Interleukin 16 contributes to gammaherpesvirus pathogenesis by inhibiting viral reactivation

Abstract

Gammaherpesviruses have evolved various strategies to take advantage of host cellular factors or signaling pathways to establish a lifelong latent infection. Like the human gammaherpesvirus Epstein-Barr virus, murine gammaherpesvirus 68 (MHV68) establishes and maintains latency in the memory B cells during infection of laboratory mice. We have previously shown that MHV68 can immortalize fetal liver-derived B cells that induce lymphomas when injected into immunodeficient mice. Here we identify interleukin 16 (IL16) as a most abundantly expressed cytokine in MHV68-immortalized B cells and show that MHV68 infection elevates IL16 expression. IL16 is not important for MHV68 lytic infection but plays a critical role in MHV68 reactivation from latency. IL16 deficiency increases MHV68 lytic gene expression in MHV68-immortalized B cells and enhances reactivation from splenic latency. Correlatively, IL16 deficiency increases the frequency of MHV68-infected plasma cells that can be attributed to enhanced MHV68 reactivation. Furthermore, similar to TPA-mediated lytic replication of Kaposi's sarcoma-associated herpesvirus, IL16 deficiency markedly induces Tyr705 STAT3 de-phosphorylation and elevates p21 expression, which can be counteracted by the tyrosine phosphatase inhibitor orthovanadate. Importantly, orthovanadate strongly blocks MHV68 lytic gene expression mediated by IL16 deficiency. These data demonstrate that virus-induced IL16 does not directly participate in MHV68 lytic replication, but rather inhibits virus reactivation to facilitate latent infection, in part through the STAT3-p21 axis.

Interleukin 16 Enhances the Host Susceptibility to Influenza A Virus Infection

“…To further confirm IL16 function, WT and IL16 KO MEFs were prepared from WT and IL16 KO mice as previously described, respectively ( Liu et al, 2020 ). The knockout efficiency was confirmed by immunoblot analyses ( Figure 4A ).…”

“…Other studies have identified CD9 as a potential alternative receptor for IL16 in mast cells and epithelial cells ( Mathy et al, 2000 ; Qi et al, 2006 ; Blake et al, 2018 ), indicating that IL16 might use different receptors in different cell types. Our recent study has shown that IL16 does not affect gammaherpesvirus lytic replication, but inhibits lytic reactivation from latency through regulation of STAT3-p21 axis, acting as a positive regulator for gammaherpesvirus latency ( Liu et al, 2020 ). The diverse functions of IL16 illustrate that IL16 is a multifunctional cytokine.…”

“…The Madin–Darby canine kidney (MDCK) cells were kindly provided by Prof. Bing Sun (Institut Pasteur of Shanghai). Wild-type (WT) or IL16-deficient MEFs were isolated from E13.5 embryos as previously described ( Liu et al, 2020 ). A549 cells, MDCK, and MEFs were cultured in Dulbecco’s modified Eagle’s Medium (DMEM; Life Technologies) supplemented with 10% heat-inactivated fetal bovine serum (FBS) and 1% penicillin–streptomycin at 37°C.…”

“…Interleukin 16-deficient C57BL/6 mice were generated by Shanghai Model Organisms Center as described previously ( Liu et al, 2020 ). Six- to eight-week-old male WT and IL16 knockout (KO) mice were intranasally inoculated with 8,000 PFU of PR8 viruses in a 20μl volume.…”

“…The mature form of IL16 has been shown to inhibit HIV-1 replication ( Baier et al, 1995 ; Center et al, 1996 ; Zhou et al, 1997 ; Zhang et al, 1998 ). We have recently demonstrated that IL16 regulates gammaherpesvirus pathogenesis by inhibiting viral reactivation ( Liu et al, 2020 ), and IL16 deficiency enhances Th1 and cytotoxic T cell (CTL) response against IAV infection ( Jia et al, 2020 ). In our current study, we showed that IL16 enhanced IAV infection in both human lung epithelial A549 cells and mouse embryonic fibroblasts (MEFs).…”