Abstract
Naturally acquired immunity to Plasmodium falciparum malaria in malaria holoendemic areas is characterized by the gradual, age-related development of protection against high-density parasitemia and clinical malaria. Animal studies, and less commonly, observations of humans with malaria, suggest that T-cell responses are important in the development and maintenance of this immunity, which is mediated primarily by antibodies that slow repeated cycles of merozoites through erythrocytes. To advance our rather limited knowledge on human T-cell immunity to blood stage malaria infection, we evaluated CD4 and CD8 T-cell effector memory subset responses to the 42 kDa C-terminal fragment of Merozoite Surface Protein 1 (MSP142), a malaria vaccine candidate, by 49 healthy 0.5 to ≥18 year old residents of a holoendemic area in western Kenya. The proportion of individuals with peripheral blood mononuclear cell MSP142 driven IFN-γ ELISPOT responses increased from 20% (2/20) among 0.5–1 year old children to 90% (9/10) of adults ≥18 years (P = 0.01); parallel increases in the magnitude of IFN-γ responses were observed across all age groups (0.5, 1, 2, 5 and ≥18 years, P = 0.001). Less than 1% of total CD4 and CD8 T-cells from both children and adults produced IFN-γ in response to MSP142. However, adults had higher proportions of MSP142 driven IFN-γ secreting CD4 and CD8 effector memory (CD45RA− CD62L−) T-cells than children (CD4: 50.9% vs. 28.8%, P = 0.036; CD8: 52.1% vs. 18.3%, respectively P = 0.009). In contrast, MSP142 driven IFN-γ secreting naïve-like, transitional (CD45RA+ CD62L+) CD4 and CD8 cells were the predominant T-cell subset among children with significantly fewer of these cells in adults (CD4: 34.9% vs. 5.1%, P = 0.002; CD8: 47.0% vs. 20.5%, respectively, P = 0.030). These data support the concept that meaningful age-related differences exist in the quality of T-cell immunity to malaria antigens such as MSP1.
Highlights
Malaria is a global health problem that affects primarily infants and children less than 5 years old [1,2], whereas older children and adults in most endemic regions develop naturally acquired immunity that protects against high-density parasitemia and malaria morbidity [3,4]
The upper range of asexual parasitemia among these healthy malaria asymptomatic individuals was highest among participants who were 1 to 5 years old compared to infants with a median age of 0.5 years, presumably due to protective maternally acquired antibodies during infancy and the development of malaria-specific immunity later in life
Our study is limited by the small samples size, results show that the overall frequency of antigenspecific CD4 and CD8 T-cells that produced IFN-c in response to MSP142 were low and did not appear to differ according to parasitemia or ages ranging from 0.5 to 5 years and $18 years but there was a shift in hierarchy among various T-cell subsets responsive to MSP142 such that the TEM subset was the dominant cell type in adults in contrast to children who had more phenotypically naıve-like, to more naıve-like (TN) cells
Summary
Malaria is a global health problem that affects primarily infants and children less than 5 years old [1,2], whereas older children and adults in most endemic regions develop naturally acquired immunity that protects against high-density parasitemia and malaria morbidity [3,4]. Greater understanding of how malaria specific T-cell memory subsets contribute to immunity in malaria endemic populations is important to the design and testing of blood stage malaria vaccines as well as understanding how decreasing malaria exposure due to vector control in Africa and elsewhere may affect age-related susceptibility to malaria infection and clinical illness
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