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Infection and Immunity, January 2001, p. 123-128, Vol. 69, No. 1
U.S. Army Medical Research Unit-Kenya and
Kenya Medical Research Institute, Kisumu, Kenya
Received 7 June 2000/Returned for modification 4 August
2000/Accepted 6 October 2000
Immunity to Plasmodium falciparum develops slowly in
areas of endemicity, and this is often ascribed to poorly immunogenic or highly variant parasite antigens. However, among populations newly
exposed to malaria, adults acquire immunity more rapidly than children.
We examined the relationship between pubertal development and
resistance to P. falciparum. During two transmission
seasons in western Kenya, we treated the same cohort of young males to eradicate P. falciparum and then obtained blood smears each
week for 4 months. We determined pubertal development by Tanner staging and by levels of dehydroepiandrosterone sulfate (DHEAS) and
testosterone in plasma. In multivariate and age-stratified analyses, we
examined the effect of pubertal development on resistance to malaria.
In both seasons (n = 248 and 144 volunteers,
respectively), older males were less susceptible than younger males.
Age-related decreases in the frequency and density of parasitemia were
greatest during puberty (15- to 20-year-olds). DHEAS and testosterone
were significant independent predictors of resistance to P. falciparum parasitemia, even after accounting for the effect of
age. Fifteen- to 20-year-old males with high DHEAS levels had a 72%
lower mean parasite density (P < 0.01) than
individuals with low DHEAS levels. Similarly, 21- to 35-year-old males
with high DHEAS levels had a 92% lower mean parasite density
(P < 0.001) and 48% lower frequency of parasitemia (P < 0.05) than individuals with low DHEAS levels.
These data suggest that the long period needed to attain full immunity
could be explained as a consequence of host development rather than as
the requirement to recognize variant or poorly immunogenic parasite antigens.
Plasmodium falciparum
malaria is a leading cause of morbidity and mortality in developing
countries, infecting hundreds of millions of individuals and killing up
to 1 million children in sub-Saharan Africa each year (2).
This death toll will rise as drug-resistant parasites spread
(35), and meanwhile the promise of a broadly effective
malaria vaccine remains unfulfilled despite important technological
advances (27). Residents of areas of endemicity develop
protective immunity that limits parasitemia and disease, providing a
model for vaccine development, but the responses conferring naturally
occurring protection have not been elucidated.
P. falciparum infection is more frequent and severe in
children than in adults (23; reviewed in reference
4), and resistance is acquired over years of
exposure. The long period required to develop resistance has supported
the widely held views that the parasite is poorly immunogenic or that
protective immunity is strain specific and requires exposure to the
many parasite variants circulating in a community (10,
14). The recent observation that adult migrants to an area of
endemicity acquire resistance more rapidly than their younger
counterparts implicates host development in decreased susceptibility to
P. falciparum (5, 7). In an area of
holoendemicity in Kenya, where malaria is ubiquitous, we examined
pubertal hormones as predictors of immunity to P. falciparum
parasitemia. We show for the first time that pubertal hormone levels
are directly related to increased resistance to falciparum malaria in
humans, and we conclude that present paradigms explaining malarial
immunity are inadequate to account for the epidemiology of infection.
Study population.
The study site in western Kenya was 10 km
north of Lake Victoria, in the adjoining villages of Wangarot, Riwa
Ojelo, and Waringa, Rarieda Division, Nyanza Province. The
entomological inoculation rate in this area can exceed 300 infectious
bites per person per year (8). This study was conducted
according to a protocol approved by ethical review boards of both the
Walter Reed Army Institute of Research and the Kenya Medical Research
Institute. All volunteers gave signed informed consent prior to entry
into the study.
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.1.123-128.2001
Human Resistance to Plasmodium falciparum Increases
during Puberty and Is Predicted by Dehydroepiandrosterone Sulfate
Levels
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Entomology. At the end of the first season, mosquitoes were collected by the daytime resting indoors method (19). This procedure was performed once at each volunteer's house between 22 July and 1 August 1996. The number of anopheline mosquitoes in each house was used to control for recent exposure in subsequent analyses.
Blood collection and processing.
In the second season,
volunteers donated 10 ml of blood into heparinized tubes 2 weeks after
treatment with quinine and doxycycline. Samples were centrifuged within
4 h of collection, and plasma was aliquoted and stored at 
70°C
for subsequent hormonal analyses.
Clinical laboratory tests. Hemograms were obtained from heparinized blood by using a model T-890 cell counter (Coulter Corp., Hialeah, Fla.). ABO blood group and hemoglobin phenotype were determined for 154 volunteers with commercially available reagents (Sigma, St. Louis, Mo.).
Hormonal assays. Quantitative assays for total plasma testosterone levels (Immuno-1; Bayer, Tarrytown, N.Y.) (normal range for 20- to 49-year-old males in the United States, 2.7 to 11.94 ng/ml) and dehydroepiandrosterone sulfate (DHEAS) levels (Immunolite; DPC, Los Angeles, Calif.) (normal range for 12- to 17-year-old males in the United States, 30 to 550 µg/dl; normal range for 18- to 29-year-old males in the United States, 280 to 640 µg/dl) were performed at a College of American Pathologists accredited clinical laboratory using automated enzyme immunoassay-based techniques.
Tanner staging. Tanner staging was performed for 141 volunteers in the second season by a single physician (J.D.K.) according to standard techniques (32). Briefly, testicular size and scrotal-penile development were scored on an ordinal scale from 1 (prepubescent) to 5 (adult). Pubic hair quantity and distribution were also scored on an ordinal scale from 1 to 6. The results of these two scores were averaged to produce the Tanner stage.
Statistical analyses. We examined relationships among age, puberty, and parasitemia. Measures of parasitemia included time to reappearance of parasitemia, frequency of parasitemia, and mean parasitemia. Data for time to reappearance of parasitemia were examined with Kaplan-Meier models for nominal covariates (group differences were evaluated with a log rank test) and Cox proportional hazards models for continuous covariates. The density and frequency of parasitemia were loge transformed [ln(value + 1)] to normalize the data; the logarithmic mean was obtained by taking the antiloge of the mean of transformed data. Mean parasitemia and frequency of parasitemia were evaluated with Pearson's correlation analysis. Potential confounding by ABO blood group, hemoglobin phenotype, and recent exposure was explored with analysis of covariance and multivariate linear regression where appropriate. Stratified analyses were performed to examine the association between age and parasitemia in several age strata. The relationship between pretreatment prevalence and age was examined with Student's two-tailed t test.
Multivariate linear regression was used to evaluate the association between measures of puberty and parasitemia after accounting for the effects of age. Stratified analyses were performed to further explore the associations among pubertal hormone levels, age, and parasitemia. Within each age strata, differences in parasitemia between hormone strata were evaluated by analysis of variance with Fisher's protected least-significant difference (PLSD) for post-hoc contrasts. DHEAS and testosterone levels were stratified into high, medium, and low strata based on the means and standard deviations of the values for adults in the cohort (ages 21 to 35). End points of malaria infection were calculated using blood smears obtained before the first treatment with Fansidar. All analyses were performed with StatView version 5.0.1 on Macintosh computers.| |
RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Parasitemia reappeared in most volunteers after eradication treatment. At the start of the rainy season in 1996 and again in 1997, the same cohort of young Kenyan males were treated to eradicate parasitemia and then monitored with weekly blood smears to quantify frequency and density of parasitemia. In the first season, 48% of the volunteers had P. falciparum present on the blood smear prior to eradication treatment. Among the 243 volunteers included for analysis, parasitemia reappeared in 50% within 5 weeks (Kaplan-Meier estimate) and reappeared in a total of 223 within 16 weeks.
In the second season, 53% of the volunteers had P. falciparum present on the blood smear prior to eradication treatment. Among the 143 volunteers included for analysis, parasitemia reappeared in 50% within 6 weeks (Kaplan-Meier estimate) and reappeared in a total of 135 within 18 weeks.Increasing age predicts resistance to P. falciparum.
At
the start of the first season, individuals with negative pretreatment
blood smears were 3.64 years older than individuals with positive
pretreatment blood smears (P < 0.0001). After malaria eradication, older individuals were more resistant to P. falciparum than younger individuals as assessed by Pearson's
analysis of age versus mean parasitemia (r = 0.195; P < 0.005) and frequency of parasitemia (r = 0.298;
P < 0.001) and Kaplan-Meier analysis of time to reappearance
of parasitemia (P < 0.0001) (Fig.
1A). In multivariate analyses, older
individuals were more resistant to parasitemia by all three measures
than younger individuals after accounting for ABO blood type,
hemoglobin phenotype, or recent exposure measured by the daytime
resting indoors method (all P < 0.01).
|
0.383; P < 0.001), frequency of
parasitemia (r = 0.404; P < 0.001), and longer
time to reappearance of parasitemia (P = 0.03) (Fig.
1B) than younger individuals.
Resistance to P. falciparum increases most rapidly
during puberty.
We examined the development of resistance before
(12- to 14-year-olds), during (15- to 20-year-olds) and after (21- to
35-year-olds) puberty. These age strata were selected based on the
results of Tanner staging in this population (Fig.
2). In both seasons, resistance to
P. falciparum increased with age during puberty but not
before puberty (Table 1). After puberty,
the frequency of parasitemia decreased with age in the second season.
Neither time to reappearance of parasitemia nor parasite density
was associated with age in this group.
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Physical and hormonal measures of puberty predict increased resistance to P. falciparum. The mean Tanner stage and DHEAS and testosterone levels increased with age. The physical changes associated with puberty (Tanner stage) occurred principally in the 15- to 20-year-old age group (Fig. 2). All three pubertal measures were strongly correlated with age (r = 0.56 to 0.68; all P < 0.0001) and themselves (r = 0.56 to 0.82; all P < 0.0001).
Increased Tanner stage and DHEAS and testosterone levels, measured at the start of the second season, were each associated with lower mean parasitemia (P < 0.005), lower frequency of parasitemia (P < 0.005), and longer time to reappearance of parasitemia (P < 0.05) (Table 2).
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Increased DHEAS and testosterone predict resistance to P. falciparum independent of age. In a multivariate linear model, DHEAS was a significant predictor of mean parasitemia (P = 0.02) even after accounting for the effect of age, hemoglobin phenotype, ABO blood group, and recent exposure. Among volunteers 15 years or older (when the effects of puberty on resistance are apparent), DHEAS was a significant predictor of mean parasitemia (P = 0.02) after accounting for both age and testosterone. Individuals with higher DHEAS levels, independent of their age and testosterone level, had lower mean parasitemias than individuals with lower DHEAS levels. After accounting for age, increased DHEAS was associated with decreased frequency of parasitemia, and this association was significant in the older age groups (P = 0.1 for all volunteers; P = 0.04 for volunteers 15 years and older).
When stratified by age and DHEAS levels, 15- to 20-year-old males with high DHEAS levels had 66 to 72% lower mean parasitemias than individuals with lower levels of DHEAS (P < 0.05 to 0.01) (Fig. 3A). Twenty-one- to 35-year-old men with medium or high DHEAS levels had 92 to 94% lower mean parasitemias than individuals with low DHEAS levels (P < 0.01 to 0.001) (Fig. 3A). Twenty-one- to 35-year-olds with high DHEAS levels had a 52% lower frequency of parasitemia than individuals with low DHEAS levels (P < 0.05) (Fig. 3B). In the two older age groups, individuals with higher DHEAS levels were more resistant to P. falciparum than individuals with lower DHEAS levels.
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], intermediate [
], and high [
]). Box plots
indicate logarithmic means (dashed lines), medians (solid lines), 75th
percentiles (boxes), and 90th percentiles (bars). Remaining values are
individually plotted as circles. Sample sizes are indicated at the
bottom.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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In areas of endemicity, children are more susceptible to malaria than adults (23). Resistance to parasitemia develops over many years, and the lengthy nature of this process has been attributed to the poor immunogenicity or highly variant nature of parasite antigens (10, 14). Adults acquire resistance to malaria more rapidly than children when nonimmune families move into malarious areas (5, 6), an observation at odds with the notion that parasite immunoevasion alone accounts for the slow acquisition of immunity. Adults and children do not differ in susceptibility at the time of their first exposure to malaria, so innate resistance cannot account for age-related differences. Instead, acquired immunity develops more quickly in adults than in children with similar exposure histories.
In this prospective study of 12- to 35-year-old males, age significantly predicted resistance to malaria. Malaria is ubiquitous in this area and reappeared after eradication in nearly all volunteers during both seasons. However, older individuals were infected less frequently and at lower parasite density than younger individuals. This relationship between increasing age and increasing resistance was most apparent among 15- to 20-year-olds, the age when this population of males undergoes puberty (Fig. 2), and was not apparent among 12- to 14-year olds. In the years just before puberty, therefore, continued exposure to malaria does not result in increased immunity. Resistance increases during puberty, which could result from either additional exposure, developmentally regulated mechanisms of resistance, or the combined influence of both factors.
To evaluate these possibilities, we considered increasing age to be a correlate of increasing cumulative exposure. Resistance increased as the Tanner stage of pubertal development increased, but this effect could not be separated from the effect of age (i.e., increased cumulative exposure). However, increased DHEAS (a measure of adrenarche) and testosterone (a measure of gonadarche) were significant predictors of increasing resistance, even after accounting for age (and, for DHEAS, even after accounting for both age and testosterone). We inferred that human pubertal development contributes to resistance to malaria, separate from any effect of increasing cumulative exposure. In healthy populations, puberty begins at a younger age in children with African as opposed to European ancestry (11, 21, 31), and it is tempting to speculate that this may be due to the selective effect of malaria in human evolution (20). Although our cohort experienced a delayed onset of puberty compared to the standards of the developed world, this is likely a consequence of malnutrition and disease associated with their low socioeconomic status (11, 13).
The increase in resistance during puberty could be mediated by innate or acquired mechanisms. Nonimmune populations require several infections with P. falciparum before adults demonstrate resistance greater than children (5), suggesting an acquired response. Our results parallel these earlier findings: moderate elevations of DHEAS were associated with increased resistance in the oldest, but not the younger, age strata (Fig. 3), implying that exposure subsequent to the elevation of DHEAS augments resistance. Thus, puberty-related resistance in humans may be an acquired form of immunity, distinguishing it from the innate resistance observed in older chicks (17, 24) and rats (18), which are less susceptible than their younger counterparts at first exposure to malaria.
DHEAS predicted a lower frequency and density of parasitemia in multiple comparisons, effects that could be mediated by the potent immunoactivating properties of this hormone. In humans, DHEAS increases specific antibody responses (3, 15) and augments NK cell number and function (12). Both immune mechanisms contribute to resistance to malaria. Human NK cells lyse P. falciparum-infected erythrocytes (30), and increased NK cell cytokine production is associated with decreased parasitemia and mortality in murine Plasmodium chabaudi infection (28). In humans, specific P. falciparum antibodies are associated with resistance to both severe parasitemia and disease (1, 16, 33).
Testosterone levels were associated only with decreased frequency of parasitemia in a single age strata. In multivariate analyses, the effect of testosterone on resistance lost significance after accounting for DHEAS and age. Although testosterone also has immunomodulatory effects (9, 22, 34), earlier studies do not support a role for testosterone in resistance to malaria. Testosterone increases the susceptibility of female mice to fatal P. chabaudi infection (9). In humans, parasite densities are lower in nonpregnant adolescent females than in adolescent males (26, 29). We believe that testosterone is a marker for another puberty-associated change (such as DHEAS) that confers increased resistance to malaria. This possibility should be addressed in studies with sample sizes sufficient to simultaneously evaluate age, DHEAS, and testosterone, as well as parallel studies in females.
In summary, resistance to falciparum malaria increased with age in males during puberty but not in males just before puberty. Pubertal hormones were related to immunity independent of host age and cumulative exposure. Further investigation is needed to define the relative contributions of DHEAS and testosterone in resistance to parasitemia and to elucidate the effects of these hormones on protective antimalarial immune responses. We conclude that resistance to malaria does not result solely from the accumulated recognition of parasite variants or from additional exposure to poorly immunogenic antigens. Host development independently predicts resistance, and an understanding of protective immune responses that are developmentally regulated could lead to new vaccine strategies. Whether susceptibility to malaria is related to development during early life, when mortality is greatest, remains an important area for future study.
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ACKNOWLEDGMENTS |
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This work was supported by the Military Infectious Disease Research Program of the U.S. Department of Defense and by the Department of Pathology and Laboratory Medicine, University of Pennsylvania. J.D.K. was a fellow of the National Research Council and the American Society of Tropical Medicine and Hygiene/Becton-Dickinson.
We gratefully thank Raphael Onyango and Samuel Oduor Wangowe for excellent supervision of the field studies, the volunteers for their participation, Jennifer Friedman and Philip Gruppuso for helpful discussions on pubertal development, Stephen McGarvey and Michal Fried for critical review of the manuscript, and David Goodman for supervising the hormonal assays. This work is published with the permission of the director of the Kenya Medical Research Institute.
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FOOTNOTES |
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* Corresponding author. Present address: Walter Reed Army Institute of Research, Department of Immunology, Bldg. 503, Rm. 3W53, 503 Robert Grant Ave., Silver Spring, MD 20910. Phone: (301) 319-9551. Fax: (301) 319-7358. E-mail: patrick.duffy{at}na.amedd.army.mil.
Present address: International Health Institute and Department of
Pathology & Laboratory Medicine, Brown University School of Medicine,
Providence, RI 02912.
Editor: J. M. Mansfield
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Infection and Immunity, January 2001, p. 123-128, Vol. 69, No. 1
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.1.123-128.2001
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