Immunoregulatory Roles of the KSHV Viral Proteins during Oral Infection

Objectives: Infection of humans by the oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) usually starts in the oral cavity. KSHV replicates in infected oral epithelial cells from which the virus is transmitted into B cells where it establishes viral latency resulting in persistent infection of the host. It is still largely unknown how KSHV escapes from being recognized and neutralized by the immune system during oral infection. Here, we investigated what KSHV proteins may have anti- or proinflammatory functions in oral epithelial cells, which can play a role in immune evasion by KSHV during oral infection.
Methods: We generated a set of recombinant adenoviruses and lentiviruses for expressing 19 different viral immunoregulatory genes of KSHV. We infected primary human gingival epithelial cells with lentiviruses for 2 days and then performed RT-qPCR analysis to test the effect of KSHV proteins on the mRNA expression of proinflammatory cytokines (IL-8, CXCL3, IL-1b) and the Intercellular Adhesion Molecule 1 (ICAM1).
Results: We found that 9 of the 19 tested KSHV proteins changed the expression levels of IL-8, CXCL3, IL-1b, and ICAM1 by more than 2-fold. Specifically, IL-1b was targeted by 7 different viral proteins, while ICAM1 expression was deregulated by only 3 viral proteins. Strikingly, viral interferon regulatory factor 1 of KSHV could suppress the expression of all three tested cytokines and ICAM as well. In contrast, 6 of the 19 tested viral proteins increased the expression of either ICAM1 or specific proinflammatory cytokines.
Conclusions: Our study revealed that KSHV immunomodulatory proteins can have highly specialized pro- or anti-inflammatory role during primary infection of oral epithelial cells. We hypothesize that these viral proteins can potentially be involved in the deregulation of immune responses during oral KSHV infection whereby facilitating KSHV infection-associated pathogenesis in the oral cavity.