T cell subtypes and reciprocal inflammatory mediator expression differentiate P. falciparum memory recall responses in asymptomatic and symptomatic malaria patients in southeastern Haiti

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.

Asymptomatic carriage ofPlasmodium falciparumin children living in a hyperendemic area occurs independently of IgG responses but is associated with a balanced inflammatory cytokine ratio

“…IL-8 is a chemoattractant cytokine known to be involved in neutrophil recruitment and activation, and previously associated with severe malaria pathogenesis (73,78). A recent study reported higher levels of IL-8 production by PBMCs from asymptomatic individuals compared to symptomatic carriers (86). Furthermore, the Malian Fulani ethnic group who are known to be less susceptible to Plasmodium falciparum malaria as reflected by lower parasitemia and fewer clinical symptoms exhibited a higher level of IL-8 than sympatric ethnic groups (87).…”

The role of monocytes in malaria infection

“…IL-18 and IL-12 work together to activate interferon γ (IFN-γ), which is necessary for the activation of monocyte proinflammatory function in order to facilitate parasite clearance [ 48 ]. Upon in vitro exposure to P. falciparum , production of GM-CSF, MIP-1β, or IL-34 cytokines initiates the immunity mechanism with lower parasite loads (premunition) by opsonic phagocytosis and cytokine secretions by monocytes [ 49 ]. Exposure of these cytokines, specifically TNF-α and IFN-γ, regulates iRBC uptake and endothelial cell activation by increasing the expression of ICAM-1 and other adhesion molecules by endothelial cells [ 50 ].…”

Setting the stage: The initial immune response to blood-stage parasites

“…Research on host recognition has found that P. falciparum GPI is also recognized by CD1d-restricted NKT cells [101]. In contrast to in vitro results and co-culture experiments, human CHMI studies have failed to indicate that NKT recognition of P. falciparum antigens is as prevalent during early stages of infection [102][103][104]. However, during CHMI lymphopenia is commonly observed after parasites are released from the liver, which includes a reduction in NKT cells.…”