Inflammation is the body's response to damage induced by physical injury or pathogen infection. The oral cavity, gastrointestinal track, skin, lung and urogenital track represent distinct anatomical sites where host cells interface extensively with diverse microbes, presenting ample opportunities for infection and inflammation. Recent advances have uncovered pivotal roles of microbiota, primarily from the gut, in human health and disease. Our understanding in mucosal immunity of the other sites, particularly the oral cavity, is extremely limited. How viruses, in addition to the microbiome, contribute to oral inflammation and diseases thereof remains unknown. Emerging clinical studies revealed that human herpesviruses (e.g., Epstein-Barr virus and cytomegalovirus) were frequently detected in the oral cavity of patients with severe forms of inflammatory diseases, such as periodontitis, peri-implantitis and mucositis. Other studies also suggest that inflammation can promote herpesvirus reactivation and replication in the oral cavity. However, how herpesviruses contribute to oral inflammation and the underlying molecular mechanisms have never been explored. Built on our recent discovery that herpesviruses deploy protein deamidation to manipulate host immune response, this study will directly address the above knowledge gap with research answering the following questions: 1) What is the role of herpesvirus infection in oral inflammatory diseases; 2) How do nucleic acid sensing pathways operate in oral immune defense and impact oral inflammatory disease; 3) How does herpesviral evasion of nucleic acid- sensing pathways impinge on oral inflammation; 4) What are the regulatory role of protein deamidation in viral infection and immune defense in the oral cavity; and 5) Can we leverage protein deamidation to tame oral inflammation and treat oral inflammatory diseases. This work will illuminate the role and molecular basis of innate immune sensing, herpesvirus infection and protein deamidation in oral inflammation. Harnessing our knowledge of protein deamidation, we will develop key reagents to rectify chronic inflammation and treat oral inflammatory diseases.

Public Health Relevance

Recent clinical investigations indicate that infection of human herpesviruses (e.g., Epstein-Barr virus, Kaposi's sarcoma-associated herpesviruses, cytomegalovirus) is highly associated with severe forms of oral inflammatory diseases. However, the molecular mechanism remains unknown. Here we will investigate the molecular detail by which herpesviruses deploy protein deamidation to induce inflammation and inflammation promotes herpesvirus replication in the oral cavity, feeding forward to escalate oral inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Unknown (R35)
Project #
5R35DE027556-02
Application #
9565552
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
Chander, Preethi
Project Start
2017-09-14
Project End
2025-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Southern California
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Zhang, Junjie; Zhao, Jun; Xu, Simin et al. (2018) Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication. Cell Host Microbe 24:234-248.e5