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Although asthmatics has been considered to be highly susceptible to respiratory viral infection and most studies have focused on exacerbation of asthma by influenza A virus (IAV) infection, few experimental evidences exist to directly demonstrate that asthmatic mice are actually resistant to IAV infection. Here, we show that asthmatic mice are not highly susceptible to IAV in the early stage of infection and type III interferon (IFN) maintains antiviral immune response in the lung of IAV-infected asthmatic mouse resulting in inhibition of initial viral spread. C57BL/6 mice with allergic asthma were infected with IAV (WS/33: H1N1) and survival rate, body weight, viral titer, histopathological findings of lung and cytokine profiles including IFNs and Th2 cytokines were measured. Notably, asthmatic mice were significantly resistant to IAV and showed lower viral load until 7 days after infection. Furthermore, IAV-infected asthmatic mice exhibited decreased Th2-related inflammation in lung tissue until 7 days. These increased antiviral resistant mechanism and reduced Th2 inflammation were attributable to rapid induction of type III IFNs and blockade of type III IFNs in asthmatic lung led to aggravated IAV infection and to enhance the production of Th2 cytokines. Asthmatic mice showed bi-phasic responses against IAV-caused lung infection such as rapid production of type III IFNs and subsequent induction of type II IFNs. Actually, IAV-infected asthmatic mice become vulnerable to IAV infection after 7 days with noticeable morbidity and severe weight loss. However, intranasal administration of type III IFNs protects completely asthmatic mice from IAV-mediated immunopathology and lung infection until 14 days after infection. Taken together, our study indicates that the rapid induction of type III IFN might be distinctive immunological findings in the respiratory tract of IAV-infected asthmatic mice at the early stage of infection and crucial for suppression of initial viral spread in vivo asthma accompanying with restriction of Th2 cytokine productions.

We studied the contribution of Duox2 in mucosal host defense against influenza A virus (IAV) infection in in vivo lung. We found that Duox2 was required for the induction of type I and III interferon (IFN)s and transient Duox2 overexpression using cationic polymer polyethyleneimine (PEI) leads to suppression of IAV infection in in vivo lung. Twenty mice (C57BL/6J) were anesthetized and challenged by intranasal administration of 213 pfu/30 μl of IAV (WS/33/H1N1), and IAV-infected mice were euthanized at 1, 3, 5, 7, 10, 14 days post infection (dpi). Duox2 small hairpin RNA (shRNA) and pCMV-Duox2 formulated with PEI were inoculated to mice to assess the regulatory mechanism between Duox2 and IFN secretion. Following intranasal IAV inoculation, viral infection was significantly aggravated from 3 dpi in in vivo lung and viral titer was highest at 7 dpi. Consistent with this, Duox2 messenger RNA (mRNA) and protein expressions were significantly induced from 3 dpi in the lung tissue of IAV-infected mice. Viral titer was much higher in IAV-infected mice that were inoculated with Duox2 shRNA accompanied with lower survival rate and extensive lung pathologies. Interestingly, severe lung pathologies in IAV-infected mice were not observed and viral titer was significantly reduced in mice with pulmonary administration of pCMV-Duox2 formulated with PEI before IAV inoculation. Both mRNA and secreted protein levels of IFN-β and IFN-λ were highly elevated in IAV-infected mice with pCMV-Duox2 formulated with PEI. Duox2 is necessary for the regulation of IFN secretion in in vivo lung, and pulmonary administration of Duox2 DNA using cationic polymer triggers the induction of type I and III IFNs resulting in more complete suppression of IAV infection. [ABSTRACT FROM AUTHOR]

The innate immune response, which constitutes the first line of defense against influenza A virus (IAV) infection, is activated by pattern recognition receptors (PRRs) that recognize viral structures. We found that the PRRs, retinoic acid-inducible gene 1 (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), which have been implicated as interferon (IFN)-stimulated genes, were dominantly responsible for the recognition of IAV in lungs of mice at 3 and 7 days post infection (dpi). Intranasal administration of IFNs enhanced RIG-I and MDA5 gene expression after IAV infection and mRNA levels of RIG-I and MDA5 were significantly reduced at 7 dpi in mice with neutralization of secreted IFNs. However, blockade of IFNs did not alter the transcription of RIG-I and MDA5 at 3 dpi. We studied the antiviral effect of Duox2 in vivo lung to elucidate the role of Duox2 in respiratory mucosa. RIG-I and MDA5 mRNA levels were induced to a lower extent in lungs of mice that were inoculated with Duox2 small hairpin RNA regardless of secreted IFNs at 3 dpi. We propose that Duox2 is responsible for IFN-independent signaling for induction of PRRs transcription and can control acute IAV lung infection at the beginning of infection. [ABSTRACT FROM AUTHOR]

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.