The human cytomegalovirus (HCMV) is a ubiquitous pathogen linked with a high risk of morbidity in immunologically suppressed and immunodeficient patients. Furthermore, HCMV is one of major viral causes of congenital infections. HCMV infections are also implicated in several chronic diseases. The strategies to cope with the consequences of HCMV infection are limited by the lack of complete understanding of the viral pathogenesis. Cytomegaloviruses (CMV) are characterized by strict species specificity. Infection of mice with mouse CMV (MCMV) has been particularly informative as a model of HCMV infection in dissecting the role of innate and adaptive immune responses. Primary CMV infections are efficiently controlled in immunocompetent hosts;however, the viral genome remains in a state of latency from which periodic reactivation may occur. The most important question is why the mammalian immune system fails to effectively resolve these infections. A large number of CMV genes modulate the innate and adaptive host immune response. The team of scientists proposing this project has characterized several MCMV genes that play a role in the subversion of NK cell response by downmodulation of cellular ligands for the NKG2D receptor expressed on NK cells and CD8+ T cells. Mutant viruses lacking these viral immunoevasion genes are attenuated in vivo. Because of the importance of the NKG2D receptor in controlling both NK- and T cell-mediated immunity, it is of paramount importance to understand the mechanisms and consequences of viral regulation of the NKG2D ligands. In this project, the regulation of the expression of MCMV immunoevasion proteins that target NKG2D ligands and the molecular mechanisms by which these viral proteins disrupt NKG2D ligand expression will be studied. Cellular proteins that interact with viral immunoevasins will be identified and the impact of viral regulation of NKG2D ligands on the efficacy of NK and memory T cell responses in controlling latency, and in resolving the recurrent virus infection, will be evaluated. This research will aid at gaining insight on how CMV persists for the lifetime in the infected hosts and may lead to the development of novel probes to characterize the cellular mechanisms that control the expression of NK receptor ligands.

Public Health Relevance

The significance of this research lies both in the advancement of our basic knowledge of persistent virus infections, and in the possibility of designing new and more efficient anti-viral treatments. The study will serve to advance our understanding of the biology and natural history of the cytomegalovirus by characterizing the regulation of important viral immunoregulatory genes and their protein products. Considering that clinical diseases associated with cytomegalovirus infections are dominantly caused by recurrent infection and that current drug treatments suffer from the emergence of drug resistant virus strains, there is an urgent need to develop new anti-viral regimens for which the mouse model of infection is optimal to experimentally define critical parameters affecting recurrent herpes virus infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI083201-03
Application #
8129610
Study Section
Special Emphasis Panel (ZRG1-IDM-P (50))
Program Officer
Beisel, Christopher E
Project Start
2009-09-18
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$81,362
Indirect Cost
Name
University of Rijeka - Medical Faculty
Department
Type
DUNS #
644611399
City
Rijeka
State
Country
Croatia
Zip Code
51000
Yossef, Rami; Gur, Chamutal; Shemesh, Avishai et al. (2015) Targeting natural killer cell reactivity by employing antibody to NKp46: implications for type 1 diabetes. PLoS One 10:e0118936
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
Jonjic, Stipan (2015) CMV immunology. Cell Mol Immunol 12:125-7
Juranic Lisnic, Vanda; Babic Cac, Marina; Lisnic, Berislav et al. (2013) Dual analysis of the murine cytomegalovirus and host cell transcriptomes reveal new aspects of the virus-host cell interface. PLoS Pathog 9:e1003611
Trsan, Tihana; Busche, Andreas; Abram, Maja et al. (2013) Superior induction and maintenance of protective CD8 T cells in mice infected with mouse cytomegalovirus vector expressing RAE-1?. Proc Natl Acad Sci U S A 110:16550-5
Stanietsky, Noa; Rovis, Tihana Lenac; Glasner, Ariella et al. (2013) Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR. Eur J Immunol 43:2138-50
Lankry, Dikla; Rovis, Tihana Lenac; Jonjic, Stipan et al. (2013) The interaction between CD300a and phosphatidylserine inhibits tumor cell killing by NK cells. Eur J Immunol 43:2151-61
Mitrovic, Maja; Arapovic, Jurica; Jordan, Stefan et al. (2012) The NK cell response to mouse cytomegalovirus infection affects the level and kinetics of the early CD8(+) T-cell response. J Virol 86:2165-75
Poglitsch, M; Weichhart, T; Hecking, M et al. (2012) CMV late phase-induced mTOR activation is essential for efficient virus replication in polarized human macrophages. Am J Transplant 12:1458-68
Mitrovic, Maja; Arapovic, Jurica; Traven, Luka et al. (2012) Innate immunity regulates adaptive immune response: lessons learned from studying the interplay between NK and CD8+ T cells during MCMV infection. Med Microbiol Immunol 201:487-95

Showing the most recent 10 out of 23 publications