Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice
Arash Shahangian, Edward K. Chow, Xiaoli Tian, Jason R. Kang, Amir Ghaffari, Su Y. Liu, John A. Belperio, Genhong Cheng, Jane C. Deng
Arash Shahangian, Edward K. Chow, Xiaoli Tian, Jason R. Kang, Amir Ghaffari, Su Y. Liu, John A. Belperio, Genhong Cheng, Jane C. Deng
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Research Article Infectious disease

Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice

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-α/β 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.

Authors

Arash Shahangian, Edward K. Chow, Xiaoli Tian, Jason R. Kang, Amir Ghaffari, Su Y. Liu, John A. Belperio, Genhong Cheng, Jane C. Deng

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Figure 2

Influenza-infected Ifnar–/– mice are resistant to secondary pneumococcal pneumonia.

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Influenza-infected Ifnar–/– mice are resistant to secondary pneumococcal...
(A) Kinetics of IFN-α induction after influenza following i.t. PR8. Ifnar+/+ C57BL/6 mice were administered i.t. PR8 on day 0, and lungs were harvested at the designated time points for assessment of IFN-α levels by ELISA in lung homogenates. (B and C) Clearance of S. pneumoniae by influenza-infected Ifnar+/+ and Ifnar–/– animals. Age- and sex-matched animals of both genotypes were administered i.t. PR8 or saline, followed 5 days later with i.t. S. pneumoniae (2,000 CFU). Lungs (B) and blood (C) were harvested on day 2 following i.t. S. pneumoniae infection, for assessment of CFU. n = 8–11 animals per group (B) and n = 4 animals per group (C). **P < 0.01. Data are representative of 3 independent experiments. (D) Following i.t. PR8 and S. pneumoniae administration 5 days apart, survival was assessed for 14 days following S. pneumoniae infection. Survival rates were 70% for Ifnar–/– mice compared with 33% for Ifnar+/+ mice at 14 days. *P = 0.05, log-rank test. n = 10–12 mice per group. Data were combined from 2 separate experiments. (E) Lung CFU in animals following IFNAR neutralization of wild-type animals with MAR1-5A3. P < 0.05, 1-tailed Mann-Whitney U test. The horizontal lines represent the statistical medians.