The Superiority of IFN-λ as a Therapeutic Candidate to Control Acute Influenza Viral Lung Infection

Abstract

Here, we studied the IFN-regulated innate immune response against influenza A virus (IAV) infection in the mouse lung and the therapeutic effect of IFN-λ2/3 in acute IAV lung infection. For viral infections, IAV (WS/33, H1N1, PR8 H1N1, H5N1) were inoculated into wild-type mice by intranasal delivery, and IAV mRNA level and viral titer were measured. To compare the antiviral effect of IFNs in vivo in the lung, neutralizing antibodies and recombinant IFNs were used. After intranasal inoculation of IAV into mice, viral infection peaked at 7 days postinfection, and the IAV titer also reached its peak at this time. We found that IFN-β and IFN-λ2/3 were preferentially induced after IAV infection and the IFN-λ2/3-mediated innate immune response was specifically required for the induction of IFN-stimulated genes (ISGs) transcription in the mouse respiratory tract. Neutralization of secreted IFN-λ2/3 aggravated acute IAV lung infection in mice with intact IFN-β induction; consistent with this finding, the transcription of ISGs was significantly reduced. Intranasal administration of IFN-λ2/3 significantly suppressed various strains of IAV infection, including WS/33 (H1N1), PR (H1N1), and H5N1 in the mouse lung, and was accompanied by greater up-regulation of ISGs. Taken together, our data indicate that the IFN-λ2/3-mediated innate immune response is necessary to protect the lungs from IAV infection, and intranasally delivered IFN-λ2/3 has the potential to be a useful therapeutic strategy for treating acute IAV lung infection.

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

“…Our inability to reduce MERS-CoV titer or improve outcomes with IFN as described above may be due to inherent differences in the animal ARTICLE models, delivery route, differences in IFN subtype and/or active viral antagonism of innate immunity. Since recent studies have demonstrated type III IFN to be most effective in ameliorating influenza pathogenesis in mice, comparative studies investigating the potency of different IFN subtypes should be pursued with MERS-CoV [43][44][45] . Acute lung injury (ALI) in humans is well defined by a set of clinical parameters (i.e., acute onset, diffuse bilateral infiltrates on X-ray, ratio of partial pressure of arterial oxygen to inspired oxygen < 300, no evidence of elevated pulmonary arterial pressure, etc.…”

Cigarette smoke dampens antiviral signaling in small airway epithelial cells by disrupting TLR3 cleavage

“…Type I IFNs, including interferon-␣ (IFN␣) and interferon-␤ (IFN␤), are important for limiting viral replication and spread. Type III interferons, known as interferon-(IFN), are also produced early after viral recognition and have been shown to be important in viral infection (19). IP-10 production is also controlled by IFN signaling.…”

Surviving Deadly Lung Infections: Innate Host Tolerance Mechanisms in the Pulmonary System

“…When IL-27 was administered early in infection, it resulted in impaired viral clearance and worsened disease; however, when administered late in infection, there was decreased pathology, increased survival, and no impact on viral clearance. Other examples of factors that modulate both tolerance and resistance in this kind of reciprocal fashion are TGF-β, IL-10, and interferons, particularly type III (72,(130)(131)(132)(133)(134)(135)(136)(137)(138)(139)(140)(141)(142)(143).…”