Abstract

As the eighth leading cause of annual mortality in the USA, influenza A viruses are a major public health concern. In 20% of patients, severe influenza progresses to acute lung injury (ALI). However, pathophysiological mechanisms underlying ALI development are poorly defined. We reported that, unlike wild-type (WT) C57BL/6 controls, influenza A virus-infected mice that are heterozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (HETs) did not develop ALI. This effect was associated with higher IL-6 and alveolar macrophages (AMs) at 6 days postinfection (d.p.i.) in HET bronchoalveolar lavage fluid (BALF). In the present study, we found that HET AMs were an important source of IL-6 at 6 d.p.i. Infection also induced TGF-β production by HET but not WT mice at 2 d.p.i. TGF-β neutralization at 2 d.p.i. (TGF-N) significantly reduced BALF IL-6 in HETs at 6 d.p.i. Neither TGF-N nor IL-6 neutralization at 4 d.p.i. (IL-6-N) altered postinfection weight loss or viral replication in either mouse strain. However, both treatments increased influenza A virus-induced hypoxemia, pulmonary edema, and lung dysfunction in HETs to WT levels at 6 d.p.i. TGF-N and IL-6-N did not affect BALF AM and neutrophil numbers but attenuated the CXCL-1/keratinocyte chemokine response in both strains and reduced IFN-γ production in WT mice. Finally, bone marrow transfer experiments showed that HET stromal and myeloid cells are both required for protection from ALI in HETs. These findings indicate that TGF-β-dependent production of IL-6 by AMs later in infection prevents ALI development in influenza A virus-infected HET mice.

Highlights

  • INFLUENZA A VIRUSES cause a highly contagious acute respiratory disease in humans, which is the eighth leading cause of attributable annual mortality in the USA

  • We reported previously that attenuation of cardiopulmonary dysfunction in HETs infected with the A/WSN/33 (H1N1) influenza strain (10,000 pfu/mouse) was associated with exaggerated alveolar macrophage (AM) and IL-6 responses at 6 d.p.i. [1]

  • We showed that HET bronchoalveolar lavage fluid (BALF) IL-6 was reduced by ϳ80% following depletion of AMs using clodronate liposomes, indicating that the exaggerated IL-6 response to influenza A virus in HETs was AM dependent

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Summary

Introduction

INFLUENZA A VIRUSES cause a highly contagious acute respiratory disease in humans, which is the eighth leading cause of attributable annual mortality in the USA. Once ALI has developed, the only treatment option is nonspecific supportive management in an intensive care unit This is often of limited efficacy, and death from ALI in patients with severe influenza is common [49, 67]. Unlike in wild-type (WT) C57BL/6 controls, influenza A virus infection did not cause ALI in C57BL/6-congenic mice that are heterozygous for the F508del mutation (a phenylalanine deletion at position 508) in CFTR (HETs) [1] This effect was associated with higher bronchoalveolar lavage fluid (BALF) IL-6 content and alveolar macrophage (AM) counts at 6 days postinfection (d.p.i.) in HETs. Notably, AM depletion in

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