Parainfluenza Virus 3 Blocks Antiviral Mediators Downstream of the Interferon Lambda Receptor by Modulating Stat1 Phosphorylation

Abstract

Parainfluenza viruses are known to inhibit type I interferon (IFN) production; however, there is a lack of information regarding the type III IFN response during infection. Type III IFNs signal through a unique heterodimeric receptor, IFN-R1/interleukin-10R2 (IL-10R2), which is primarily expressed by epithelial cells. Parainfluenza virus 3 (PIV-3) infection is highly restricted to the airway epithelium. We therefore sought to examine type III IFN signaling pathways during PIV-3 infection of epithelial cells. We used three strains of PIV-3: human PIV-3 (HPIV-3), bovine PIV-3 (BPIV-3), and dolphin PIV-1 (Tursiops truncatus PIV-1, or TtPIV-1). Here, we show that message levels of IL-29 are significantly increased during PIV-3 infection, yet downstream antiviral signaling molecules are not upregulated to levels similar to those of the positive control. IMPORTANCEParainfluenza virus (PIV) in humans is associated with bronchiolitis and pneumonia and can be especially problematic in infants and the elderly. Also seen in cattle, bovine PIV-3 causes respiratory infections in young calves. In addition, PIV-3 is one of a number of pathogens that contribute to the bovine respiratory disease complex (BRDC). As their name suggests, interferons (IFNs) are produced by cells to interfere with viral replication. Paramyxoviruses have previously been shown to block production and downstream signaling of type I IFNs. For the first time, it is shown here that PIV-3 can induce protective type III IFNs in epithelial cells, the primary site of PIV-3 infection. However, we found that PIV-3 modulates signaling pathways downstream of the type III IFN receptor to block production of several specific molecules that aid in a productive antiviral response. Importantly, this work expands our understanding of how PIV-3 effectively evades host innate immunity. P arainfluenza virus 3 (PIV-3) causes a prominent respiratory infection in both cattle and humans. The CDC reports that, in humans, most children have antibodies against human PIV-3 (HPIV-3) by 5 years of age (http://www.cdc.gov/parainfluenza /hcp/clinical.html). There is currently no vaccine available for control of HPIV-3 infection; however, a few studies have examined the use of an attenuated bovine PIV-3 (BPIV-3) to protect against HPIV-3 because of the homology between bovine and human strains (1-3). Given the lack of an efficacious vaccine for HPIV-3, there is a critical need to understand the mechanisms of HPIV-3-induced disease and the molecular pathways associated with viral modulation of the host antiviral defenses.Paramyoxviruses are negative-sense single-stranded RNA viruses which are part of the Paramyxoviridae family and Paramyxovirinae subfamily (4). PIV-3 is found within the genus Respirovirus. PIV-3 is a respiratory virus that primarily infects the epithelial cells of the lung. Symptoms of HPIV-3 infection include bronchiolitis and pneumonia, and HPIV-3 is especially problematic in infants (4). Airway epithelial cells recognize viral infection through pattern recog...

Impaired virus replication and decreased innate immune responses to viral infections in nasal epithelial cells from patients with allergic rhinitis

“…Our study demonstrated that PIV3 and RV1B induce IFN-k1 generation both at the protein and mRNA levels in human nasal epithelial cells. This observation is in line with earlier studies documenting that PIV3 induces a type III IFN response in the epithelial cells, although it may interfere with downstream anti-viral signalling pathways [38]. Type I IFN (IFN-b) was detected only at mRNA level after infection with both RV1B and PIV3.…”

Interferon Lambda: Modulating Immunity in Infectious Diseases

“…Only a few studies have explored this in the context of IFN-λs. Parainfluenza virus 3 blocks antiviral mediators downstream of the IFNLR signaling by modulation of the STAT1 phosphorylation in BEAS 2B cells, a bronchial epithelial cell line (144). Dengue virus was recently shown to induce IFNL1 via its non-structural protein (NS1) in order to facilitate dendritic cell migration (114).…”

The Immunology of Bovine Respiratory Disease

“…15 BHV, and many other viruses of the BRD complex, including BVDV, BRSV, and PIV, however, have mechanisms in place to actively suppress the host IFN response. [16][17][18][19] In 1 report, coinfection of bovine epithelial cells with BVDV inhibited type I IFN production, enabling significantly increased replication of BRSV in the same cell cultures, 19 suggesting a synergistic interaction between the 2 viruses.…”