Human Herpesvirus Impact on Periodontal Inflammation Afsar Raza Naqvi, Ph.D. Human Herpesviruses (HHV) are large, enveloped DNA viruses that establish lifelong latency. In adult humans, one or more types of viruses are persistently detected signifying HHV adaptation inside human body. Multiple lines of evidence show higher prevalence of these viruses in various oral inflammatory diseases but how HHV exacerbate these infections remains unexplored. A unique feature of HHV, unlike other viruses, is that they also encode viral miRNAs (v-miRs). These viral microRNAs (vmiRs) are multifunctional as they regulate expression of both virus and host derived transcripts and thus control host-virus interaction. In this proposal, we will study the impact of five most common oral inflammatory diseases associated HHV viz., HCMV, HSV-1, EBV, KSHV and HHV-6B on periodontal inflammation, a highly common oral inflammatory disease. The levels of viral miRNAs will be quantified in patients with diseased gingiva and correlate with viral genome and life cycle associated transcripts.
We aim to characterize the role of candidate vmiRs in regulating HHV infection in host gingival epithelial cells and macrophages. Identifying positive and negative regulatory v- miRs can yield novel insights into host-virus interaction. The impact of vmiRs on key biological functions of primary human oral keratinocytes and macrophages will be examined primarily by evaluating their influence on innate response against periopathogens (P. gingivalis and A. actinomycetemcomitans). This will shed novel insights into virus-bacterial synergy. Our next aim will test whether vmiRs can render host immune system dysfunctional. This will be examined by enforced expression of vmiRs in macrophages and dendritic cells. The key biological functions of these cells include pathogen uptake, antigen processing and presentation to T helper (CD4+) and T cytotoxic (CD8+) cells. In addition, we will assess the impact of v-miRs on the polarization of CD4+ T cells. The data generated will provide significant information to existing knowledge gaps. Interestingly, as vmiRs are not endogenous RNAs, they have the potential to be deployed as potential therapeutic targets. Given their immunomodulatory role, manipulation of these small RNAs may also be useful in the diagnosis and treatment of oral inflammatory diseases.
The oral cavity is a niche to diverse microbes including viruses. Herperviruses are ubiquitous viruses that persist as lifelong latent, subclinical infection. Emerging lines of evidences show role of Herpesviruses in various oral inflammatory disease including pulpitits, periodontitis, etc suggesting their role in augmenting disease manifestation. Small regulatory RNA called viral microRNAs (vmiRs) encoded by viruses are important in viral persistence and modulation of immune responses. The focus of our study is to identify viral miRNAs that change in periodontitis. Candidate viral miRNAs will be evaluated for their role in modulating host oral mucosal cell functions including the innate and adaptive immune responses critical to periopathogenesis. The knowledge to be gained from this study will be utilized to assess the diagnostic/prognostic potential of these vmiRs as well as to develop therapeutic targets that will be of value to medicine and dentistry.
| Naqvi, Afsar R; Shango, Jennifer; Seal, Alexandra et al. (2018) Herpesviruses and MicroRNAs: New Pathogenesis Factors in Oral Infection and Disease? Front Immunol 9:2099 |
