Development of an effective intervention strategy against congenital cytomegalovirus (CMV) is a major public health priority. However, candidate CMV vaccines strategies have been unsuccessful in completely preventing congenital infection in a pre-clinical animal model and an effective vaccine remains an elusive goal. The pathogenicity of CMV transplacental infection is poorly defined and a better understanding may provide fresh insight for the development of a novel intervention or vaccine strategy. In this proposal, we will examine two key aspects of placental infection: (1) Toll-like receptor (TLR) mediated innate immune response of the placenta to CMV; (2) Viral tropism and placental infection. The inflammatory innate immune response mediated via TLRs expressed on key placental cells (trophoblasts) is potentially an important aspect of controlling placental invasion congenital infection by both bacteria and viruses. CMV is known to be recognized by multiple TLRs but the placental TLR mediated response to CMV is poorly defined as is the mechanism by which CMV potentially circumvents the placental innate immunity and infects the fetus in utero. It is our hypothesis that successful congenital infection is reliant upon the ability of CMV to efficiently enter and usurp TLR expressing trophoblast cells, an important component of the placental barrier and placental innate immunity. Potentially, the newly identified endocytic pathway of viral cell entry could be an important factor in the invasion of the placenta and infection of epithelial trophoblasts. We propose to determine the significance of the TLR mediated innate immune response of the placenta to CMV infection in the only small animal model (guinea pig) for congenital CMV. Additionally, using the same animal model, we will define important tropism genes that potentially enable the virus to establish infectious foci in th placenta and subsequently infect the fetus in utero. These studies will employ conventional histopathological and immunohistochemical approaches as well as novel techniques including the use of bioluminescence imaging of viral dissemination in the animal model.

Public Health Relevance

Cytomegalovirus (CMV) is a ubiquitous pathogen that causes significant mortality and morbidity in immunocompromised populations including transplant and AIDS patients and the fetus in utero. Congenital CMV infection causes mental retardation and deafness in surviving newborn. CMV is the most common AIDS related secondary infection. There is no vaccine to CMV. Although current antivirals are available for transplant and AIDS patients these result in the emergence of resistant strains that cause disease. Additionally, drug toxic side effects preclude their use in the prevention of congenital CMV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI100933-05
Application #
8890099
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Beisel, Christopher E
Project Start
2012-07-05
Project End
2017-06-30
Budget Start
2015-07-01
Budget End
2017-06-30
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Texas A&M University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
Coleman, Stewart; Choi, K Yeon; McGregor, Alistair (2017) Cytomegalovirus UL128 homolog mutants that form a pentameric complex produce virus with impaired epithelial and trophoblast cell tropism and altered pathogenicity in the guinea pig. Virology 509:205-221
Hornig, Julia; Choi, K Yeon; McGregor, Alistair (2017) The essential role of guinea pig cytomegalovirus (GPCMV) IE1 and IE2 homologs in viral replication and IE1-mediated ND10 targeting. Virology 504:122-140
Choi, K Yeon; Root, Matthew; McGregor, Alistair (2016) A Novel Non-Replication-Competent Cytomegalovirus Capsid Mutant Vaccine Strategy Is Effective in Reducing Congenital Infection. J Virol 90:7902-19
Coleman, Stewart; Choi, K Yeon; Root, Matthew et al. (2016) A Homolog Pentameric Complex Dictates Viral Epithelial Tropism, Pathogenicity and Congenital Infection Rate in Guinea Pig Cytomegalovirus. PLoS Pathog 12:e1005755
Coleman, Stewart; Hornig, Julia; Maddux, Sarah et al. (2015) Viral Glycoprotein Complex Formation, Essential Function and Immunogenicity in the Guinea Pig Model for Cytomegalovirus. PLoS One 10:e0135567
Coleman, Stewart M; McGregor, Alistair (2015) A bright future for bioluminescent imaging in viral research. Future Virol 10:169-183
Hornig, Julia; McGregor, Alistair (2014) Design and development of antivirals and intervention strategies against human herpesviruses using high-throughput approach. Expert Opin Drug Discov 9:891-915
Schleiss, Mark R; Buus, Ryan; Choi, K Yeon et al. (2013) An Attenuated CMV Vaccine with a Deletion in Tegument Protein GP83 (pp65 Homolog) Protects against Placental Infection and Improves Pregnancy Outcome in a Guinea Pig Challenge Model. Future Virol 8:1151-1160