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 attenu-ated the establishment of chronic gammaherpesvirus infection and gammaherpesvi-rus-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; how-ever, 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 gammaherpesvi-rus 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.
Original language | English (US) |
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Article number | e00566-21 |
Journal | mBio |
Volume | 12 |
Issue number | 2 |
DOIs | |
State | Published - Mar 1 2021 |
Funding
IL-17RA2/2 mice were a kind gift from Amgen. MHV68.ORF73bla was a kind gift from Scott Tibbetts. These studies were supported by the American Cancer Society Postdoctoral Award (134165-PF-19-176-01-MPC, C.N.J.), F31 CA243364 (K.E.J.), F31 CA247000 (C.A.), American Heart Association predoctoral award 20PRE35200108 (P.S.), K08 DE026189 and Children’s Hospital of Wisconsin Research Institute (A.R.H.); CA203923 (V.L.T.). C.N.J. and V.L.T. led the conceptual design of the study and wrote the manuscript. C.N.J., K.E.J., C.A., P.S., and G.X. designed, performed, and analyzed experiments. W.C. and A.R.H. contributed to the conceptual design of the study and manuscript writing and editing.
Keywords
- Chronic infection
- Gammaherpesvirus
- Germinal center response
- IL-17 signaling
ASJC Scopus subject areas
- Microbiology
- Virology