Virally encoded interleukin-6 facilitates KSHV replication in monocytes and induction of dysfunctional macrophages

• Published in: PLoS pathogens 2023-10, Vol.19 (10), p.e1011703-e1011703
• Main Authors: Shimoda, Michiko, Inagaki, Tomoki, Davis, Ryan R, Merleev, Alexander, Tepper, Clifford G, Maverakis, Emanual, Izumiya, Yoshihiro
• Format: Article
• Language: English
• Subjects: Analysis; Angiogenesis; Antisense RNA; Antiviral agents; B cells; Biology and Life Sciences; Care and treatment; CD14 antigen; Complications and side effects; Control; Cytokines; Dendritic cells; Disease; Disease susceptibility; DNA viruses; Dosage and administration; Gene expression; Genes; Genetic aspects; Genomics; Health aspects; Herpes viruses; Herpesviridae Infections - metabolism; Herpesvirus 8, Human - physiology; Herpesviruses; HIV; Human immunodeficiency virus; Humans; Identification and classification; Immunologic Factors - metabolism; Immunoproliferative diseases; Immunosurveillance; Infection; Infections; Inflammation; Interleukin 6; Interleukin-6 - metabolism; Interleukins; Kaposi's sarcoma; Lymphocytes; Lymphocytes T; Lymphoma; Macrophages; Macrophages - metabolism; Medicine and Health Sciences; Monocytes; Monocytes - metabolism; Nonsense mutation; Proteins; Replication; Research and Analysis Methods; Ribonucleic acid; RNA; Sarcoma; Sarcoma, Kaposi; Stat1 protein; Stop codon; T cells; Tumorigenesis; Viral infections; Virus Replication; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011703

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus and the etiologic agent of Kaposi's sarcoma and hyperinflammatory lymphoproliferative disorders. Understanding the mechanism by which KSHV increases the infected cell population is crucial for curing KSHV-associated diseases. Using scRNA-seq, we demonstrate that KSHV preferentially infects CD14+ monocytes, sustains viral lytic replication through the viral interleukin-6 (vIL-6), which activates STAT1 and 3, and induces an inflammatory gene expression program. To study the role of vIL-6 in monocytes upon KSHV infection, we generated recombinant KSHV with premature stop codon (vIL-6(-)) and its revertant viruses (vIL-6(+)). Infection of the recombinant viruses shows that both vIL-6(+) and vIL-6(-) KSHV infection induced indistinguishable host anti-viral response with STAT1 and 3 activations in monocytes; however, vIL-6(+), but not vIL-6(-), KSHV infection promoted the proliferation and differentiation of KSHV-infected monocytes into macrophages. The macrophages derived from vIL-6(+) KSHV infection showed a distinct transcriptional profile of elevated IFN-pathway activation with immune suppression and were compromised in T-cell stimulation function compared to those from vIL-6(-) KSHV infection or uninfected control. Notably, a viral nuclear long noncoding RNA (PAN RNA), which is required for sustaining KSHV gene expression, was substantially reduced in infected primary monocytes upon vIL-6(-) KSHV infection. These results highlight the critical role of vIL-6 in sustaining KSHV transcription in primary monocytes. Our findings also imply a clever strategy in which KSHV utilizes vIL-6 to secure its viral pool by expanding infected monocytes via differentiating into longer-lived dysfunctional macrophages. This mechanism may facilitate KSHV to escape from host immune surveillance and to support a lifelong infection.