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Cited by 479interferon and immune responsesChemokine receptors and signalingInfluenza Virus Research Studies

Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice

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Shahangian, Arash, Chow, Edward K., Tian, Xiaoli, Kang, Jason R., Ghaffari, Amir, Liu, Su Y., Belperio, John A., Cheng, Genhong +1 more·2009·Journal of Clinical Investigation
DOI 10.1172/jci35412PMC PMC2701856
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Abstract

Influenza-related complications continue to be a major cause of mortality worldwide. Due to unclear mechanisms, a substantial number of influenza-related deaths result from bacterial superinfections, particularly secondary pneumococcal pneumonia. Here, we report what we believe to be a novel mechanism by which influenza-induced type I IFNs sensitize hosts to secondary bacterial infections. Influenza-infected mice deficient for type I IFN-alpha/beta receptor signaling (Ifnar-/- mice) had improved survival and clearance of secondary Streptococcus pneumoniae infection from the lungs and blood, as compared with similarly infected wild-type animals. The less effective response in wild-type mice seemed to be attributable to impaired production of neutrophil chemoattractants KC (also known as Cxcl1) and Mip2 (also known as Cxcl2) following secondary challenge with S. pneumoniae. This resulted in inadequate neutrophil responses during the early phase of host defense against secondary bacterial infection. Indeed, influenza-infected wild-type mice cleared secondary pneumococcal pneumonia after pulmonary administration of exogenous KC and Mip2, whereas neutralization of Cxcr2, the common receptor for KC and Mip2, reversed the protective phenotype observed in Ifnar-/- mice. These data may underscore the importance of the type I IFN inhibitory pathway on CXC chemokine production. Collectively, these findings highlight what we believe to be a novel mechanism by which the antiviral response to influenza sensitizes hosts to secondary bacterial pneumonia.

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  • Activation of antiviral immune responses, including type I and type II IFNs, have been associated with increased susceptibility to secondary bacterial pneumonia.

    “activation of antiviral immune responses, including type I and type II IFNs, have been associated with increased susceptibility to secondary bacterial pneumonia”

    From Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia. (2018) · cites this paper as [65]

  • Prior viral infections dysregulate both alveolar macrophages and neutrophils, thereby inhibiting bactericidal activity.

    “Prior viral infections dysregulate both alveolar macrophages (64, 131–136) and neutrophils (65, 128, 129), thereby inhibiting bactericidal activity.”

    From Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia. (2018) · cites this paper as [65]

  • Type I IFN-mediated inhibition of Th17 immunity reduces CD4+ T cells and gamma delta T cells, leading to reduced production of IL-17 and IL-22 and preventing clearance of bacteria.

    “and therefore there is a reduction in the levels of CD4+ T cells and gamma delta T cells and hence a reduction in the production of IL-17 and IL-22, preventing the clearance of bacteria (Shahangian et al., 2009; Kudva et al., 2011; Mulcahy and McLoughlin, 2016).”

    From Secondary bacterial infections associated with influenza pandemics (2017) · cites this paper as Shahangian et al., 2009

  • Type I IFNs inhibit IL-23-dependent induction of Th17 immunity.

    “Additionally, Type I IFNs inhibit interleukin 23 (IL-23) dependent induction of T helper cell 17 (Th17) immunity”

    From Secondary bacterial infections associated with influenza pandemics (2017) · cites this paper as Shahangian et al., 2009

  • During co/secondary S. pneumoniae infection, type I IFNs inhibit production of KC/CXCL1 and Mip2/CXCL2, resulting in attenuated neutrophil response.

    “During co/secondary S. pneumoniae infection, type I IFNs have been shown to inhibit the production of specific chemokines (KC/CXCL1 and Mip2/CXCL2) resulting in an attenuated neutrophil response (Shahangian et al., 2009).”

    From Secondary bacterial infections associated with influenza pandemics (2017) · cites this paper as Shahangian et al., 2009

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Authors
Shahangian, A., Chow, E. K., Tian, X., Kang, J. R., Ghaffari, A., Liu, S. Y., Belperio, J. A., Cheng, G., & Deng, J. C.
Affiliations
  • University of California, Los Angeles (US)
  • University of California, San Francisco (US)
Corresponding author
Deng, Jane C.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2009-07-01
Volume
119
Issue
7
Pages
1910-1920
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci35412
PMC
PMC2701856
OpenAlex
W2106377620
Cited by
479
References
55
Citations by year
2026: 12 · 2025: 13 · 2024: 14 · 2023: 18 · 2022: 26 · 2021: 26 · 2020: 28 · 2019: 32 · 2018: 40 · 2017: 30 · 2016: 39 · 2015: 35 · 2014: 40 · 2013: 35 · 2012: 33
FWCI
13.09
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (AI007323)
  • National Heart, Lung, and Blood Institute (K08HL081229)
  • National Institute of General Medical Sciences (GM-08042, T32GM008042)
  • National Institute of Allergy and Infectious Diseases (R01AI069120, R01AI056154, T32AI007323)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
  • Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
Keywords
type I interferon, influenza, secondary bacterial pneumonia, Streptococcus pneumoniae, pneumococcal pneumonia, secondary bacterial infection, CXCL1, CXCL2, CXCR2, neutrophil chemotaxis, antiviral response
MeSH terms
Animals, Interferon Type I, Lung, Mice, Inbred C57BL, Neutrophils, Orthomyxoviridae Infections, Pneumonia, Pneumococcal, Interleukin-10, Mice, Chemokine CXCL1, Chemokine CXCL2

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