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

Identifieur interne : 000190 ( PubMed/Checkpoint ); précédent : 000189; suivant : 000191

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

Auteurs : Xiaofang Wang [République populaire de Chine] ; Jun Yuan [République populaire de Chine] ; Hong Wang [République populaire de Chine] ; Ning Gan ; Qun Zhang [République populaire de Chine] ; Bichen Liu [République populaire de Chine] ; Jingyao Wang [République populaire de Chine] ; Zhaoche Shu [République populaire de Chine] ; Lubei Rao [République populaire de Chine] ; Xuemei Gou [République populaire de Chine] ; Hong Zhang [République populaire de Chine] ; Yibing Yin [République populaire de Chine] ; Xuemei Zhang [République populaire de Chine]

Source :

RBID : pubmed:31519865

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.

DOI: 10.4049/jimmunol.1900248
PubMed: 31519865


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<div type="abstract" xml:lang="en">
<i>Streptococcus pneumoniae</i>
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/
<i>S. pneumoniae</i>
-coinfected patients. C57BL/6 wild-type (WT) and PGRN-deficient (PGRN
<sup>-/-</sup>
) mice were infected with influenza virus PR8 and then superchallenged with
<i>S. pneumoniae</i>
serotype 19F. Coinfected PGRN
<sup>-/-</sup>
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
<i>S. pneumoniae</i>
coinfection. Administration of recombinant PGRN improved survival of WT and PGRN
<sup>-/-</sup>
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
<sup>-/-</sup>
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
<i>S. pneumoniae</i>
coinfection via suppressing ERS-mediated apoptosis. Impaired bacterial clearance and increased lung inflammation are associated with the lethal outcome of coinfected PGRN
<sup>-/-</sup>
mice. Our study provides therapeutic implication of PGRN to reduce morbidity and mortality in influenza/
<i>S. pneumoniae</i>
coinfection.</div>
</front>
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<DateRevised>
<Year>2019</Year>
<Month>10</Month>
<Day>08</Day>
</DateRevised>
<Article PubModel="Print-Electronic">
<Journal>
<ISSN IssnType="Electronic">1550-6606</ISSN>
<JournalIssue CitedMedium="Internet">
<Volume>203</Volume>
<Issue>8</Issue>
<PubDate>
<Year>2019</Year>
<Month>Oct</Month>
<Day>15</Day>
</PubDate>
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<Title>Journal of immunology (Baltimore, Md. : 1950)</Title>
<ISOAbbreviation>J. Immunol.</ISOAbbreviation>
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<ArticleTitle>Progranulin Decreases Susceptibility to
<i>Streptococcus pneumoniae</i>
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<AbstractText>
<i>Streptococcus pneumoniae</i>
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/
<i>S. pneumoniae</i>
-coinfected patients. C57BL/6 wild-type (WT) and PGRN-deficient (PGRN
<sup>-/-</sup>
) mice were infected with influenza virus PR8 and then superchallenged with
<i>S. pneumoniae</i>
serotype 19F. Coinfected PGRN
<sup>-/-</sup>
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
<i>S. pneumoniae</i>
coinfection. Administration of recombinant PGRN improved survival of WT and PGRN
<sup>-/-</sup>
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
<sup>-/-</sup>
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
<i>S. pneumoniae</i>
coinfection via suppressing ERS-mediated apoptosis. Impaired bacterial clearance and increased lung inflammation are associated with the lethal outcome of coinfected PGRN
<sup>-/-</sup>
mice. Our study provides therapeutic implication of PGRN to reduce morbidity and mortality in influenza/
<i>S. pneumoniae</i>
coinfection.</AbstractText>
<CopyrightInformation>Copyright © 2019 by The American Association of Immunologists, Inc.</CopyrightInformation>
</Abstract>
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<LastName>Wang</LastName>
<ForeName>Xiaofang</ForeName>
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<Affiliation>Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine, Chongqing Medical University, Chongqing 400016, China.</Affiliation>
</AffiliationInfo>
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<LastName>Yuan</LastName>
<ForeName>Jun</ForeName>
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<Affiliation>Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine, Chongqing Medical University, Chongqing 400016, China.</Affiliation>
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<name sortKey="Gou, Xuemei" sort="Gou, Xuemei" uniqKey="Gou X" first="Xuemei" last="Gou">Xuemei Gou</name>
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<name sortKey="Shu, Zhaoche" sort="Shu, Zhaoche" uniqKey="Shu Z" first="Zhaoche" last="Shu">Zhaoche Shu</name>
<name sortKey="Wang, Hong" sort="Wang, Hong" uniqKey="Wang H" first="Hong" last="Wang">Hong Wang</name>
<name sortKey="Wang, Jingyao" sort="Wang, Jingyao" uniqKey="Wang J" first="Jingyao" last="Wang">Jingyao Wang</name>
<name sortKey="Yin, Yibing" sort="Yin, Yibing" uniqKey="Yin Y" first="Yibing" last="Yin">Yibing Yin</name>
<name sortKey="Yuan, Jun" sort="Yuan, Jun" uniqKey="Yuan J" first="Jun" last="Yuan">Jun Yuan</name>
<name sortKey="Zhang, Hong" sort="Zhang, Hong" uniqKey="Zhang H" first="Hong" last="Zhang">Hong Zhang</name>
<name sortKey="Zhang, Qun" sort="Zhang, Qun" uniqKey="Zhang Q" first="Qun" last="Zhang">Qun Zhang</name>
<name sortKey="Zhang, Xuemei" sort="Zhang, Xuemei" uniqKey="Zhang X" first="Xuemei" last="Zhang">Xuemei Zhang</name>
</country>
</tree>
</affiliations>
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