Gammaherpesvirus Co-infection with Malaria Suppresses Anti-parasitic Humoral Immunity
Caline G. Matar, Neil R. Anthony, Brigid M. O’Flaherty, Nathan T. Jacobs, Lalita Priyamvada, Christian R. Engwerda, Samuel H. Speck , Tracey J. Lamb
Abstract[size=0.8125]Immunity to non-cerebral severe malaria is estimated to occur within 1-2 infections in areas of endemic transmission for Plasmodium falciparum. Yet, nearly 20% of infected children die annually as a result of severe malaria. Multiple risk factors are postulated to exacerbate malarial disease, one being co-infections with other pathogens. Children living in Sub-Saharan Africa are seropositive for Epstein Barr Virus (EBV) by the age of 6 months. This timing overlaps with the waning of protective maternal antibodies and susceptibility to primaryPlasmodium infection. However, the impact of acute EBV infection on the generation of anti-malarial immunity is unknown. Using well established mouse models of infection, we show here that acute, but not latent murine gammaherpesvirus 68 (MHV68) infection suppresses the anti-malarial humoral response to a secondary malaria infection. Importantly, this resulted in the transformation of a non-lethal P. yoelii XNL infection into a lethal one; an outcome that is correlated with a defect in the maintenance of germinal center B cells and T follicular helper (Tfh) cells in the spleen. Furthermore, we have identified the MHV68 M2 protein as an important virus encoded protein that can: (i) suppress anti-MHV68 humoral responses during acute MHV68 infection; and (ii) plays a critical role in the observed suppression of anti-malarial humoral responses in the setting of co-infection. Notably, co-infection with an M2-null mutant MHV68 eliminates lethality of P. yoelii XNL. Collectively, our data demonstrates that an acute gammaherpesvirus infection can negatively impact the development of an anti-malarial immune response. This suggests that acute infection with EBV should be investigated as a risk factor for non-cerebral severe malaria in young children living in areas endemic for Plasmodiumtransmission.
Author Summary[size=0.8125]Nearly 1 million deaths occur annually as a result of complications associated with P.falciparum infection, with children younger than 5 being the most susceptible age group. Earlier studies have demonstrated that children co-infected with P. falciparum and Epstein-Barr virus (EBV) have impaired immune responses to control EBV, and this can result in the development of a jaw tumor called endemic Burkitt’s lymphoma (eBL). It is not known if there is any impact of acute EBV infection on the generation of anti-malarial immunity. We have used mouse models of EBV [murine gammaherpesvirus 68 (MHV68)] and malaria (P. yoelii XNL) to demonstrate that acute gammaherpesvirus infection can impair the generation of antibodies that control Plasmodium parasitemia, in turn causing a non-lethal P. yoelii XNL infection to become lethal. We identify a critical role for the MHV68 M2 protein in mediating the suppressive effect of acute MHV68 infection on the generation of humoral immunity to a secondary malaria infection. This work demonstrates that gammaherpesvirus infections can suppress the generation of an effective anti-malaria immune response and suggests that acute EBV infection should be investigated as a risk factor for the development of severe malaria in young children. http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004858
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发表于 2015-6-18 14:21:45
