title: The pathological effects of CCR2+ inflammatory monocytes are amplified by an IFNAR1-triggered chemokine feedback loop in highly pathogenic influenza infection.
abstract: BACKGROUND
  Highly pathogenic influenza viruses cause high levels of morbidity, including excessive infiltration of leukocytes into the lungs, high viral loads and a cytokine storm. However, the details of how these pathological features unfold in severe influenza infections remain unclear. Accumulation of Gr1 + CD11b + myeloid cells has been observed in highly pathogenic influenza infections but it is not clear how and why they accumulate in the severely inflamed lung. In this study, we selected this cell population as a target to investigate the extreme inflammatory response during severe influenza infection.
  
  
  RESULTS
  We established H1N1 IAV-infected mouse models using three viruses of varying pathogenicity and noted the accumulation of a defined Gr1 + CD11b + myeloid population correlating with the pathogenicity. Herein, we reported that CCR2+ inflammatory monocytes are the major cell compartments in this population. Of note, impaired clearance of the high pathogenicity virus prolonged IFN expression, leading to CCR2+ inflammatory monocytes amplifying their own recruitment via an interferon-α/β receptor 1 (IFNAR1)-triggered chemokine loop. Blockage of IFNAR1-triggered signaling or inhibition of viral replication by Oseltamivir significantly suppresses the expression of CCR2 ligands and reduced the influx of CCR2+ inflammatory monocytes. Furthermore, trafficking of CCR2+ inflammatory monocytes from the bone marrow to the lung was evidenced by a CCR2-dependent chemotaxis. Importantly, leukocyte infiltration, cytokine storm and expression of iNOS were significantly reduced in CCR2-/- mice lacking infiltrating CCR2+ inflammatory monocytes, enhancing the survival of the infected mice.
  
  
  CONCLUSIONS
  Our results indicated that uncontrolled viral replication leads to excessive production of inflammatory innate immune responses by accumulating CCR2+ inflammatory monocytes, which contribute to the fatal outcomes of high pathogenicity virus infections.
authors.affiliation: Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. suejane.lin@mail.cgu.edu.tw.|Graduate institute of Medical Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. suejane.lin@mail.cgu.edu.tw.|Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. suejane.lin@mail.cgu.edu.tw.
authors.forename: Sue-Jane
authors.initials: SJ
authors.lastname: Lin
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan. loming1986@gmail.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Lo
authors.affiliation: Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. rlkuo@mail.cgu.edu.tw.|Graduate institute of Medical Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. rlkuo@mail.cgu.edu.tw.|Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. rlkuo@mail.cgu.edu.tw.
authors.forename: Rei-Lin
authors.initials: RL
authors.lastname: Kuo
authors.affiliation: Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. srshih@mail.cgu.edu.tw.|Graduate institute of Medical Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. srshih@mail.cgu.edu.tw.|Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. srshih@mail.cgu.edu.tw.
authors.forename: Shin-Ru
authors.initials: SR
authors.lastname: Shih
authors.affiliation: Department of Molecular Cell Biology, Health Sciences Research Institute, University of California, Merced, CA, USA. dojcius@ucmerced.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Ojcius
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan. joyce.jean.lu@gmail.com.
authors.forename: Jean
authors.initials: J
authors.lastname: Lu
authors.affiliation: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan. leeck@ntu.edu.tw.
authors.forename: Chien-Kuo
authors.initials: CK
authors.lastname: Lee
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan. hcchen725@mail.cmu.edu.tw.
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Chen
authors.affiliation: Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. meeiyunlin@yahoo.com.
authors.forename: Meei Yun
authors.initials: MY
authors.lastname: Lin
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan. cmleu@ym.edu.tw.
authors.forename: Chuen-Miin
authors.initials: CM
authors.lastname: Leu
authors.affiliation: Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. chianilin@cgmh.org.tw.|Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan. chianilin@cgmh.org.tw.
authors.forename: Chia-Ni
authors.initials: CN
authors.lastname: Lin
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan. chtsai@ntu.edu.tw.
authors.forename: Ching-Hwa
authors.initials: CH
authors.lastname: Tsai
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D018925:Chemokines / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000502:physiology*; D007251:Influenza, Human / Q000503:physiopathology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000503:physiopathology* / Q000821:virology; D053139:Oseltamivir / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta / Q000235:genetics* / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism; D012720:Severity of Illness Index; D013047:Specific Pathogen-Free Organisms; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C515335:Ccr2 protein, mouse; D018925:Chemokines; C508032:Ifnar1 protein, mouse; D054390:Receptors, CCR2; D053633:Receptor, Interferon alpha-beta; D053139:Oseltamivir