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Progranulin Decreases Susceptibility to Streptococcus pneumoniae in Influenza and Protects against Lethal Coinfection

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  • Progranulin Decreases Susceptibility to Streptococcus pneumoniae in Influenza and Protects against Lethal Coinfection

    J Immunol. 2019 Sep 13. pii: ji1900248. doi: 10.4049/jimmunol.1900248. [Epub ahead of print]
    Progranulin Decreases Susceptibility to Streptococcus pneumoniae in Influenza and Protects against Lethal Coinfection.

    Wang X1, Yuan J1, Wang H1, Gan N2, Zhang Q3, Liu B1, Wang J1, Shu Z1, Rao L1, Gou X1, Zhang H1, Yin Y1, Zhang X4.
    Author information

    1 Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine, Chongqing Medical University, Chongqing 400016, China. 2 Stomatological Hospital, Chongqing Medical University, Chongqing 400016, China; and. 3 Affiliated Children's Hospital, Chongqing Medical University, Chongqing 400016, China. 4 Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine, Chongqing Medical University, Chongqing 400016, China; zhangxuemei@cqmu.edu.cn.

    Abstract

    Streptococcus pneumoniae coinfection is a major cause of mortality in influenza pandemics. Growing evidence shows that uncontrolled immune response results in severe tissue damage and thereby promotes death in coinfection. Progranulin (PGRN) is widely expressed in immune and epithelial cells and exerts anti-inflammatory role in many diseases. We found that PGRN levels were significantly elevated in clinical influenza/S. pneumoniae-coinfected patients. C57BL/6 wild-type (WT) and PGRN-deficient (PGRN-/-) mice were infected with influenza virus PR8 and then superchallenged with S. pneumoniae serotype 19F. Coinfected PGRN-/- mice showed increased mortality and weight loss compared with WT mice. PGRN deficiency led to increased bacterial loads in lungs without altering influenza virus replication, suggesting a role of PGRN in decreasing postinfluenza susceptibility to S. pneumoniae coinfection. Administration of recombinant PGRN improved survival of WT and PGRN-/- mice in lethal coinfection. Additionally, loss of PGRN resulted in aggravated lung damage along with massive proinflammatory cytokine production and immune cell infiltration during coinfection. Endoplasmic reticulum stress (ERS) during influenza, and coinfection was strongly induced in PGRN-/- mice that subsequently activated apoptosis signaling pathways. Treatment of recombinant PGRN or inhibition of ERS by 4-phenylbutyrate decreased apoptosis and bacterial loads in lungs of coinfected mice. These results suggest that PGRN decreases postinfluenza susceptibility to S. pneumoniae coinfection via suppressing ERS-mediated apoptosis. Impaired bacterial clearance and increased lung inflammation are associated with the lethal outcome of coinfected PGRN-/- mice. Our study provides therapeutic implication of PGRN to reduce morbidity and mortality in influenza/S. pneumoniae coinfection.
    Copyright 2019 by The American Association of Immunologists, Inc.


    PMID: 31519865 DOI: 10.4049/jimmunol.1900248
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