Gammaherpesvirus Usurps Host IL-17 Signaling To Support the Establishment of Chronic Infection

Abstract

Gammaherpesviruses establish lifelong infection and are associated with a variety of cancers, including B cell lymphomas. These viruses manipulate the B cell differentiation process to establish lifelong infection in memory B cells. Specifically, gammaherpesviruses infect naive B cells and promote entry of both infected and uninfected naive B cells into germinal centers, where the virus usurps rapid proliferation of germinal center B cells to exponentially increase its cellular latent reservoir. In addition to facilitating the establishment of latent infection, germinal center B cells are thought to be the target of viral transformation. In this study, we have uncovered a novel proviral role of host interleukin 17A (IL-17A), a well-established antibacterial and antifungal factor. Loss of IL-17A signaling attenuated the establishment of chronic gammaherpesvirus infection and gammaherpesvirus-driven germinal center response in a route of inoculation-dependent manner. Further, IL-17A treatment directly supported gammaherpesvirus reactivation and de novo lytic infection. This study is the first demonstration of a multifaceted proviral role of IL-17 signaling. IMPORTANCE Gammaherpesviruses establish lifelong infections in a majority of humans and are associated with B cell lymphomas. IL-17A is a host cytokine that plays a well-established role in the clearance of bacterial and fungal infections; however, the role of IL-17A in viral infections is poorly understood. In this study, we show that IL-17A signaling promoted the establishment of chronic gammaherpesvirus infection following the mucosal route of infection, viral lytic replication, and reactivation from latency. Thus, our study unveils a novel proviral role of IL-17A signaling in gammaherpesvirus infection.

IL-21 signaling promotes the establishment of KSHV infection in human tonsil lymphocytes by increasing early targeting of plasma cells

“…Interestingly, this study showed that the mechanisms of decreased infection were related to decreases in both germinal center and plasma cell frequencies as well as decreased infection in both the germinal center and plasma cell compartment at later timepoints post-infection [22], infection via promotion of the MHV68-mediated germinal center response [31] and is mechanistically linked to suppression of T cell-intrinsic IRF-1 [32]. These results are particularly interesting in light of our current findings showing that IL-21 secretion from, and baseline levels of, RoRT+ T cells correlate with the early targeting of plasma cells during KSHV infection (Fig 6B and 6D), suggesting that the Th17/Tc17 environment in the tonsil may be a critical factor influencing donor-specific susceptibility to KSHV infection.…”

“…Both IL-21 and IL-6, which is highly induced in our KSHV-infected cultures (Fig 1), are involved in the maintenance and function of RoRγT+ T cells via STAT3 signaling. Th17/Tc17 cells produce IL-17A, which is another cytokine that promotes the establishment of chronic MHV68 infection via promotion of the MHV68-mediated germinal center response [31] and is mechanistically linked to suppression of T cell-intrinsic IRF-1 [32]. These results are particularly interesting in light of our current findings showing that IL-21 secretion from, and baseline levels of, RoRγT+ T cells correlate with the early targeting of plasma cells during KSHV infection (Fig 7C and Supplemental Fig 2C), suggesting that the Th17/Tc17 environment in the tonsil may be a critical factor influencing donor-specific susceptibility to KSHV infection.…”

T Cell-Specific STAT1 Expression Promotes Lytic Replication and Supports the Establishment of Gammaherpesvirus Latent Reservoir in Splenic B Cells

“…To define infected splenocyte populations, Cre negative and positive littermates were infected with an MHV68 marker virus that expresses β-lactamase fused to MHV68 mLANA, a latent viral protein that is critical for viral episome maintenance during latency ( 56 ). Measurement of β-lactamase activity using a cell-permeable substrate offers a highly sensitive and accurate approach to define MHV68 tropism by flow cytometry ( 57 – 59 ). At 16 days postinfection, the frequency of β-lactamase+ latently infected germinal center B cells was significantly decreased in Cre positive, compared to Cre negative mice ( Fig.…”

Effect of Pre-Treatment with a Recombinant Chicken Interleukin-17A on Vaccine Induced Immunity against a Very Virulent Marek’s Disease Virus

“…Viruses can utilize IL-17A to modulate the host immune system to support productive infection. Gammaherpesviruses , such as murine gammaherpesvirus 68 (MHV68), preferentially modulate the mouse immune system following primary infection, leading to IL-17A expression [ 42 ]. As such, during early infection, IL-17A can antagonize Th1 activity while promoting productive MHV68 viral infection.…”