IRF-3, IRF-7, and IPS-1 promote host defense against acute human metapneumovirus infection in neonatal mice

Spann, Kirsten M., Loh, Zhixuan, Lynch, Jason P., Ullah, Ashik, Zhang, Vivian, Baturcam, Engin, Werder, Rhiannon B., Khajornjiraphan, Natthida, Rudd, Penny, Loo, Yeuh-Ming, Suhrbier, Andreas, Gale Jr., Michael, Upham, John W. and Phipps, Simon (2014) IRF-3, IRF-7, and IPS-1 promote host defense against acute human metapneumovirus infection in neonatal mice. American Journal of Pathology, 184 6: 1795-1806. doi:10.1016/j.ajpath.2014.02.026


Author Spann, Kirsten M.
Loh, Zhixuan
Lynch, Jason P.
Ullah, Ashik
Zhang, Vivian
Baturcam, Engin
Werder, Rhiannon B.
Khajornjiraphan, Natthida
Rudd, Penny
Loo, Yeuh-Ming
Suhrbier, Andreas
Gale Jr., Michael
Upham, John W.
Phipps, Simon
Title IRF-3, IRF-7, and IPS-1 promote host defense against acute human metapneumovirus infection in neonatal mice
Journal name American Journal of Pathology   Check publisher's open access policy
ISSN 1525-2191
0002-9440
Publication date 2014
Sub-type Article (original research)
DOI 10.1016/j.ajpath.2014.02.026
Open Access Status
Volume 184
Issue 6
Start page 1795
End page 1806
Total pages 12
Place of publication New York, NY, United States
Publisher Elsevier
Collection year 2015
Language eng
Subject 2734 Pathology and Forensic Medicine
Abstract Human metapneumovirus (hMPV) is a leading cause of respiratory tract disease in children and is associated with acute bronchiolitis, pneumonia, and asthma exacerbations, yet the mechanisms by which the host immune response to hMPV is regulated are poorly understood. By using gene-deleted neonatal mice, we examined the contributions of the innate receptor signaling molecules interferon (IFN)-β promoter stimulator 1 (IPS-1), IFN regulatory factor (IRF) 3, and IRF7. Viral load in the lungs was markedly greater in IPS-1 -/- > IRF3/7-/- > IRF3-/-, but not IRF7-/-, mice compared with wild-type mice. IFN-β and IFN-λ2/3 (IL-28A/B) production was attenuated in the bronchoalveolar lavage fluid in all factor-deficient mice compared with wild-type mice at 1 day after infection, although IFN-λ2/3 was greater in IRF3/7-/- mice at 5 days after infection. IRF7-/- and IRF3/7-/- mice presented with airway eosinophilia, whereas only IRF3/7-/- mice developed an exaggerated type 1 and 17 helper T-cell response, characterized by natural killer T-cell and neutrophilic inflammation. Despite having the highest viral load, IPS-1-/- mice did not develop a proinflammatory cytokine or granulocytic response to hMPV infection. Our findings demonstrate that IFN-β, but not IFN-λ2/3, produced via an IPS-1-IRF3 signaling pathway, is important for hMPV clearance. In the absence of a robust type I IFN-α/β response, targeting the IPS-1 signaling pathway may limit the overexuberant inflammatory response that occurs as a consequence of viral persistence.
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