Alterations in Cellular Gene Expression Due to Co‐Infection With Kaposi's Sarcoma‐Associated Herpesvirus and SARS‐CoV‐2: Implications for Disease Severity

An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 pandemic, has resulted in over 7 million confirmed deaths. In addition to severe respiratory and systematic symptoms, several comorbidities increase the risk of fatal outcomes. Therefore, it is essential to investigate the impact of COVID-19 on pre-existing conditions in patients, such as cancer and other infectious diseases. Recent clinical studies have reported the reactivation of human herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV), in severe COVID-19 patients or vaccinated individuals. To support these clinical observations, we established a KSHV/SARS-CoV-2 co-infection system in A549-hACE2 cells. Our findings indicate that co-infection with live SARS-CoV-2 sharply induces KSHV lytic reactivation. Transcriptomic analysis revealed significant changes in global cellular gene expression in KSHV-infected A549-hACE2 cells, both with and without SARS-CoV-2 co-infection. These data provide a molecular basis for understanding whether patients with pre-existing oncogenic herpesvirus infections are at increased risk for more severe COVID-19 or for developing virus-associated cancers even after full recovery from COVID-19.