Respiratory Syncytial Virus's Non-structural Proteins: Masters of Interference

Abstract

Respiratory Syncytial Virus (RSV) is a highly prevalent virus that affects the majority of the population. The virus can cause severe disease in vulnerable populations leading to high hospitalization rates from bronchiolitis or secondary bacterial infections leading to pneumonia. Two early and non-structural proteins (Ns1 and Ns2), strongly over-ride the antiviral innate system but also diminish the adaptive response as well. This review will cover interactions of Ns1 and Ns2 with the host antiviral response with a focus on alterations to signaling pathways, cytokine gene expression, and effects of the Ns proteins on mitochondria.

Keywords: antiviral pathway; innate immunity; mitochondria; nonstructural (NS) proteins; respiratory syncitial virus.

Figure 1

Interferon signaling pathway altered by Ns. TLR7 pathway's arrows are in orange and activation leads to activation of NF-κB and IFN induction. TLR3 pathway's arrows are in yellow. Activation of TRIF by TLR3 can either activate TRAF3 or TRAF6. Whichever one is activated leads to slight variations in the cascade. The IFNR pathway's arrows are in green and the RIG-I pathway is in blue.

Figure 2

The many functions of Ns1 and Ns2. (A) Ns2 and Ns1-Ns2 complex home to the mitochondria where the majority of these proteins reside. The Ns formed degradosome also traffics to the mitochondria while Ns1 homes to the nucleus. (B) Ns1 inhibits viral replication. (C) Ns1, Ns2, and degradosome interactions with the RIG-I and TLR pathway showing which proteins and at what steps they inhibit IFN induction and signaling. (D) Ns1 and Ns2 upregulate anti-apoptotic proteins and prevent apoptosis. (E) Ns1 suppresses Trm and Th17 differentiation while promoting Th2 cell differentiation and the percentage of T cells expressing Il-4. Both Ns1 and Ns2 inhibit DC maturation.