in vivo has shown a much more complex profile [10,11]. Results of a study in some human subjects with long periods of nonexposure to P. falciparum malaria have shown decrease in cytokines and chemokines profiles [12]. Severe malaria comes with great fatalities and groups of chemokines have been implicated to influence the disease outcomes [13–15]. Current views have proposed that inflammatory responses contribute to the expression of severe malaria through a likely association with parasite density [16,14]. Also, progression from


J.N. Che et al. / Parasitology International 64 (2015) 139–144

uncomplicated to severe malaria is a possibility and the mechanism could be mediated by complex immune responses. Furthermore, in malaria-endemic regions, malaria co-exists with other pathogens in the blood, and this is a factor that could aggravate its pathological conditions. In order to ascertain the importance of chemokines in relation to symptoms of uncomplicated malaria in an effort towards partly understanding the dynamics of progression from mild to possibly documented severe cases, the profiles of some chemokines were determined and their roles were discussed. Also, chemokine reponses to malaria co-infections with HIV and Loa loa were highlighted. 2. Materials and methods

2° 48′ N–4° 32′ N and 9° 54′ E–13° 30′ E. Also, the villages are located in Nyong valley which has Rain Forest vegetation; and within it, portions of the Nyong River (690 km long) and its tributaries run. The climatic conditions of the area favours mosquito breeding and as such malaria transmission is meso-endemic with highest transmission index during the rainy season. Four climatic seasons characterise this region annually, viz; two dry seasons and two rainy seasons. These seasons are a long rainy season with low intensity from March to June; a short dry season from July to August; a short rainy season with high intensity from September to November and a long dry season from mid-November to February. The majority of the houses seen in this area are mud houses; and many are without door or/and window nettings to prevent mosquitoes and other flying or creeping insects from gaining entry.

2.1. Study area 2.2. Study population This study was conducted in November 2012 and samples collected were from rural Cameroon. Eight villages were selected: Koukoum, Minkotmbem, Kaya, Libamba, Bonde, Bondjock, Ngombas and Bakoukoué (Figure 1. These villages are inhabited by the Bakoko-Bassa and Eton ethnic groups and are within the Centre Region of Cameroon, namely Nyong-and-Kelle Division and in Makak Subdivision between coordinates

The human population size of these villages is about two thousand with farming being the major preoccupation. Others are workers in industries including the hydroelectric cooperation. Prior to the mass screening exercise, ethical clearance from the Cameroon National Ethical Committee was obtained; and subsequently, community

Fig. 1. Map of Cameroon showing study areas (Cellule Cartographie DAT). Legends: Study area

. Study Region (the Centre Region) .

J.N. Che et al. / Parasitology International 64 (2015) 139–144


Table 1 % prevalence of microscopically positive individuals with symptoms of malaria infection. Clinical status (microscopy positive) Clinical signs Prevalence

Fever 150 (51.11)

Symptomatic n (%) Headache 76(26.11)

Pallor 20 (6.87)

Asymptomatic n (%) Arthralgia 98 (41.98)

Splenomegaly 19 (6.52)

Hepathomegaly 17(5.84)


Total number examined = 1045; serology positive = 653 (62.49%); microscopy positive = 312(29.85%); symptomatic individuals = 291 (93.26%).

mobilisations were carried out. Informed consents were equally sought and obtained from the 1045 volunteers (451 males and 594 females) recruited for this survey. Among the 1045 subjects, the population structure by age was as follows: ≤5 yrs (n = 108); 6–16 yrs (n = 191); 17–50 yrs (n = 394); N50 yrs (n = 352). Similarly, of the 312 microscopically positive (Table 1), a total of 89 were selected for immunological study having met the inclusion criteria of sole infection with malaria or co-infection with HIV or L. loa. The sex structure of the number selected for chemokine analysis was 31 males and 58 females. Age distribution was as thus: ≤5 yrs (n = 12); 6–16 yrs (n = 17); 17–50 yrs (n = 38) and N 50 yrs (n = 22). Among these 89, some were symptomatic (n = 77) and others were asymptomatic (n = 12). The number among symptomatic group with malaria sole infection was 54, while malaria co-infections with HIV and L. loa were 16 and 7 respectively. All co-infected cases were symptomatic and no HIV positives had developed to AIDS. Malaria infection was defined as having a positive thick blood smear with or without any malaria symptoms. Sympomatic group with uncomplicated malaria was defined as positive Plasmodium falciparum blood smear (b 10,000 parasites/μL) with fever ≥37.5 °C at the point of blood collection or/and headache, pallor, althralgia, mild splenomegally and mild hepatomegaly; while asymptomatic were positive but no associated symptoms with malaria. 2.3. Parasites/HIV analysis and clinical examination Blood samples (5 mL each) were aseptically collected by venipuncture into EDTA tubes. For the identification of P. falciparum species, microscopy and Diaspot P.f rapid test (Detekt Biomedical) were used. For microscopy, thin and thick blood films were made from blood. Prior to staining, the thin films were fixed with absolute alcohol and both films were flooded with 10% Giemsa-staining solution and allowed to stain for 10 min. Slides were examined under 40× and 100× objectives for malaria parasite stages. The number of Plasmodium parasites per 100 white blood cells was recorded. In addition, the DiaSpot Malaria P. falciparum rapid test device complemented the detection and identification of P. falciparum antigen in whole blood. The volunteers were examined physically for the signs and symptoms of malaria and then recorded. In the course of screening for other infections, rapid antibody tests were carried out for HIV diagnosis, while the detection of microfilariae in the blood was through microscopy. 2.4. Chemokine analysis Blood samples (5 mL) were collected from infected and uninfected volunteers in dry tubes and centrifuged within 30 min of collection at

2000G for 15 min. The serum obtained was aliquot into cryolated tubes. All samples were transported from the villages in a cool box to our Centre for the Diagnosis and Control of Tropical Disease at Nkolbisson, Yaounde for analysis. The serum was stored frozen until analysed. The Enzyme-Linked Immunosorbent Assay (ELISA) (Abcam, UK) was applied to determine the serum levels of CX3CL1, CXCL5, CXCL7, CXCL9, CXCL11 and CCL28 using specific enzyme immune assay test kits following the manufacturer's protocol. Microplates were coated with human antibodies specific for antigens of the different chemokines. All immunoenzymatic techniques were based on measuring the absorbance after a peroxidation reaction at 450 nm. Between the reaction steps, the plates were washed manually. The absorbance was measured using a microplate reader (MR-96A). The concentrations were extrapolated from an obtained standard curve. 2.5. Statistical analysis Differences in the chemokine levels between the malarial positives and healthy controls were analysed using chi-square test. Independent sample t-test was applied to determine the level of significance of the differences in the profiles of chemokines recorded for symptomatic and asymptomatic groups. Spearman rank correlation was used to determine the association between parasite density and chemokine concentrations. One-way ANOVA was employed to estimate the degree of variation in chemokine levels between single and co-infected cases. Data were analysed using SPSS and InStat statistical packages. 3. Results Table 2 shows the results of symptomatic malaria positives and negatives, correlation analysis between malaria load and chemokine concentrations, symptomatic and asymptomatic malaria-infected subjects and analysis of single and co-infections. The mean level of CXCL5 was significantly depressed in malarial positives in comparison to the control group; while for CCL28, a positive association with raised mean concentration was recorded. The other chemokines analysed showed no significant variations between positives and controls but a positive correlation with parasite load was noted for all. There were significant differences between malaria positive and negative individuals for CXCL5 (χ2 = 708.48; p b 0.001) and CCL28 (χ2 = 235.62; p N 0.001). A majority of symptomatic individuals presented with fever, althragia, pallor, headache, mild splenomegally and mild hepatomegally. Samples of individuals that presented with other symptoms outside the aforementioned ones were not analysed due to limited number. The mean concentration of CXCL11 was higher in symptomatic than asymptomatic

Table 2 Chemokine profile of malaria single infection and co-infections. Chemokine (pg/mL)

Symptomatic malaria positive n = 54

Asymptomatic malaria positive n = 12

Malaria + HIV n = 16

Malaria + L. loa n=7

Control (non-infected) n = 20

Correlation value with malaria load


1.14 ⁎9428.77 60.61 598.33 162.84 ⁎21.92

1.95 9828.57 61.05 540.95 ⁎64.43 ⁎76.19

2.30.13 ⁎6412.34 20.45 ⁎2211.21 119.35 10.14

1.22 ⁎4812.43 33.23 ⁎660.12 125.12 34.13

1.41 12,013.33 75.53 465.33 158.13 1.73

0.65 −0.85 0.53 0.42 0.30 0.66

± ± ± ± ± ±

0.54 51.39 3.42 46.88 25.83 2.27

± ± ± ± ± ±

0.27 58.33 8.91 51.42 5.87 9.15

± ± ± ± ± ±

1.31 23.67 2.28 28.83 26.92 2.45

± ± ± ± ± ±

0.13 23.41 3.23 11.13 24.13 3.21

± ± ± ± ± ±

0.13 45.99 8.83 29.93 23.43 0.51

⁎ significant, malaria positives = microscopically positives; controls = serologically and microscopically negatives. Malaria density ranged between 3785 and 9270 parasites/μL of blood.


J.N. Che et al. / Parasitology International 64 (2015) 139–144

Table 3 Mean chemokines profile with symptoms of uncomplicated malaria. Chemokine (pg/mL)/symptom




1.48 10,350.23 87.17 491.11 ⁎285.25 ⁎1.44

n(17) ± ± ± ± ± ±

0.58 58.53 2.33 42.29 37.07 0.12

1.11 9745.71 56.65 597.71 130.36 22.86


p(27) ± ± ± ± ± ±

0.41 89.79 2.93 41.43 28.77 9.24

0.66 10,293.33 ⁎33.52 715.35 217.25 20.87

n(21) ± ± ± ± ± ±

0.22 50.77 6.57 47.14 25.89 4.75

1.45 9650.19 78.09 503.97 133.48 27.59

p(11) ± ± ± ± ± ±

0.15 51.15 7.39 41.30 26.91 2.13

2.33 ⁎5335.32 41.23 750.21 150.73 10.54

n(15) ± ± ± ± ± ±

0.47 35.11 2.11 67.31 21.22 1.51

1.20 9921.83 63.14 573.95 162.18 18.69

± ± ± ± ± ±

0.61 51.85 3.89 44.84 24.95 1.53

⁎ significant; symptomatic individuals had a combination of two or more clinical presentations. The positives (p) are patients showing malaria symptoms including the specific symptom by which a pair of ‘p’ and ‘n’ is named; while the negatives (n) showed same malaria symptoms seen in the positives (p) without the specific symptom by which its pair is named.

(t = 3.12; p b 0.01), while CCL28 mean concentration was significantly lower in symptomatic individuals (t = 2.13; p b 0.05). Other chemokines are assumed not to be impacted by malaria-associated symptoms. In addition, the analysis of single and co-infections on chemokines showed that mean CXCL5 level was significantly higher in malaria sole infection than co-infections with HIV and L. Loa (F = 132.12; p b 0.01). In contrast, for CXCL9, raised mean level of malaria + HIV co-infection was recorded when compared with malaria sole infection and co-infection with L. loa (F = 97.23; p b 0.01). These results may not be a complete representation of chemokine responses to these co-infections because of the small sample sizes. The mean chemokine concentrations showing a comparison of symptomatic malaria positives (p) and negatives (n) in particular relation to the symptom each pair is identified are presented in Table 3. For the fever positives, mean CXCL11 level was higher (t = 6.5; p b 0.001) and lower for CCL28 (t = 4.2; p b 0.001). Mean CXCL7 concentration was higher in headache negatives than positives (t = 2.58; p b 0.05), while lower mean level of pallor positives was noted for CXCL5 (t = 2.01; p b 0.05). Similarly, depressed mean concentrations of CXCL5 (1.67; p = 0.1) and CXCL11 (t = 3.92; p b 0.001) were recorded for mild splenomegaly positives; and in mild hepatomegaly positives, lower mean serum level of CXCL7 was seen (t = 2.04; p b 0.01). These results should be viewed with caution since some other factors might influence these responses due to the complex nature of the immune system in association with unforeseen internal conditions. 4. Discussion The mean serum concentration of CXCL5 was lower in malaria positives than controls. Also CXCL5 showed negative correlation with increase in parasite load. Human CXCL5, which is also known as epithelial cell-derived neutrophil-activating particle-78 (ENA-78) are involved in a variety of inflammatory diseases [17,18]. It has been speculated that parallels exist between malaria tolerance and bacterial endotoxin tolerance [19]. The traditional view of endotoxin tolerance holds that immune cells that are exposed to endotoxin have an altered response when re-challenged with endotoxin [20]. It has also been demonstrated that the Duffy Antigen Receptor for Chemokines (DARC) which is a promiscuous silent receptor, is highly expressed on erythrocytes and post-capillary venules, and is capable of binding to CXC and CC chemokines [21,22]. DARC which lacks the motif to enable G protein coupling and signalling [23], expresses itself on erythrocytes and has been suggested to modulate chemokine bioavailability by acting as chemokine sink [24] and a reservoir [25]. Hence, CXCL5-bound erythrocyte DARC could impair chemokine scavenging roles in blood leading to decreased neutrophil influx, increased pathogen burden and mortality as seen in pneumonia model [26]. So we suggest that the lower levels of CXCL5 in positives than control subjects as well as the negative correlation with increased parasite density could be a result of the scavenging roles of the innate immune system where CXCL5-bound erythrocyte DARC complex may have been primed at first infection to subsequently absorb this elicited chemokine during re-infections.

This study showed raised mean level of CCL28 in malarial positives in comparison with their parasite-negative counterparts. We hypothesise that the erythrocytic stage of malaria infection being characterised by decrease in hepatic elimination and biliary excretion [27] may have induced the upregulation of biliary CCL28 [28] by promoting the recruitment of immunosuppressive Treg which expresses CCR10. IgA secreting B-cells and subsets of regulatory T-cells also express CCR10 allowing an engagement with the mucosa through interaction with CCL28 which is widely expressed in a range of organs including the liver [29]. Malaria parasites initiate asymptomatic infection in the liver when sporocytes invade hepatocyte. We noted that in asymptomatic subjects, CCL28 was raised when compared to symptomatic cases. This could be an indication of the chemotactic involvement of CCL28 during the liver stage of infection in mobilising immune cells, a likely response of host innate immunity. Conversely, higher levels of CCXL11 were recorded for symptomatic than asymptomatic individuals. This response may thus indicate an initial role of this chemokine to inflammation when symptoms are mild and uncomplicated. While the concentrations of some serum chemokines including CXCL9 were unaltered in this study, CXCL9 has been widely implicated in severe malaria with evidence of upregulation [30–32]. Much of the symptoms of malaria attacks are consequences of the inflammatory responses orchestrated by the cells of the innate immune system [33]. The group positive of malaria presenting with fever showed increased levels of CXCL11 and depressed CCL28. A possible indication that CXCL11 was induced and upregulated by malaria infection and thus could be involved in malarial-fever pathogenesis. Some chemokines have been demonstrated to invoke intense and functionally different febrile responses when applied directly on pyrogen-sensitive cells in the hypothalamus [34]. In addition, for other symptoms such as headache, pallor, mild splenomegaly and mild hepatomegaly in the malarial positives, some chemokines showed depressed levels while others were unchanged. This observation of decreased chemokine levels for the symptoms associated with uncomplicated malaria could be associated with a hypothesis of an initial depressed response in preventing a likely progression to complicated form. Circulating sets of chemokines have been significantly elevated in cerebral-malaria cases compared with mild malaria or healthy controls [35–37]. Cerebral malaria could be due to the compromise of the blood–brain barrier mediated by increased level of chemokines [38]. Also, severe symptoms associated with malaria like placental malaria, liver and renal failures have been linked to upregulation of chemokines [39–41]. Thus, the depressed chemokines as well the raised CXCL11 could be targets in the development of improved anti-malaria therapy towards the management of malaria symptoms. Currently, sub-Saharan Africa is home to 90% of the world's P. falciparum infections [42] and 64% of the HIV-1 infections [43] with high prevalence of co-infection [44]. One important mechanism common to these diseases is inflammatory mediators' production which may contribute to their perturbation [45,46]. Thus, results on CXCL9 chemokine showed an increased production in malariapositive individuals co-infected with HIV when compared to cases with only malaria, thereby supporting a similar finding in which

J.N. Che et al. / Parasitology International 64 (2015) 139–144


Mild splenomegaly

p(20) 0.48 9054.05 46.56 667.57 195.08 41.32

n(22) ± ± ± ± ± ±

0.08 47.53 3.16 34.69 24.88 2.11

1.69 10,460.78 74.75 509.41 138.07 31.88

p(11) ± ± ± ± ± ±

0.06 53.54 7.39 46.65 26.81 6.71

1.22 ⁎6736.21 90.27 505.77 ⁎75.46 25.13

Mild hepathomegaly n(25)

± ± ± ± ± ±

0.23 15.63 7.28 45.62 8.17 3.34

monocytosis was a contributory factor to increased CXCL9 in patients with malaria and HIV [47]. Similarly, increased CXCL9 in malariapositive individuals has been implicated in promoting enhanced HIV-1 pathogenesis with severe anaemia being a consequence [48,49]. In contrast, CXCL5 was lower in co-infected than individuals with malaria only. We earlier assumed an organisation of CXCL5-bound erythrocyte DARC which has been shown to impair chemokine scavenging activities in the blood following malarial infection [26]. We thus suggest that CXCL5 levels induced by co-infection of HIV or L. Loa were considerably reduced through a possible absorptive mechanism by CXCL5-bound erythrocyte DARC after infection with falciparum malaria [24]. In conclusion, the complex interaction of chemokines to given disease conditions is highlighted in this investigation such that malariapositive subjects showed depressed serum CXCL5 concentrations while raised levels were recorded for co-infected cases. Meanwhile, CXCL5 was depressed in malarial positives with symptoms of pallor and mild splenomegaly, a likely indication of strong participation in the pathogenesis of uncomplicated malaria. Also, CXCL11 being upregulated in symptomatic group, could be a marker for malarial positives presenting with fever. Conversely, CCL28 was depressed in symptomatic group and showed same status among fever positives, a probable indication of an anti-inflammatory role during infection with P. falciparum malaria. Overall, the lower chemokine levels associated with the symptoms of uncomplicated malaria may be an attempt of the immune system to prevent a progression process from uncomplicated to severe outcomes. This proposition has received credence with the use of anti-chemokine therapies to improve outcomes of severe malaria cases [50].

Acknowledgements We thank all the volunteers that participated in this project. Appreciation goes to the Yaounde Initiative Foundation (65.414) for financial support.

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