title: Gammaherpesvirus Co-infection with Malaria Suppresses Anti-parasitic Humoral Immunity.
abstract: 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 primary Plasmodium 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 Plasmodium transmission.
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America; Microbiology and Molecular Genetics Graduate Program, Laney Graduate School, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Caline G
authors.initials: CG
authors.lastname: Matar
authors.affiliation: Division of Pediatric Infectious Disease, Department of Pediatrics, Emory University School of Medicine, Emory Children's Centre, Atlanta, Georgia, United States of America.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Anthony
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America; Microbiology and Molecular Genetics Graduate Program, Laney Graduate School, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Brigid M
authors.initials: BM
authors.lastname: O'Flaherty
authors.affiliation: Division of Pediatric Infectious Disease, Department of Pediatrics, Emory University School of Medicine, Emory Children's Centre, Atlanta, Georgia, United States of America; Population Biology, Ecology and Evolution Graduate Program, Laney Graduate School, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Nathan T
authors.initials: NT
authors.lastname: Jacobs
authors.affiliation: Microbiology and Molecular Genetics Graduate Program, Laney Graduate School, Emory University, Atlanta, Georgia, United States of America; Division of Pediatric Infectious Disease, Department of Pediatrics, Emory University School of Medicine, Emory Children's Centre, Atlanta, Georgia, United States of America.
authors.forename: Lalita
authors.initials: L
authors.lastname: Priyamvada
authors.affiliation: Immunology and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Engwerda
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America; Emory Vaccine Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Speck
authors.affiliation: Division of Pediatric Infectious Disease, Department of Pediatrics, Emory University School of Medicine, Emory Children's Centre, Atlanta, Georgia, United States of America.
authors.forename: Tracey J
authors.initials: TJ
authors.lastname: Lamb
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D060085:Coinfection / Q000276:immunology*; D005260:Female; D006564:Herpesviridae / Q000276:immunology*; D006566:Herpesviridae Infections / Q000276:immunology*; D056724:Immunity, Humoral / Q000276:immunology*; D008288:Malaria / Q000276:immunology* / Q000821:virology*; D008810:Mice, Inbred C57BL; D014775:Virus Activation / Q000276:immunology; D017735:Virus Latency / Q000276:immunology