Abstract

The human oral cavity contains highly diverse microbes, including bacteria, fungi, and viruses. Human herpesviruses are ubiquitous pathogens, and the oral cavity is conducive to the replication, dissemination, and pathogenesis of human herpesviruses. Herpesviruses are generally pathogenic in immunodeficient individuals, such as AIDS patients and organ transplant recipients. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma and two types of rare lymphoma, that is, primary effusion lymphoma and multicentric Castleman's disease. Mounting evidence indicates that KSHV viral load positively correlates with ongoing bacterial infection in the oral cavity, suggesting that bacteria potentially stimulate KSHV replication. However, the mechanism by which oral bacteria may promote KSHV lytic replication is poorly understood. In this study, we performed DNA sequencing and 16S ribosomal RNA analysis of saliva samples of AIDS-KS patients. A correlation analysis identified a panel of oral residential bacteria and uncommon ones that paralleled with KSHV viral load. Performing functional assays, we discovered that the sexually transmitted Neisseria gonorrhoeae (N.g.) significantly increased KSHV lytic replication. Increased KSHV lytic replication was evidenced by elevated levels of mRNA and proteins of viral lytic genes. N.g. stimulation increases the expression of RTA that drives viral lytic replication. Metabolomic analysis reveals the synergistic effect of KSHV and N.g. on cellular metabolism, including the glycolysis and purine and pyrimidine synthesis, that likely underpins the elevated KSHV lytic replication. Findings from our study shed light on the molecular detail of bacteria-virus interaction in the oral cavity and provide references to develop an innovative strategy to treat diseases associated with KSHV.