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DIFFERENCE IN SUSCEPTIBILITY TO MALARIA BETWEEN TWO SYMPATRIC ETHNIC GROUPS IN MALI

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  • 1 Malaria Research and Training Center, Département d’Epidémiologie des Affections Parasitaires, Faculté de Médecine, de Pharmacie et d’Odonto-Stomatologie, Bamako, Mali; Dipartimento di Scienze di Sanita Pubblica, Sezione di Parassitologia, World Health Organization Collaborating Centre for Malaria Epidemiology and Control, University of Rome Rome, Italy; Department of Immunology, Stockholm University, Stockholm, Sweden

We compared malaria indicators among sympatric groups to study human heterogeneities in the response to Plasmodium falciparum malaria infection. Four cross-sectional surveys and two longitudinal surveys in two sympatric ethnic groups (Dogon and Fulani) in Mali were carried out from 1998 to 2000. Spleen and parasite rates were evaluated during the cross-sectional surveys and disease incidence was assessed during longitudinal surveys. In spite of similar sociocultural factors and entomologic inoculation rates between ethnic groups, the Fulani had a significantly higher spleen enlargement rate, lower parasite rate, and were less affected by the disease than the Dogon group, whose frequency of hemoglobin C was higher than that recorded among the Fulani group. The Fulani group had significantly higher levels of IgG and IgE against crude malaria antigen than the Dogon group, suggesting a role of anti-malaria antibodies in the immune protection seen in this group.

INTRODUCTION

Malaria is a public health problem in 90 countries, affecting 40% of the world’s population.1 Control programs based on chemoprophylaxis, case management, and anti-vector strategies have had limited effect.2 Differences in susceptibility to malaria between ethnic groups suggest host genetic factors have a role in determining host susceptibility to malaria.3–7

Available data suggest that immunogenetic factors are involved in the resistance to malaria among the Fulani ethnic group in west Africa. Studies carried out in both Nigeria and The Gambia have indicated that the frequency of splenomegaly is higher in the Fulani ethnic group than in other sympatric groups with similar exposure.4,5 Furthermore, studies on susceptibility to malaria in different sympatric ethnic groups in Burkina Faso (Mossi, Rimaibé, and Fulani) indicate that the Fulani have lower parasite density, lower malaria incidence, and higher levels of anti-malaria humoral immune responses to a variety of malaria antigens,8–11 despite the same level of malaria transmission, based on entomologic data collected at the time of these studies.

No previous studies have addressed these questions in Mali. In collaboration with the University of Rome and the University of Stockholm, the Malaria Research and Training Center team from the University of Bamako designed this study to assess differences in susceptibility to malaria infection and disease between the Dogon and the Fulani, two sympatric ethnic groups in the Sahelian Dogon Country in east central Mali. Specifically, we examined 1) bed net use, 2) malariometric indexes (i.e., spleen enlargement rates, parasite rates, gametocyte rates, and parasite densities), and 3) anti-malaria specific immune response antigen among adults and children living in four adjacent villages in the Dogon country. We conducted this study between 1998 and 2000.

MATERIALS AND METHODS

Study sites.

The study was carried out in four rural villages (Mantéourou, Naye, Binédama, and Anakédié) where people from the Dogon and Fulani ethnic groups live together in sympatry. The study area was located approximately 850 km from Bamako, the capital of Mali. One village had only Fulani and another had only Dogon; these two villages were 1 km apart. The other villages contained members of both groups and were separated by 0.5 km. All four villages were located within 7 km of each other (Figure 1) in a Sahelian area with a dry season from October to May and a rainy season from June to October. The Dogon are farmers who lived with the Malinke ethnic group in the Malian Empire until the 13th century. They then migrated to the cliffs of Bandiagara and moved to their present location 50 years ago (oral communication with the chief of the village). The Fulani, cattle breeders who have lived in our study area for the last 200 years, migrated from the area of Douentza, situated approximately 150 km from our study area (oral communication with the chief of the village). There is no inter-marriage between Dogon and Fulani ethnic groups in these localities.

Study design.

All adults and children in the four villages were invited to participate in our study, which was comprised of four cross-sectional surveys for malaria indices during rainy seasons from 1998 to 2000. During three of the four cross-sectional surveys, mosquitoes were also collected in all Dogon and Fulani sites to determine the entomolologic inoculation rate (EIR). During two rainy seasons (August to December of 1999 and 2000), we also followed study volunteers for malaria incidence by active and passive methods. A research team, including a physician, was based in a health center of the village of Mantéourou. The physician visited each village twice a week to identify, treat, and record all illnesses. In addition, all persons who became ill were encouraged to visit the health center at any time. For children with signs of fever, blood was collected by finger prick for the preparation of thick smears on days 0, 3, 7, and 14. In cases of mild malaria, chloroquine (10 mg/kg/day on days 0 and 1 and 5 mg/kg on day 2) was given in accordance with Malian National Malaria Control Program Guidelines. Alternatively, intramuscular quinine was used to treat severe malaria and patients who were vomiting.

Sociodemographic methods.

We conducted a complete census of the population at the beginning of the transmission season in 1998, and updated it in 1999 and 2000 to collect sociodemographic information on the two ethnic groups. In addition, in June 2000, information on bed net use was collected.

Entomologic methods.

Adult mosquitoes were collected using the spray-catch method (knockdown collection) to determine the biting rate. The method involves collection of mosquitoes resting inside dwellings. White sheets are spread on the floor, and a pyrethroid spray is used to kill or knock down the mosquitoes resting on the walls.12 We used an enzyme-linked immunosorbent assay (ELISA) to determine their infection rate, and then calculated the EIRs.

We used a standard sandwich ELISA to detect the Plasmodium falciparum circumsporozoite protein (CSP) secreted by the malaria parasite early during its sporogenic development in the mosquito. Briefly, mosquitoes were individually grounded in a 1.5-mL Eppendorf (Hamburg, Germany) tube and added to flexible, U-bottom, 96-well microtiter plates (Dynatech Laboratories Inc., Chantilly, VA) precoated with a monoclonal antibody to CSP (Kirkegaard and Perry Laboratories, Gaithersburg, MD). After incubation for 30 minutes, aperoxidase-conjugated anti-CSP monoclonal antibody directed against another CSP epitope (Kirkegaard and Perry Laboratories) was added and incubated for one hour to detect bound CSP. A 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) solution (Kirkegaard and Perry Laboratories) was used to visualize the reaction.

Parasitologic-clinical studies.

During cross-sectional survey, the study physician measured axillary temperature and spleen size for all participants. Thick blood smears were collected and stained with 3% Giemsa and read by experienced microscopists. The number of parasites present in the field with 300 leukocytes was counted, and parasite densities were calculated by assuming a mean leukocyte count of 7,500/mm3. Spleen-size was scored by Hackett method. For analysis, spleen size was dichotomized as enlarged or not enlarged, and parasite carriage was defined as the presence of any parasite in a participant’s blood.

During the periods of longitudinal surveillance, a staff physician was stationed at the local health center at all times. The physician examined all ill participants and treated them appropriately. Clinical malaria was defined as fever (axillary temperature ≥ 37.5°C) plus the presence of P. falciparum parasites on a thick blood smear, in the absence of any other known illnesses. The diagnoses of all diseases episodes were recorded.

Hematologic methods.

A subset of samples for hemoglobin determination was obtained by systematic sampling. Hemoglobin types were determined by analyzing red blood cell lysates using cellulose acetate electrophoresis at an alkaline pH. Cellulose acetate plates (Titan® III-H; Helena Laboratories, Beaumont, TX) were stained with Ponceau red stain. The different hemoglobin types were determined by comparing the migration of hemoglobin to standards of HbA, HbF, HbS, and HbC.13,14

Immunologic methods.

At each visit, 300 μL of blood were collected in 1.5-mL Eppendorf tubes containing anticoagulant (EDTA). Within 3–6 hours of collection, plasma was removed and stored at 4°C in the field until transported to our laboratory in Bamako, where it was frozen at -20°C. A subset of blood samples matched by age between ethnic groups was used for the immunologic study. Lysates of blood infected with P. falciparum laboratory strain F32 were prepared as previously described.15 Crude parasite antigen, isolated from late stage-infected erythrocytes enriched on 60% Percoll, was used as antigen.16 Briefly, plates were coated with 50 μL of crude parasite antigen solution (10 μg/mL) kept at 4°C overnight, blocked with 100 μL of 0.5% bovine serum albumin in coating buffer for three hours at 37°C, and washed four times with phosphate-buffered saline plus 0.05% Tween. Samples were diluted 1:1,000 for the anti-malarial IgG assay and 1:50 for the malaria-specific IgE assay, and all samples were tested in duplicate. Plasma was allowed to react for one hour for the detection of anti-malaria IgG antibodies and overnight for the detection of anti-malaria IgE antibodies, as previously described.17 For the detection of bound antibodies, goat anti-human immunoglobulin IgG conjugated to alkaline phosphatase (dilution = 1:7,500) or biotinylated anti- human immunoglobin IgE (dilution = 1:1,000) (Vector Laboratories, Burlingame, CA) in Tween buffer were used and incubated for one hour at 37°C. For IgE, after washings, the plates were developed with a biotinylated antibody, 50 μL of alkaline phosphatase–conjugated streptavidin (Mabtech, Nacka, Sweden) diluted 1:2,000 in Tween buffer and incubated for one hour at 37°C. After washings, the plates were developed with 50 μL of p-nitrophenylphosphate (1 tablet/5 mL of substrate buffer) and the optical density was read at 405 nm.

Data management and statistical analysis.

Data were recorded on standard case report forms. Epi-Info version 6 (Centers for Disease Control and Prevention, Atlanta, GA) was used to enter and analyze the data. For analysis, socioeconomic, entomologic, clinical, parasitologic, immunologic, and hematologic variables were compared between Dogon and Fulani subjects. We used the chi-square test and Fisher’s exact probability test to compare qualitative variables and the t-test to compare antibody concentrations between ethnic groups.

Ethical clearance.

The Institutional Review Board of the University of Mali reviewed and approved this study. Treatment of malaria and other illnesses detected during the course of the study was provided to the study population at no cost to participants. Community informed consent was obtained before the beginning of the study. Individual oral consent was also obtained for each examination or blood collection from adults or the parents or guardians of children.

RESULTS

Sociodemographic.

According to our census of the study population conducted by the Malaria Research and Training Center from 1998 to 2000, the study population was approximately 70% Dogon and 30% Fulani.

The participation rates among the two ethnic groups showed the same pattern in all four cross-sectional surveys, with significantly lower participation among the Fulani than among the Dogon ethnic group (P < 0.001). We combined data from all four surveys periods to yield a global participation rate of 61.7% in the Dogon ethnic group and 35.5% in the Fulani ethnic group. According to a chi-square test, the age distribution of participants by ethnic group showed little difference across the four cross-sectional surveys (Table 1). The use of bed nets by the two ethnic groups (Dogon and Fulani) was comparable (20.3% among Dogon and 25.5% among Fulani in 2000; P not significant).

Entomologic.

A total of 640, 76, and 4,538 mosquitoes were collected in July 1998, November 1998, and September 2000, respectively. These were comprised primarily of Anopheles gambiae s.l (≈ 99%) and An. funestus (< 1%). The EIRs and biting rates observed were similar among the two ethnic groups. None of the mosquitoes collected in November 1998 carried sporozoite antigens, as determined by the ELISA (Table 2).

Clinical.

During the four cross-sectional surveys, a total of 5,814 individuals were clinically assessed at the health center. In these surveys, we consistently found the spleen enlargement rate to be significantly higher in the Fulani than in the Dogon (Table 3).

Disease surveillance showed that the percentage of subjects having a single episode of clinical malaria was lower among the Fulani than the Dogon. Furthermore, the percentage of subjects having more than one episode of clinical malaria was also lower in the Fulani than the Dogon (P < 0.001) (Table 4). Figure 2 shows that the age distribution of malaria clinical episodes was similar in the two ethnic groups during the clinical surveillances in 1999 and 2000.

Since the distribution of all types of disease was very similar in the 1999 and 2000 study period, we combined the data from both periods for analytical purposes. A total of 4,261 cases of clinical illness (3,762 Dogon and 994 Fulani) were recorded among the study population in 1999 and 2000. In both ethnic groups, malaria was the single most frequently observed disease over the two transmission seasons, consisting of 42.3% of all disease episodes in the Dogon group (1,390 of 3,267) versus 29.4% in the Fulani group (292 of 994). Episodes of clinical malaria were more common in the Dogon ethnic group than in the Fulani ethnic group (P < 0.001), but cases of intestinal parasitosis were found more frequently in the Fulani (4.6% in the Fulani versus 1.4% in the Dogon; P < 0.001). The incidence of other diseases recorded in the population, including pulmonary infections, diarrhea, rheumatologic, dental, ophthalmologic, and dermatological diseases, was the same in both groups.

Parasitologic.

As shown in Table 3, we determined that malaria parasite rates were significantly lower among the Fulani than among the Dogon, except in July 1999. Gametocyte rates were also lower in the Fulani than in the Dogon, but the difference was statistically significant only in September 2000 (0.8% in the Fulani and 2.7% in the Dogon; P = 0.03).

Immuno-hematologic.

The frequency of HbC was higher in the Dogon group than in the Fulani group (P = 0.007, HbAA versus HbAC between the Dogon and Fulani) (Table 5). As shown in Table 6, the Fulani had significantly higher levels of both IgG and IgE against crude malaria antigen than the Dogon.

DISCUSSION

The inter-ethnic differences in antibody responses to P. falciparum among sympatric ethnic groups living in Mali seen in the present study confirms and extends what was recently reported in Burkina Faso on the role of antimalaria antibodies in immune protection.8,9 In line with the results of the study by Modiano and others,8,9 our study showed that the Fulani in Mali were relatively more protected against malaria than the Dogon ethnic group, as reflected by lower parasite rates and a lower frequency of clinical episode. This difference was observed despite the fact that the two tribes were equally exposed to malaria (they showed similar EIRs) and had the same frequency of bed net use. These observed differences might reflect their different historic and geographic origins, or other sociocultural differences.

The Fulani in our study had higher levels of IgG and IgE antibodies against crude malaria antigen. These higher anti-malaria levels paralleled the stronger resistance to malaria in the Fulani, suggesting a role for anti-malarial IgG and possibly for IgE antibodies in malaria protection in the Fulani. Our results also confirm and extend previous findings from The Gambia18 and Burkina Faso.8–11 In Burkina Faso, the Fulani had higher IgG responses to several P. falciparum antigens (CSP, thrombospondin-related adhesive protein, merozoite surface antigen 1, Pf155 ring-infected erythrocyte surface antigen, and Pf332 blood-stage antigen) and at the same time displayed lower P. falciparum parasite rates and incidence of clinical malaria, suggesting a lower susceptibility to P. falciparum malaria among the Fulani than in other sympatric ethnic groups.8–11 The role of IgE anti-malarial antibodies in P. falciparum malaria has been less clear. One study in 199417 found an association between high levels of IgE and cerebral malaria; more recently, this relationship was also demonstrated in severe malaria without cerebral involvement.19,20

The high prevalence of splenomegaly among the Fulani could explain their malaria antibody production. In fact, studies performed in animal and human indicate positive associations between splenomegaly and malaria-specific antibody production.21,22

In the present study, we evaluated potential confounding factors such as hemoglobin type, given that their distributions differ by ethnic groups. The frequency of HbAC was higher in the Dogon group than in the Fulani group. In a recent study in another Dogon region (the area around Bandiagara, Mali), hemoglobin C was found to be associated with protection from severe malaria.23 However, since the occurrence of HbAC is rare in the Fulani ethnic group, this factor may not explain the differences in susceptibility to malaria that was observed between the Dogon and Fulani in our study area. Immunogenetic factors may be associated with the difference of susceptibility between ethnic groups.

We found the presence of only one type of non-malaria illness that differed between the two groups, i.e., that the Fulani succumbed more frequently to intestinal parasitosis than the Dogon. This finding was not confirmed by stool examination, but by patient description suggesting Taenia and pinworm as the primary causes. Based on clinical findings, schistosomiasis was rare; therefore, the difference observed in splenomegaly cannot be explained by intestinal parasitosis. Further studies are needed to better understand the high frequency of intestinal parasitosis in the Fulani ethnic group in this region. Nacher and others found that intestinal helminths infections in general appear to be associated with protection against cerebral malaria in a study performed in Thailand.24,25 In the present study, based on the low frequency of intestinal helminths (4.6% in the Fulani versus 1.4% in the Dogon), the difference observed in malaria susceptibility is unlikely to be due differences in intestinal parasitosis.

A limitation in our study was that in the last three cross-sectional surveys, participation rates among Fulani group decreased due to early dropouts at certain Fulani sites. In spite of lower participation rates of Fulani in the study, the study was performed on statistically significant samples.

The results of our study suggest that immunogenetic factors may be responsible for the observed differences in malaria disease between the Fulani and Dogon ethnic groups of Mali. This conclusion is supported by findings from Burkina Faso where higher anti-malarial antibody levels were associated with the -590T allele in the interleukin-4 promoter.26 However, this allele was also present in the Mossi tribe, where it was not associated with higher anti-malarial antibodies, indicating that such polymorphism is non-functional or is linked to other polymorphisms.26 A better understanding of the mechanisms underlying the reduced susceptibility of the Fulani to malaria could provide information essential for the rational design of malaria vaccines or alternative therapeutic strategies.

Table 1

Age distribution of participants by ethnic group in each study period

0–4 Years old5–9 Years old10–19 Years old> 19 Years oldTotal no.
PeriodEthnic groupNo.%No.%No.%No.%No.P
JulDogon21718.021417.723619.654044.71,2070.06
1998Fulani6823.45619.24214.412543.0291
NovDogon28323.422118.321317.649340.71,2100.04
1998Fulani2720.93224.8129.35845.0129
NovDogon18322.917822.314818.529136.38000.72
1999Fulani4924.33818.84120.37436.6202
SepDogon26122.325221.522118.943637.31,1700.06
2000Fulani7822.35315.17220.614742.0350
Table 2

Biting rate (BR), mosquito infection rate (MIR), and entomologic inoculation rate (EIR) at the study sites

July 1998November 1998September 2000
BR/monthMIREIRBR/monthMIREIRBR/monthMIREIR
Dogon site29.10.0270.782.40.00.0260.10.06817.7
Fulani site8.10.0850.683.60.00.02850.05916.8
Table 3

Spleen enlargement rate (SR) and parasite rate (PR) in the Dogon and Fulani ethnic groups during four cross-sectional surveys

Jul 1998Nov 1998Nov 1999Sept 2000
ParticipantsDogon1,2071,2088001,167
Fulani293130199347
No. positive%No. positive%%No. positive%
SRDogon211.728723.831138.926422.6
Fulani3311.35542.38241.215143.5
P< 0.001< 0.0010.540.001
PRDogon1149.444236.622928.626823.0
Fulani217.22519.23115.66117.6
P0.22< 0.001< 0.0010.0327
Table 4

Incidence of malaria according to ethnic group during the transmission seasons of 1999 and 2000

YearNumber of clinical episodesDogonFulaniχ2P
199901,633 (78.7%)763 (89.0%)
1305 (14.7%)87 (10.2%)59.05
> 1138 (6.6%)7 (0.8%)< 0.001
Total2,076857
200001,488 (82.1%)785 (92.7%)
1252 (13.9%)55 (6.5%)54.69
> 173 (4.0%)7 (0.8%)< 0.001
Total1,813847
Table 5

Distribution of hemoglobin (Hb) types by ethnic group

Ethnic groupHbAA(%)HbAC(%)HbAS(%)Total
Dogon139(84.7)23(14.0)2(1.2)164
Fulani104(98.1)2(1.8)0(0.0)106
    Total243(90.0)25(9.3)2(0.7)270
Table 6

Mean IgG and IgE anti-malaria (Plasmodium falciparum) antibody concentrations by ethnic group

Ethnic groupNo.Mean age (years)IgG (3g/mL)IgE (ng/mL)
Dogon3119.2913.610.81
Fulani3121.6844.631.67
P0.28< 0.0010.028
Figure 1.
Figure 1.

Study site in Mali.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 72, 3; 10.4269/ajtmh.2005.72.243

Figure 2.
Figure 2.

Age distribution (%) of clinical episodes by age and ethnic group in 1999 and 2000 in Mali.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 72, 3; 10.4269/ajtmh.2005.72.243

Authors’ addresses: Amagana Dolo, Boubacar Maiga, Modibo Daou, Guimogo Dolo, Hamadoun Guindo, Mamadou Ba, Hama Maiga, Drissa Coulibaly, Yeya Tiemoko Touré, and Ogobara Doumbo, Malaria Research and Training Center, Département d’Epidémiologie des Affections Parasitaires, Faculté de Médecine, de Pharmacie et d’Odonto-Stomatologie, BP 1805 Bamako, Mali, Telephone/Fax: 223-222-8109, E-mail: adolo@mrtcbko.org. David Modiano and Mario Coluzzi, Dipartimento di Scienze di Sanita Pubblica, Sezione di Parassitologia, World Health Organization Collaborating Centre for Malaria Epidemiology and Control, University of Rome, La Sa-pienza, 00185, Rome, Italy. Hedvig Perlman and Marita Troye Blomberg, Department of Immunology, Stockholm University, Stockholm, Sweden.

Acknowledgments: We thank the rector of the University of Bamako for his support and the population of the different villages in the study area for their cooperation. We are grateful to staff from the National Institute of Allergy and Infectious Disease and Family Health International for their comments during the preparation of this paper.

Financial support: This study was supported by grants from the Tropical Disease Research/World Health Organization (re-entry grant T16/181/456ID.970889) and the European Union (IC18-CT98-0361), and by a grant from the Swedish Agency for Research Cooperation with Developing Countries (SAREC) and the Swedish Medical Research Council.

REFERENCES

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    World Health Organization, 1992. A Global Strategy for Malaria Control. Geneva: World Health Organization.

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    Shiff C, 2002. Integrated approach to malaria control. Clin Microbiol Rev 15 :278–293.

  • 3

    Hill AVS, 1996. Genetic susceptibility to malaria and other infectious diseases: from the MHC to the whole genome. Parasitology 112 :S75–S84.

    • Search Google Scholar
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