Congenital human cytomegalovirus (HCMV) represents the most common viral infection acquired by the developing fetus. Although most infants infected in-utero do not suffer long term symptoms, approximately 10% can have long term sequelae. Central nervous system (CNS) damage is the singular cause of these long term sequelae. Prevention of CNS infection and disease is the target of current antiviral treatment and has been proposed as a goal of prophylactic vaccines. The pathogenesis of CNS disease in congenitally infected human infants remains undefined and to date studies in animal models of CNS infection by HCMV have provided little information secondary to significant limitations inherent in these models. We have recently developed a murine model of infection of the developing CNS with the related murine CMV that recapitulates many key characteristics of the human disease, including hearing loss that is common in infants with congenital CMV infections. Using this model we propose to define mechanisms of protective antibodies that limit CNS infection and disease. In addition, we will explore the use of engineered viruses that are attenuated in their capacity to cause CNS disease and establish persistent infection to induce protective antibody responses. We anticipate that these studies will identify strategies for development of targeted biologics such as antibodies and attenuated viruses that can provide immunologically mediated protection from CNS infection and damage that can follow congenital HCMV infection. Because of the relatedness between MCMV and HCMV, these strategies could be rapidly transitioned into development of similar biologics for human use.

Public Health Relevance

Project Narrative: Using a mouse model of congenital human cytomegalovirus (HCMV), we will carry out studies to define HCMV infection of the brain of the developing fetus. These studies will serve as an important starting point for our experiments to identify biological molecules such as antibody and/or viral vaccines attenuated in their capacity to infect the brain or cause brain disease that can limit infection and disease associated with HCMV infection. In addition, results from the proposed studies will serve as a platform for the rationale design of effective and safe therapies for use in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI089956-06A1
Application #
9593263
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Beisel, Christopher E
Project Start
2011-05-13
Project End
2023-04-30
Budget Start
2018-05-17
Budget End
2019-04-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Pediatrics
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Zicari, Sonia; Arakelyan, Anush; Palomino, Rogers Alberto Ñahui et al. (2018) Human cytomegalovirus-infected cells release extracellular vesicles that carry viral surface proteins. Virology 524:97-105
Brizi?, Ilija; Lisni?, Berislav; Brune, Wolfram et al. (2018) Cytomegalovirus Infection: Mouse Model. Curr Protoc Immunol :e51
Tršan, Tihana; Vukovi?, Kristina; Filipovi?, Petra et al. (2017) Cytomegalovirus vector expressing RAE-1? induces enhanced anti-tumor capacity of murine CD8+ T cells. Eur J Immunol 47:1354-1367
Sell, Sabrina; Dietz, Monika; Schneider, Andrea et al. (2015) Control of murine cytomegalovirus infection by ?? T cells. PLoS Pathog 11:e1004481
Slavuljica, Irena; Kveštak, Daria; Huszthy, Peter Csaba et al. (2015) Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model. Cell Mol Immunol 12:180-91
Wiegers, Anna-Katharina; Sticht, Heinrich; Winkler, Thomas H et al. (2015) Identification of a neutralizing epitope within antigenic domain 5 of glycoprotein B of human cytomegalovirus. J Virol 89:361-72
Bradford, Russell D; Yoo, Young-Gun; Golemac, Mijo et al. (2015) Murine CMV-induced hearing loss is associated with inner ear inflammation and loss of spiral ganglia neurons. PLoS Pathog 11:e1004774
Dreher, A Mackenzie; Arora, Nitin; Fowler, Karen B et al. (2014) Spectrum of disease and outcome in children with symptomatic congenital cytomegalovirus infection. J Pediatr 164:855-9
Smith, Phillip D; Shimamura, Masako; Musgrove, Lois C et al. (2014) Cytomegalovirus enhances macrophage TLR expression and MyD88-mediated signal transduction to potentiate inducible inflammatory responses. J Immunol 193:5604-12
Renzette, Nicholas; Gibson, Laura; Jensen, Jeffrey D et al. (2014) Human cytomegalovirus intrahost evolution-a new avenue for understanding and controlling herpesvirus infections. Curr Opin Virol 8:109-15

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