KSHV uses viral IL6 to expand infected immunosuppressive macrophages

Abstract

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. Here we demonstrate that KSHV preferentially infects CD14+monocytes and sustains viral replication through the viral (v)IL6-mediated activation of STAT1 and 3. Using vIL6-sufficient and vIL6-deficient recombinant KSHV, we demonstrated that vIL6 plays a critical role in promoting the proliferation and differentiation of KSHV-infected monocytes into macrophages. Those macrophages from vIL6-sufficient (wild type) 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 vIL6-deficient KSHV infection or uninfected control. These results highlight a clever strategy, in which KSHV utilizes vIL6 to secure its initial viral pool by expanding infected dysfunctional macrophages. This mechanism also facilitates KSHV to escape from host immune surveillance to establish a lifelong infection.SummaryKSHV causes multiple inflammatory diseases, however, the mechanism is not clear. Shimoda et al. demonstrate that KSHV preferentially infects monocytes and utilizes virally encoded IL6 to expand and deregulate infected monocytes. This helps the virus escape from host immune surveillance.

Single-Cell Transcriptomic Analysis of Kaposi Sarcoma

“…In addition to viral genes, several cellular genes were commonly expressed in the KSHV-positive cells including prospero homeobox protein 1 (PROX1), mannose receptor C-type 1 (MRC1; CD206), fms-related tyrosine kinase 4 (FLT4), and Kir2.1 inwardrectifier potassium channel (KCNJ2) (Table S1). These markers have been previously described in KS lesions and provide confirmation for the sensitivity and reproducibility of scRNAseq data obtained from primary skin lesions (21)(22)(23). Differential expression analysis revealed 1,022 significantly enriched genes in KSHV+ cells in Cluster 15 cells including several voltage gated ion channel (VGSC) genes with SCN9A as a top biomarker candidate along with KSHV genes LANA and Kaposin (Figure 5, Table S1).…”

“…Our study identified several potential cellular biomarkers of KSHV infection, including some that were previously described (21)(22)(23). One of these markers, PROX1, colocalizes with CD34 in KS lesions (21) and in other cancers (56), and may be involved in regulation of endothelial to mesenchymal transition.…”