Human Resistance toPlasmodium falciparumIncreases during Puberty and Is Predicted by Dehydroepiandrosterone Sulfate Levels

Abstract

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 ubiqu...

Identification of Protective B-Cell Epitopes within the Novel Malaria Vaccine Candidate Plasmodium falciparum Schizont Egress Antigen 1

“…Antibody levels were dichotomized as high (greater than the median value) or low (less than or equal to the median value). We adjusted for several confounders and effect modifiers that had been previously identified as significant predictors of malaria outcomes in this same cohort, including age (12 to 14 years, 15 to 19 years, and 20 to 35 years of age groups), baseline parasitemia, and Tanner score (1 to 2.5, 3 to 4.5, and 5 to 5.5), a physical measure of pubertal development (8). A P value of Ͻ0.05 was considered statistically significant.…”

“…We performed a secondary analysis with data and serum samples that were collected from a cohort of Kenyan males as part of a treatment-reinfection study (7)(8)(9).…”

A high corticosterone/DHEA-s ratio in young rats infected with Trypanosoma cruzi is associated with increased susceptibility

“…In addition, CT increase was paralleled by a reduction in DHEA-s, which suggests that there were decreased levels of the nonsulfated DHEA. Because DHEA has been shown to protect against other protozoan infections, such as malaria (Kurtis et al 2001) and leishmaniasis (Galindo-Sevilla et al 2007), a decrease in DHEA could weaken the ability to fight the T. cruzi infection. Furthermore, Santos et al (2008Santos et al ( , 2010 showed that DHEA supplementation exerted stimulatory effects on the cell-mediated specific immune response during T. cruzi infection, which decreased the parasite load in blood and tissues; this suggests that DHEA-s can be used as an adjuvant for the host's immune response against infection.…”

Advancement Towards an Approved Vaccine to Target Plasmodium Falciparum Malaria

“…24,25 Duly, this entails cumulative exposure to multiple variants of a particular species which generally requires the first twenty years of life to develop completely. 24,26 Infections are more severe in children, in which most malaria-related mortality occurs.…”

“…24,25 Duly, this entails cumulative exposure to multiple variants of a particular species which generally requires the first twenty years of life to develop completely. 24,26 Infections are more severe in children, in which most malaria-related mortality occurs. 4,27 In endemic areas, P. falciparum infection in children of under 5 years of age can lead to severe disease and is the cause a quarter of juvenile deaths in Africa.…”