Interação molecular, imunológica e patológica entre gama-herpesvírus, Plasmodium e cancro

The Project’s MAJOR GOAL (MG) is to generate knowledge that may inform novel interventions against eBL and malaria. Our SPECIFIC AIMS (SA) address the following SPECIFIC OBJECTIVES (SO): SA1 - Epidemiological studies suggest that Pf infection can reactivate latent EBV, but several key questions remain unanswered in this regard. Having shown that a patent P. berghei (Pb) infection reactivates latent MHV68 in our rodent model (Fig. 2), we will dissect the individual contributions of the Plasmodium liver (including whole-organism malaria vaccines, which employ liver-infective Plasmodium sporozoites as immunization agents) and blood stages on viral reactivation, and identify novel targets for inhibition of lytic viral infection. We will: SO1.1. Independently assess MHV68 reactivation by the clinically silent but obligatory liver phase, and the symptomatic blood stage of Pb infection; SO1.2. Elucidate the kinetics of viral infection following antimalarial treatment of MHV68/Pb co-infected mice; SO1.3. Unveil the relationship between the immunological events taking place in mono- and co-infected mice and the dynamics of MHV68 reactivation/latency. SA2 - The effect of EBV infection on malaria progression is scarcely documented. Having shown that MHV68 inhibits the development of ECM in Pb-infected C57BL/6 mice (Fig. 3) and that MHV68 infection elicits the production of CD8+/CD11b+ T cells in the spleens of infected mice (Fig. 4), we now aim to clarify how MHV68 infection impacts Pb infection and modulates malaria symptoms, and potentially identify new targets for intervention against severe malaria. We will: SO2.1. Investigate the impact of both lytic and latent MHV68 infection on Pb parasitemia and development of severe malaria; SO2.2. Unveil the immunological and inflammatory mechanisms responsible for MHV68-mediated effects on malaria severity. SA3 - Although co-infections by EBV and Plasmodium are established causes of eBL, their relative contributions and possible synergies leading to cancer development remain poorly understood. We will employ our established models of mono- and co-infection (Fig. 1) to unveil the determinants of independent or concurrent MHV68 and P. berghei (Pb) infections on lymphomagenesis. We will: SO3.1. Dissect the relative impacts of MHV68 and Pb on the molecular and immunological events leading to lymphoproliferative disease in MHV68- or Pb- mono-infected mice and in co-infected animals; SO3.2. Elucidate the impact of concomitant antimalarial and antiviral treatment of MHV68/Pb co-infected mice on the inhibition of lymphomagenesis. SA4 - Although epidemiological studies have established a link between either EBV or Plasmodium infection and eBL, a detailed investigation of this three-party interplay in human subjects has not been reported. We will employ clinical samples from an age-matched cohort of children from Guinea Bissau with or without tumorous manifestations to obtain a complete picture of the relationship between EBV, Plasmodium and eBL, and, guided and complemented by the data obtained in SA3, identify immunological markers of infection and disease. We will: SO4.1- Confirm the diagnosis of eBL and detect EBV markers; SO4.2- Analyze P. falciparum parasitemia; SO4.3- Profile the circulating cellular immune landscape. The Project avoids bottlenecks by ensuring that the four SAs can proceed largely independently from each other. Their complementary results will be used synergistically to achieve our MG