Abstract
Asymptomatic Plasmodium falciparum infection is responsible for maintaining malarial disease within human populations in low transmission countries such as Haiti. Investigating differential host immune responses to the parasite as a potential underlying mechanism could help provide insight into this highly complex phenomenon and possibly identify asymptomatic individuals. We performed a cross-sectional analysis of individuals who were diagnosed with malaria in Sud-Est, Haiti by comparing the cellular and humoral responses of both symptomatic and asymptomatic subjects. Plasma samples were analyzed with a P. falciparum protein microarray, which demonstrated serologic reactivity to 3,877 P. falciparum proteins of known serologic reactivity; however, no antigen-antibody reactions delineating asymptomatics from symptomatics were identified. In contrast, differences in cellular responses were observed. Flow cytometric analysis of patient peripheral blood mononuclear cells co-cultured with P. falciparum infected erythrocytes demonstrated a statistically significant increase in the proportion of T regulatory cells (CD4+ CD25+ CD127-), and increases in unique populations of both NKT-like cells (CD3+ CD8+ CD56+) and CD8mid T cells in asymptomatics compared to symptomatics. Also, CD38+/HLA-DR+ expression on γδ T cells, CD8mid (CD56-) T cells, and CD8mid CD56+ NKT-like cells decreased upon exposure to infected erythrocytes in both groups. Cytometric bead analysis of the co-culture supernatants demonstrated an upregulation of monocyte-activating chemokines/cytokines in asymptomatics, while immunomodulatory soluble factors were elevated in symptomatics. Principal component analysis of these expression values revealed a distinct clustering of individual responses within their respective phenotypic groups. This is the first comprehensive investigation of immune responses to P. falciparum in Haiti, and describes unique cell-mediated immune repertoires that delineate individuals into asymptomatic and symptomatic phenotypes. Future investigations using large scale biological data sets analyzing multiple components of adaptive immunity, could collectively define which cellular responses and molecular correlates of disease outcome are malaria region specific, and which are truly generalizable features of asymptomatic Plasmodium immunity, a research goal of critical priority.
Highlights
Human malaria, caused by five parasite species of the genus, Plasmodium, accounted for 214 million cases worldwide with an estimated 500,000 deaths in 2015 [1]
There is a real potential to accomplish this due to the epidemiology of malaria in Hispaniola, as well as due to several advantages that would support the potential of malaria elimination on the island: 1) Haiti and the Dominican Republic have a lower rate of importation of malaria infections from other areas, compared to other malaria endemic countries [3,4,5]; 2) P. falciparum (Pf) is the one and only cause of endemic malaria on Hispaniola and elimination efforts are being concentrated on this one organism [4]; 3) chloroquine resistance to P. falciparum is rarely reported in Haiti, despite wide use as the standard of treatment for both Haiti and the Dominican Republic [5,6,7]
Since T cells are involved with the initiation of a memory response to protein antigens, we investigated the T cell arm of the adaptive immune response to the Pf asexual blood stages
Summary
Human malaria, caused by five parasite species of the genus, Plasmodium, accounted for 214 million cases worldwide with an estimated 500,000 deaths in 2015 [1]. Following the January 2010 earthquake, these issues worsened exponentially, and the public health response to numerous infectious diseases including malaria was further compromised Despite this prevailing obstacle, both Haiti and its eastern neighbor, the Dominican Republic, have mandated a strategy to eliminate malaria on the island of Hispaniola by the year 2020 [2]. There is a real potential to accomplish this due to the epidemiology of malaria in Hispaniola, as well as due to several advantages that would support the potential of malaria elimination on the island: 1) Haiti and the Dominican Republic have a lower rate of importation of malaria infections from other areas, compared to other malaria endemic countries [3,4,5]; 2) P. falciparum (Pf) is the one and only cause of endemic malaria on Hispaniola (there is a lack other Plasmodium species associated with human infection on the island) and elimination efforts are being concentrated on this one organism [4]; 3) chloroquine resistance to P. falciparum is rarely reported in Haiti, despite wide use as the standard of treatment for both Haiti and the Dominican Republic [5,6,7]
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