Activation of Plasmacytoid Dendritic Cells by Kaposi's Sarcoma-Associated Herpesvirus

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with multiple human malignancies, including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Following primary infection, KSHV typically goes through a brief period of lytic replication prior to the establishment of latency. Plasmacytoid dendritic cells (pDCs) are the major producers of type 1 interferon (IFN), primarily in response to virus infection. Toll-like receptors (TLRs) are key components of the innate immune system, and they serve as pathogen recognition receptors that stimulate the host antiviral response. pDCs express exclusively TLR7 and TLR9, and it is through these TLRs that the type 1 interferon response is activated in pDCs. Currently, it is not known whether KSHV is recognized by pDCs and whether activation of pDCs occurs in response to KSHV infection. We now report evidence that KSHV can infect human pDCs and that pDCs are activated upon KSHV infection, as measured by upregulation of CD83 and CD86 and by IFN-␣ secretion. We further show that induction of IFN-␣ occurs through activation of TLR9 signaling and that a TLR9 inhibitor diminishes the production and secretion of IFN-␣ by KSHV-infected pDCs.

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

“…These include inhibiting apoptosis, overcoming G1 phase arrest, lowering the threshold for B cell receptor (BCR) activation, and providing ligand-independent progrowth signals. In addition to B cells, this virus can also enter CD34 cells, T cells, monocytes, and pDCs (36,(85)(86)(87)(88), though it is unclear if these cell types contribute to systemic persistence or serve as sentinels to detect infection. EpsteinBarr virus (EBV) also uses B cells as the predominant latent reservoir, as does murine herpesvirus 68 (reviewed in ref .…”

“…Following primary infection, KSHV has been shown to activate the RNA sensor TLR3 in monocytes, (35) and the DNA sensor TLR9 in plasmacytoid DCs (pDCs) (36). Activation of either TLR results in interferon production and upregulation of cytokines and chemokines.…”

Innate Barriers to Viral Infection

“…Damania discussed how KSHV primary infection of human pDCs led to activation of TLR9, a DNA sensor [21]. Inhibition of TLR9 in pDCs resulted in decreased IFN-a secretion following KSHV infection.…”

Viral Interferon Regulatory Factors Are Critical for Delay of the Host Immune Response against Rhesus Macaque Rhadinovirus Infection

“…Collectively, these data illustrate the functional breadth and diversity of pathways/cellular functions that are targeted by the vIRFs, but these data do not adequately address the role of vIRFs during in vivo infection. Moreover, increased production of IFN-␣ was most evident within plasmacytoid dendritic cells (pDCs), which are also important in Toll-like receptor 9-mediated detection of KSHV (50). Therefore, we hypothesized that vIRF-ko RRV infection of RMs would result in increased induction of IFN, promoting a more effective adaptive immune response and potentially limiting viral replication, persistence, and/or acute RRV-associated pathology.…”