Differentiation of Th Subsets Inhibited by Nonstructural Proteins of Respiratory Syncytial Virus Is Mediated by Ubiquitination

Abstract

Human respiratory syncytial virus (RSV), a major cause of severe respiratory diseases, constitutes an important risk factor for the development of subsequent asthma. However, the mechanism underlying RSV-induced asthma is poorly understood. Viral non-structural proteins NS1 and NS2 are critically required for RSV virulence; they strongly suppress IFN-mediated innate immunity of the host cells. In order to understand the effects of NS1 and NS2 on differentiation of Th subsets, we constructed lentiviral vectors of NS1 or NS2 to infect 16 HBE and analyzed the expression of HLA-DR, CD80 and CD86 and differentiation of Th1, Th2 and Th17 by Flow Cytometric Analysis and real-time PCR. The results showed that NS1 inhibited expression of HLA-DR, CD80 and CD86 and differentiation of Th1, Th2 and Th17 lymphocytes, which could be reversed by deleting elongin C binding domain. NS2 inhibited the differentiation of Th2 and Th17, which was reversed by proteasome inhibitors of PS-341. Our results indicated that NS1 inhibited the differentiation of T lymphocytes through its mono-ubiquitination to interacted proteins, while NS2 inhibited differentiation of Th2 and Th17 through ubiquitin-proteasome pathway, which may be related with the susceptibility to asthma after RSV infection.

Regulatory T cells and T helper 17 cells in viral infection

“…NS1 and NS2 are both non‐structural proteins of RSV and are of paramount importance for viral replication . NS1 inhibited T cell differentiation via mono‐ubiquitination of interacting proteins, and NS2 suppressed the differentiation of Th2 and Th17 subsets via the ubiquitin‐proteasome pathway . There are a variety of Toll‐like receptors (TLRs) on the surface of Tregs including TLR2, TLR4, TLR5 and TLR11 .…”

The role of Th17 and Treg responses in the pathogenesis of RSV infection

“…RSV's NS1 protein inhibits differentiation of Th1, Th2 (and Th17) cells. The NS2 protein inhibits differentiation of Th2 (and Th17) (16). Another skewing of the Th1/Th2 response is present when primary RSV infection occurs at the neonatal age: a Th2 rather than the appropriate Th1 response will develop upon reinfection, while this is not seen in adults (17).…”

Viral manipulation of the host immune response

“…The RSV fusion (F) protein has been implicated in mediating Th2 skewing in a strain dependent manner in vivo [37]. More recently, the RSV non-structural proteins NS1 and NS2 were found to play a role in altering CD4 T cell polarization [41,42]. NS1 inhibits MHC expression resulting in reduced CD4 T cell polarization [41].…”

“…More recently, the RSV non-structural proteins NS1 and NS2 were found to play a role in altering CD4 T cell polarization [41,42]. NS1 inhibits MHC expression resulting in reduced CD4 T cell polarization [41]. NS1 also inhibits the proliferation of Th17 cells while promoting activation of Th2 cells [42].…”