Complement Receptor C5aR1 Inhibition Reduces Pyroptosis in hDPP4-Transgenic Mice Infected with MERS-CoV
Identifieur interne : 001214 ( Pmc/Curation ); précédent : 001213; suivant : 001215Complement Receptor C5aR1 Inhibition Reduces Pyroptosis in hDPP4-Transgenic Mice Infected with MERS-CoV
Auteurs : Yuting Jiang ; Junfeng Li ; Yue Teng ; Hong Sun ; Guang Tian ; Lei He ; Pei Li ; Yuehong Chen ; Yan Guo ; Jiangfan Li ; Guangyu Zhao ; Yusen Zhou [République populaire de Chine] ; Shihui SunSource :
- Viruses [ 1999-4915 ] ; 2019.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic virus with a crude mortality rate of ~35%. Previously, we established a human DPP4 transgenic (hDPP4-Tg) mouse model in which we studied complement overactivation-induced immunopathogenesis. Here, to better understand the pathogenesis of MERS-CoV, we studied the role of pyroptosis in THP-1 cells and hDPP4 Tg mice with MERS-CoV infection. We found that MERS-CoV infection induced pyroptosis and over-activation of complement in human macrophages. The hDPP4-Tg mice infected with MERS-CoV overexpressed caspase-1 in the spleen and showed high IL-1β levels in serum, suggesting that pyroptosis occurred after infection. However, when the C5a-C5aR1 axis was blocked by an anti-C5aR1 antibody (Ab), expression of caspase-1 and IL-1β fell. These data indicate that MERS-CoV infection induces overactivation of complement, which may contribute to pyroptosis and inflammation. Pyroptosis and inflammation were suppressed by inhibiting C5aR1. These results will further our understanding of the pathogenesis of MERS-CoV infection.
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DOI: 10.3390/v11010039
PubMed: 30634407
PubMed Central: 6356766
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last="Li">Junfeng Li</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Teng, Yue" sort="Teng, Yue" uniqKey="Teng Y" first="Yue" last="Teng">Yue Teng</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Sun, Hong" sort="Sun, Hong" uniqKey="Sun H" first="Hong" last="Sun">Hong Sun</name><affiliation><nlm:aff id="af2-viruses-11-00039">Department of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, China;<email>xun1@hotmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Tian, Guang" sort="Tian, Guang" uniqKey="Tian G" first="Guang" last="Tian">Guang Tian</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="He, Lei" sort="He, Lei" uniqKey="He L" first="Lei" last="He">Lei He</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Li, Pei" sort="Li, Pei" uniqKey="Li P" first="Pei" last="Li">Pei Li</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Chen, Yuehong" sort="Chen, Yuehong" uniqKey="Chen Y" first="Yuehong" last="Chen">Yuehong Chen</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Guo, Yan" sort="Guo, Yan" uniqKey="Guo Y" first="Yan" last="Guo">Yan Guo</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Li, Jiangfan" sort="Li, Jiangfan" uniqKey="Li J" first="Jiangfan" last="Li">Jiangfan Li</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Zhao, Guangyu" sort="Zhao, Guangyu" uniqKey="Zhao G" first="Guangyu" last="Zhao">Guangyu Zhao</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Zhou, Yusen" sort="Zhou, Yusen" uniqKey="Zhou Y" first="Yusen" last="Zhou">Yusen Zhou</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-viruses-11-00039">Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052</wicri:regionArea></affiliation></author><author><name sortKey="Sun, Shihui" sort="Sun, Shihui" uniqKey="Sun S" first="Shihui" last="Sun">Shihui Sun</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30634407</idno><idno type="pmc">6356766</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356766</idno><idno type="RBID">PMC:6356766</idno><idno type="doi">10.3390/v11010039</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">001214</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001214</idno><idno type="wicri:Area/Pmc/Curation">001214</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001214</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Complement Receptor C5aR1 Inhibition Reduces Pyroptosis in hDPP4-Transgenic Mice Infected with MERS-CoV</title><author><name sortKey="Jiang, Yuting" sort="Jiang, Yuting" uniqKey="Jiang Y" first="Yuting" last="Jiang">Yuting Jiang</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Li, Junfeng" sort="Li, Junfeng" uniqKey="Li J" first="Junfeng" last="Li">Junfeng Li</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Teng, Yue" sort="Teng, Yue" uniqKey="Teng Y" first="Yue" last="Teng">Yue Teng</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Sun, Hong" sort="Sun, Hong" uniqKey="Sun H" first="Hong" last="Sun">Hong Sun</name><affiliation><nlm:aff id="af2-viruses-11-00039">Department of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, China;<email>xun1@hotmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Tian, Guang" sort="Tian, Guang" uniqKey="Tian G" first="Guang" last="Tian">Guang Tian</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="He, Lei" sort="He, Lei" uniqKey="He L" first="Lei" last="He">Lei He</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Li, Pei" sort="Li, Pei" uniqKey="Li P" first="Pei" last="Li">Pei Li</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Chen, Yuehong" sort="Chen, Yuehong" uniqKey="Chen Y" first="Yuehong" last="Chen">Yuehong Chen</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Guo, Yan" sort="Guo, Yan" uniqKey="Guo Y" first="Yan" last="Guo">Yan Guo</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Li, Jiangfan" sort="Li, Jiangfan" uniqKey="Li J" first="Jiangfan" last="Li">Jiangfan Li</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Zhao, Guangyu" sort="Zhao, Guangyu" uniqKey="Zhao G" first="Guangyu" last="Zhao">Guangyu Zhao</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author><author><name sortKey="Zhou, Yusen" sort="Zhou, Yusen" uniqKey="Zhou Y" first="Yusen" last="Zhou">Yusen Zhou</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-viruses-11-00039">Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052</wicri:regionArea></affiliation></author><author><name sortKey="Sun, Shihui" sort="Sun, Shihui" uniqKey="Sun S" first="Shihui" last="Sun">Shihui Sun</name><affiliation><nlm:aff id="af1-viruses-11-00039">State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</nlm:aff></affiliation></author></analytic><series><title level="j">Viruses</title><idno type="eISSN">1999-4915</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic virus with a crude mortality rate of ~35%. Previously, we established a human DPP4 transgenic (hDPP4-Tg) mouse model in which we studied complement overactivation-induced immunopathogenesis. Here, to better understand the pathogenesis of MERS-CoV, we studied the role of pyroptosis in THP-1 cells and hDPP4 Tg mice with MERS-CoV infection. We found that MERS-CoV infection induced pyroptosis and over-activation of complement in human macrophages. The hDPP4-Tg mice infected with MERS-CoV overexpressed caspase-1 in the spleen and showed high IL-1β levels in serum, suggesting that pyroptosis occurred after infection. However, when the C5a-C5aR1 axis was blocked by an anti-C5aR1 antibody (Ab), expression of caspase-1 and IL-1β fell. These data indicate that MERS-CoV infection induces overactivation of complement, which may contribute to pyroptosis and inflammation. Pyroptosis and inflammation were suppressed by inhibiting C5aR1. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Viruses</journal-id><journal-id journal-id-type="iso-abbrev">Viruses</journal-id><journal-id journal-id-type="publisher-id">viruses</journal-id><journal-title-group><journal-title>Viruses</journal-title></journal-title-group><issn pub-type="epub">1999-4915</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30634407</article-id><article-id pub-id-type="pmc">6356766</article-id><article-id pub-id-type="doi">10.3390/v11010039</article-id><article-id pub-id-type="publisher-id">viruses-11-00039</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Complement Receptor C5aR1 Inhibition Reduces Pyroptosis in hDPP4-Transgenic Mice Infected with MERS-CoV</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-7404-5250</contrib-id><name><surname>Jiang</surname><given-names>Yuting</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00039">1</xref><xref ref-type="author-notes" rid="fn1-viruses-11-00039">†</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Junfeng</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00039">1</xref><xref ref-type="author-notes" rid="fn1-viruses-11-00039">†</xref></contrib><contrib contrib-type="author"><name><surname>Teng</surname><given-names>Yue</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00039">1</xref><xref ref-type="author-notes" rid="fn1-viruses-11-00039">†</xref></contrib><contrib contrib-type="author"><name><surname>Sun</surname><given-names>Hong</given-names></name><xref ref-type="aff" rid="af2-viruses-11-00039">2</xref></contrib><contrib contrib-type="author"><name><surname>Tian</surname><given-names>Guang</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00039">1</xref></contrib><contrib contrib-type="author"><name><surname>He</surname><given-names>Lei</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00039">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Pei</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00039">1</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Yuehong</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00039">1</xref></contrib><contrib contrib-type="author"><name><surname>Guo</surname><given-names>Yan</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00039">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Jiangfan</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00039">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhao</surname><given-names>Guangyu</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00039">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Yusen</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00039">1</xref><xref ref-type="aff" rid="af3-viruses-11-00039">3</xref><xref rid="c1-viruses-11-00039" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Sun</surname><given-names>Shihui</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00039">1</xref><xref rid="c1-viruses-11-00039" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-viruses-11-00039"><label>1</label>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;<email>captain99@126.com</email> (Y.J.);<email>lijunfeng2113@126.com</email> (J.L.);<email>yueteng@me.com</email> (Y.T.);<email>tglnx05@tom.com</email> (G.T.);<email>helei_happy@126.com</email> (L.H.);<email>lwhisperer@163.com</email> (P.L.);<email>chenyuehong.happy@163.com</email> (Y.C.);<email>muhan0425@126.com</email> (Y.G.);<email>anatee@163.com</email> (J.L.)<email>guangyu0525@163.com</email> (G.Z.)</aff><aff id="af2-viruses-11-00039"><label>2</label>Department of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, China;<email>xun1@hotmail.com</email></aff><aff id="af3-viruses-11-00039"><label>3</label>Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China</aff><author-notes><corresp id="c1-viruses-11-00039"><label>*</label>Correspondence: <email>yszhou@bmi.ac.cn</email> (Y.Z.); <email>sunsh01@163.com</email> (S.S.); Tel./Fax: +86-10-63858045 (Y.Z.)</corresp><fn id="fn1-viruses-11-00039"><label>†</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="epub"><day>09</day><month>1</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>1</month><year>2019</year></pub-date><volume>11</volume><issue>1</issue><elocation-id>39</elocation-id><history><date date-type="received"><day>28</day><month>11</month><year>2018</year></date><date date-type="accepted"><day>02</day><month>1</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic virus with a crude mortality rate of ~35%. Previously, we established a human DPP4 transgenic (hDPP4-Tg) mouse model in which we studied complement overactivation-induced immunopathogenesis. Here, to better understand the pathogenesis of MERS-CoV, we studied the role of pyroptosis in THP-1 cells and hDPP4 Tg mice with MERS-CoV infection. We found that MERS-CoV infection induced pyroptosis and over-activation of complement in human macrophages. The hDPP4-Tg mice infected with MERS-CoV overexpressed caspase-1 in the spleen and showed high IL-1β levels in serum, suggesting that pyroptosis occurred after infection. However, when the C5a-C5aR1 axis was blocked by an anti-C5aR1 antibody (Ab), expression of caspase-1 and IL-1β fell. These data indicate that MERS-CoV infection induces overactivation of complement, which may contribute to pyroptosis and inflammation. Pyroptosis and inflammation were suppressed by inhibiting C5aR1. These results will further our understanding of the pathogenesis of MERS-CoV infection.</p></abstract><kwd-group><kwd>MERS-CoV</kwd><kwd>inflammation</kwd><kwd>pyroptosis</kwd><kwd>complement</kwd></kwd-group></article-meta></front><floats-group><fig id="viruses-11-00039-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>MERS-CoV infection induces pyroptosis in THP-1 macrophages. THP-1 monocytes and macrophages were infected with MERS-CoV for 24 h. Total RNA and protein was then extracted from the cells using TRIzol Reagent. (<bold>A</bold>–<bold>C</bold>) Total RNA was used for RT-qPCR to detect transcription of pro-caspase-1, pro-IL-1β, and NLRP3. Data are expressed as means ± SEM (<italic>n</italic> = 2 per group). (<bold>D</bold>) Samples of total protein were subjected to Western blotting to detect pro-caspase-1, pro-IL-1β, activated IL-1β, and MERS NP.</p></caption><graphic xlink:href="viruses-11-00039-g001"></graphic></fig><fig id="viruses-11-00039-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>MERS-CoV infection induces pyroptosis in hDPP4-transgenic mice. (<bold>A</bold>–<bold>C</bold>) Transcription of NLRP3, pro-caspase-1, and pro-IL-1β in lung tissue at Day 3 post-MERS-CoV infection (<italic>n</italic> = 5–6 per group). (<bold>D</bold>) Concentration of IL-1β in serum at Day 3 post-MERS-CoV infection. Data are expressed as means ± SEM (<italic>n</italic> = 5–6 per group). * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01 (Student’s <italic>t</italic> test with Welch’s correction). (<bold>E</bold>) Representative images of immunohistochemical staining of caspase-1 in lung tissue on Day 7 post-challenge of sham-infected and MERS-CoV-infected mice (scale bars = 100 μm).</p></caption><graphic xlink:href="viruses-11-00039-g002"></graphic></fig><fig id="viruses-11-00039-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>MERS-CoV infection induces systemic inflammation in hDPP4-transgenic mice. (<bold>A</bold>–<bold>C</bold>) Concentration of TNF-α, IFN-γ, and IL-6 in serum at Day 3 post-MERS-CoV infection. Data are expressed as means ± SEM (<italic>n</italic> = 5–6 per group). * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01 (Student’s <italic>t</italic> test with Welch’s correction). (<bold>D</bold>) Macrophage infiltration and expression of IFN-γ receptor were assessed by immunohistochemical staining of lung and spleen at 7 days post-challenge (scale bars = 100 μm).</p></caption><graphic xlink:href="viruses-11-00039-g003"></graphic></fig><fig id="viruses-11-00039-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>MERS-CoV infection alters complement expression in monocytes and macrophages. (<bold>A</bold>–<bold>D</bold>) Transcription of C3, C3aR, C5aR1, and C5aR2 in THP-1 monocytes and macrophages at 24 h post-MERS-CoV infection. Data are expressed as means ± SEM (<italic>n</italic> = 2 per group).</p></caption><graphic xlink:href="viruses-11-00039-g004"></graphic></fig><fig id="viruses-11-00039-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>Blocking the C5a-C5aR1 axis reduces pyroptosis in hDPP4-transgenic mice. (<bold>A</bold>) Representative images of immunohistochemical staining of caspase-1 in lungs from PBS-treated and anti-C5aR1 Ab-treated groups on Day 7 post-challenge (scale bars = 100 μm). (<bold>B</bold>) Transcription of pro-IL-1β in lung tissues from PBS-treated and anti-C5aR1 Ab-treated groups at Day 7 post-infection (<italic>n</italic> = 4–5 per group). (<bold>C</bold>) Concentration of IL-1β in serum at Day 1 post-MERS-CoV infection. Data are expressed as means ± SEM (<italic>n</italic> = 4–5 per group). ** <italic>p</italic> < 0.01 (Student’s <italic>t</italic> test with Welch’s correction).</p></caption><graphic xlink:href="viruses-11-00039-g005"></graphic></fig><fig id="viruses-11-00039-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>Blockade of the C5a-C5aR1 axis reduces pyroptosis in hDPP4-transgenic mice. (<bold>A</bold>–<bold>C</bold>) Concentration of IFN-γ, TNF-α, and IL-6 in serum at Day 1 post-MERS-CoV infection. Data are expressed as means ± SEM (<italic>n</italic> = 4–5 per group). * <italic>p</italic> < 0.05 (Student’s <italic>t</italic> test with Welch’s correction). (<bold>D</bold>) Infiltration of the lungs and spleen by macrophages and expression of IFN-γ receptor were assessed by immunohistochemical staining 7 days after challenge (scale bars = 100 μm).</p></caption><graphic xlink:href="viruses-11-00039-g006"></graphic></fig><fig id="viruses-11-00039-f007" orientation="portrait" position="float"><label>Figure 7</label><caption><p>Diagram illustrating the relationship between complement and pyroptosis during MERS-CoV infection. MERS-CoV infection induces activation of complement and transcription of pro-IL-1β. Activated complement component C5a is released into the extracellular space where it interacts with C5aR1, which triggers assembly of the NLRP3 inflammasome. Activated caspase-1 cleaves pro-IL-1β into its active form thereby triggering pyroptosis. An anti-C5aR1 antibody prevents interaction between C5a and C5aR1, thereby ameliorating pyroptosis.</p></caption><graphic xlink:href="viruses-11-00039-g007"></graphic></fig><table-wrap id="viruses-11-00039-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">viruses-11-00039-t001_Table 1</object-id><label>Table 1</label><caption><p>Primers used to amplify inflammasome and complement components.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Primer</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Species</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Gene</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Orientation</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Sequence (5′-3′)</th></tr></thead><tbody><tr><td rowspan="2" align="center" valign="middle" colspan="1">1</td><td rowspan="14" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Human</td><td rowspan="2" align="center" valign="middle" colspan="1">NLRP3</td><td align="center" valign="middle" rowspan="1" colspan="1">F</td><td align="center" valign="middle" rowspan="1" colspan="1">ATTCGGAGATTGTGGTTGGG</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">R</td><td align="center" valign="middle" rowspan="1" colspan="1">AGGGCGTTGTCACTCAGGTC</td></tr><tr><td rowspan="2" align="center" valign="middle" colspan="1">2</td><td rowspan="2" align="center" valign="middle" colspan="1">pro-caspase-1</td><td align="center" valign="middle" rowspan="1" colspan="1">F</td><td align="center" valign="middle" rowspan="1" colspan="1">CTCAGGCTCAGAAGGGAATGTC</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">R</td><td align="center" valign="middle" rowspan="1" colspan="1">TGTGCGGCTTGACTTGTCC</td></tr><tr><td rowspan="2" align="center" valign="middle" colspan="1">3</td><td rowspan="2" align="center" valign="middle" colspan="1">pro-IL-1b</td><td align="center" valign="middle" rowspan="1" colspan="1">F</td><td align="center" valign="middle" rowspan="1" colspan="1">GCTCGCCAGTGAAATGATGG</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">R</td><td align="center" valign="middle" rowspan="1" colspan="1">CAGAGGGCAGAGGTCCAGG</td></tr><tr><td rowspan="2" align="center" valign="middle" colspan="1">4</td><td rowspan="2" align="center" valign="middle" colspan="1">C3</td><td align="center" valign="middle" rowspan="1" colspan="1">F</td><td align="center" valign="middle" rowspan="1" colspan="1">CACTATGATCCTTGAGATCTGTACCA</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">R</td><td align="center" valign="middle" rowspan="1" colspan="1">GGAGCAAAGCCAGTCATCA</td></tr><tr><td rowspan="2" align="center" valign="middle" colspan="1">5</td><td rowspan="2" align="center" valign="middle" colspan="1">C3aR</td><td align="center" valign="middle" rowspan="1" colspan="1">F</td><td align="center" valign="middle" rowspan="1" colspan="1">GACATCCAGGTGCTGAAGCC</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">R</td><td align="center" valign="middle" rowspan="1" colspan="1">ACTGGGGGCTCATTCCATG</td></tr><tr><td rowspan="2" align="center" valign="middle" colspan="1">6</td><td rowspan="2" align="center" valign="middle" colspan="1">C5aR1</td><td align="center" valign="middle" rowspan="1" colspan="1">F</td><td align="center" valign="middle" rowspan="1" colspan="1">GCTGACCATACCCTCCTTCCT</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">R</td><td align="center" valign="middle" rowspan="1" colspan="1">CCGTTTGTCGTGGCTGTAGTC</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">7</td><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">C5aR2</td><td align="center" valign="middle" rowspan="1" colspan="1">F</td><td align="center" valign="middle" rowspan="1" colspan="1">TGCTGTTTGTCTCTGCCCATC</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">R</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GTCAGCAGGATGATGGAGGG</td></tr><tr><td rowspan="2" align="center" valign="middle" colspan="1">8</td><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Mouse</td><td rowspan="2" align="center" valign="middle" colspan="1">pro-caspase-1</td><td align="center" valign="middle" rowspan="1" colspan="1">F</td><td align="center" valign="middle" rowspan="1" colspan="1">AATGAAGTTGCTGCTGGAGGA</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">R</td><td align="center" valign="middle" rowspan="1" colspan="1">CAGAAGTCTTGTGCTCTGGGC</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">9</td><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">pro-IL-1b</td><td align="center" valign="middle" rowspan="1" colspan="1">F</td><td align="center" valign="middle" rowspan="1" colspan="1">TGGACCTTCCAGGATGAGGACA</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">R</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GTTCATCTCGGAGCCTGTAGTG</td></tr></tbody></table></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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