Immune responses to infections in early life are not well understood;however, they can result in profound changes in development and function of organs impacting health. For example, human cytomegalovirus (HCMV) infection in utero (congenital) can result in growth retardation, microcephaly, sensorineural hearing loss, and even death. HCMV infection also occurs postnatally in newborns via viral transmission in breast milk. As most of these infants are asymptomatic, it has been proposed that this route of infection could represent a type of natural immunization. The effectiveness of exposure to the virus through breastfeeding in the ability of the neonate to develop effective immune control of viral dissemination and shedding is not well characterized. This exploratory study is designed to define the evolution of the immune response following murine CMV (MCMV) infection acquired by maternal transmission during breastfeeding. Our goals are to determine the developmental progression of the CD8+ and CD4+ T cell response to MCMV in neonatal mice following infection acquired via this natural route. There is concern for infants of mothers with latent HCMV, as reactivation of the virus can occur specifically within the mammary gland during lactation. This could be the consequence of latently infected monocyte recruitment from the blood followed by differentiation to macrophages in the breast during branching morphogenesis in the mammary gland. As breast milk is enriched with monocytes/macrophages and HCMV-specific antibodies, it is possible that these maternal antibodies can influence postnatal infection through the gastrointestinal tract. Specifically, maternal antibody:MCMV complexes could either aid in virus transport utilizing the FcRn pathway and/or enhance viral immunogenicity. Therefore, we hypothesize that maternal antibodies from latent MCMV moms transferred to nursing pups will augment the generation of virus specific CD8+ and CD4+ T cells or their effector functions necessary for immune control of MCMV in the pups. Our goals are to track the state of viral reactivation in Latent Moms prior to and during lactation. We will also determine the kinetics and effector function of MCMV-specific CD8+ and CD4+ T cell responses in pups from mothers with latent infection and correlate this with viral clearance. Finally, we will determine the impact of FcRn in delivery of infectious virus in the gastrointestinal tract. To this end, our aims are:
AIM 1. Define how breast milk-mediated transmission of MCMV impacts the development of antiviral immunity in offspring and AIM 2. Identify factors contributing to neonatal acquisition of MCMV during breastfeeding and their impact on immunological outcomes.
The relevance of this project to public health is based on the need for a CMV vaccine to protect infants, children and immune compromised individuals (A M Arvin et. al , """"""""Vaccine development to prevent cytomegalovirus disease: report from the national vaccine advisory committee"""""""", Vaccines 39:233). Susceptible individuals share significant challenges for vaccination, as they are less competent to generate long-term protective immunity. Our exploratory project aims to develop an animal model to understand immune responsiveness in neonates acquiring CMV infection via breast milk;our ultimate goal being to exploit this model to identify general strategies to enhance immune-mediated protection in immune compromised individuals.
|Wu, Carol A; Paveglio, Sara A; Lingenheld, Elizabeth G et al. (2011) Transmission of murine cytomegalovirus in breast milk: a model of natural infection in neonates. J Virol 85:5115-24|