The humoral response to malaria is critical in the control of blood stage parasitemia and the breadth of the antibody response is protective against the development of clinical malaria. It is not understood why some children fail to develop adequate humoral immune responses to Plasmodium infection early in life. Both Plasmodium falciparum malaria and Epstein Barr virus (EBV) are childhood infections in sub- Saharan Africa. The majority of children become seropositive for EBV within the first years of life, an event that is normally asymptomatic but accompanied by potent immunosuppression. The long term goal of this proposal is to provide mechanistic evidence that overlapping acute gammaherpesvirus coin- fections are responsible for suppressing the development of humoral immunity during Plasmodium infection in children. Using well-established mouse models of EBV (MHV68) and malaria the objective of this proposal is to identify how acute MHV68 co-infections suppress the development of anti-malaria humoral immunity. The central hypothesis of this proposal is that the induction of IL-10 by M2 in MHV68-infected B cells impairs the ability of T follicular helper cells to provide B cell help for effective antibody production to incoming Plasmodium infection. This hypothesis has been formulated from our published and preliminary data showing that M2 induces substantial amount of IL-10 in MHV68-infected B cells and that MHV68 can only suppress humoral immune responses to both primary and challenge Plasmodium infection when it can synthesize the M2 protein. The rationale for the proposed work is that the development of new therapeutic strategies to ensure protective humoral immunity develops in children depends on an understanding of the contributing factors that prevent the development of the humoral response in the first place. Guided by strong preliminary data, the central hypothesis will be tested by pursuing 3 specific aims:
Aim 1 : Dissect how Tfh cells respond to an incoming Plasmodium infection in the context of IL-10 secretion from MHV68-infected B cells Aim 2: Determine whether M2 is sufficient to globally suppress anti-Plasmodium humoral immune responses Aim 3: Demonstrate that humoral immunity to P. falciparum in children is reduced during acute immunosuppressive EBV infection The approach is innovative because to our knowledge we are the first to propose that impaired anti- malarial humoral responses could be a result of a gammaherpesvirus mediated suppression. The proposed research is significant because it is expected to advance understanding of how the development of immunity to malaria can be adversely impacted by viral co-infections
The proposed research is relevant to public health because identifying that the development of protective humoral immunity against Plasmodium infection is negatively affected by overlapping acute Epstein-Barr virus infection could flag EBV as a risk factor for the development of severe malaria in turn potentially changing monitoring and treatment regimes for children in countries where malaria is endemic. Thus the proposed research is relevant to the part of the NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of human disease and disability.
