Mechanisms sustaining lytic herpesviral infection in the oral cavity

Abstract The oral epithelium is often the gateway for many different viruses into the human body. The oral cavity has a complex multi-species microbiome, which includes bacteria, fungi, and viruses. The interaction between the different microbiome elements and the bacterial secretions such as short-chain fatty acids (SCFAs) play a crucial role in regulating oral infections, however, the underlying mechanisms are still largely unknown. Clinical studies on periodontitis showed that the amount of oral bacteria (e.g., P. gingivalis) correlates with that of herpesviruses including the human oncogenic DNA virus, Kaposi's sarcoma-associated herpesvirus (KSHV). The primary route of KSHV infection in humans is through the oral cavity, which is the least understood step in KSHV infection. The goal of our study is to determine the molecular mechanisms that control the infection of oral epithelial cells by KSHV and how oral KSHV infection is affected by oral bacteria and their metabolites such as SCFAs. We found that P. gingivalis and bacterial metabolites can increase the expression of stress response-related cellular transcription factors in oral epithelial cells, and they are crucial for the robust herpesvirus infection of oral epithelial cells. Based on our preliminary data, we hypothesize that the reason that the oral epithelial cells are supportive of lytic KSHV infection is because they have unique cellular properties, which SCFAs can upregulate resulting in enhanced KSHV infection. In Aim 1 of this proposal, we will investigate the mechanism by which SCFA increases the protein level of stress response-related host transcription factors in oral epithelial cells and how they promote KSHV infection. Aim 2 will focus on the identification of KSHV factors that can also induce stress response-related host transcription factors, and their importance in the KSHV infection of oral epithelial cells will be investigated. We envision that understanding of how the metabolites of oral bacteria support KSHV infection in the oral epithelium will help to find targets that can be used for developing new therapeutic antivirals to block oral infection not only by the cancer-causing virus KSHV but potentially by other human pathogens as well.