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 in- fection in children. Using well established mouse models of EBV (MHV68) and malaria the objective of this proposal is to identify how the humoral immune response to malaria is altered by an MHV68 la- tency associated protein (M2), and to identify which features of the humoral response are affected (magnitude, breadth, affinity and longevity). 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, broad spectrum antibody production to incoming Plasmodium infection. This hypothe- sis has been formulated from our published and preliminary data showing that M2 induces substantial amount of IL-10 in B cells and that pre-existing suppression of humoral immunity to Plasmodium by MHV68 in a primary infection also resulted in an ineffective memory responses upon challenge infec- tion. The rationale for the proposed work is that the development of new therapeutic strategies to en- sure 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 pre- liminary data, the central hypothesis will be tested by pursuing 3 specific aims: 1) To determine how the response of Tfh cells to an incoming Plasmodium infection is altered by M2-induced IL-10 secretion from MHV68-infected B cells 2) To determine how the breadth, affinity and longevity of the anti-malarial humoral response is altered by pre-existing gammaherpesvirus infection (3) To demonstrate that hu- moral immunity to P. falciparum in children is reduced by acute immunosuppressive EBV infection. The approach is innovative because our proposed research uses novel rodent models of EBV and Plasmo- dium co-infection and incorporates transcriptional profiling of B cell populations to enable the breadth of humoral immune responses to malaria to be determined. The proposed research is significant because it is expected to advance understanding of how the development of immunity to malaria can be ad- versely impacted by viral co-infections.
The proposed research is relevant to public health because identifying that the development of protective hu- moral 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 re- search 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.
