Exploitation of the Complement System by Oncogenic Kaposi's Sarcoma-Associated Herpesvirus for Cell Survival and Persistent Infection

Abstract

During evolution, herpesviruses have developed numerous, and often very ingenious, strategies to counteract efficient host immunity. Specifically, Kaposi's sarcoma-associated herpesvirus (KSHV) eludes host immunity by undergoing a dormant stage, called latency wherein it expresses a minimal number of viral proteins to evade host immune activation. Here, we show that during latency, KSHV hijacks the complement pathway to promote cell survival. We detected strong deposition of complement membrane attack complex C5b-9 and the complement component C3 activated product C3b on Kaposi's sarcoma spindle tumor cells, and on human endothelial cells latently infected by KSHV, TIME-KSHV and TIVE-LTC, but not on their respective uninfected control cells, TIME and TIVE. We further showed that complement activation in latently KSHV-infected cells was mediated by the alternative complement pathway through down-regulation of cell surface complement regulatory proteins CD55 and CD59. Interestingly, complement activation caused minimal cell death but promoted the survival of latently KSHV-infected cells grown in medium depleted of growth factors. We found that complement activation increased STAT3 tyrosine phosphorylation (Y705) of KSHV-infected cells, which was required for the enhanced cell survival. Furthermore, overexpression of either CD55 or CD59 in latently KSHV-infected cells was sufficient to inhibit complement activation, prevent STAT3 Y705 phosphorylation and abolish the enhanced survival of cells cultured in growth factor-depleted condition. Together, these results demonstrate a novel mechanism by which an oncogenic virus subverts and exploits the host innate immune system to promote viral persistent infection.

Screening of the Human Kinome Identifies MSK1/2-CREB1 as an Essential Pathway Mediating Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication during Primary Infection

“…However, IL-6 primarily activates the STAT3 pathway (59). We did not observe any significant change in STAT3 phosphorylation during primary KSHV infection, although STAT3 is implicated in KSHV latent infection (60,61) and can be activated by KSHV vIL6, RTA, vGPCR (ORF74), and kaposin B, as well as through complement activation (61)(62)(63)(64)(65). In contrast to that of JAK1/2, the phosphorylation level of STAT5A was significantly reduced.…”

TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway

“…Of interest, instead of inhibiting the innate immune pathways, KSHV appears to hijack the pathways to promote viral latency and cell survival. We have shown that KSHV hijacks the complement pathway to promote cell survival by downregulating cell surface complement regulatory proteins CD55 and CD59 (13). Here, we have demonstrated that KSHV miRNA cluster, particularly miR-K1, -K3 and -K11, mediates the upregulation of TLR4 to induce chronic inflammation, and promote cellular transformation and tumorigenesis (Fig.…”

“…ΔmiR cells stably expressing 12 individual pre-miRs (-K1 to -K12) were also grown under the same condition (20, 21). Telomerase-immortalized human microvascular endothelial cells (TIME) and KSHV-infected TIME cells (TIME-KSHV) were maintained as previously described (13). All cell lines were routinely tested for mycoplasma contamination using LookOut ® Mycoplasma qPCR Detection Kit (Sigma MP0035–1KT).…”

“…In contrast, KSHV hijacks host innate immune pathways to promote latent infection. For example, KSHV activates the complement pathway to activate the STAT3 pathway and promote cell survival (13). Furthermore, KSHV induces a proinflammatory immune response to promote KS development during latency.…”

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

“…KCP is part of the virion and functions as a cofactor for factor I-mediated cleavage of C3b and C4b, the complement system's opsonizing factors (52,53). KSHV has also been reported to exploit the host complement system to promote viral persistent infection (54).…”