PMID- 31597767
OWN - NLM
STAT- MEDLINE
DCOM- 20200611
LR  - 20200611
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 94
IP  - 1
DP  - 2019 Dec 12
TI  - Differential Modulation of Innate Immune Responses in Human Primary Cells by 
      Influenza A Viruses Carrying Human or Avian Nonstructural Protein 1.
LID - 10.1128/JVI.00999-19 [doi]
LID - e00999-19
AB  - The influenza A virus (IAV) nonstructural protein 1 (NS1) contributes to disease 
      pathogenesis through the inhibition of host innate immune responses. Dendritic 
      cells (DCs) release interferons (IFNs) and proinflammatory cytokines and promote 
      adaptive immunity upon viral infection. In order to characterize the 
      strain-specific effects of IAV NS1 on human DC activation, we infected human DCs 
      with a panel of recombinant viruses with the same backbone (A/Puerto 
      Rico/08/1934) expressing different NS1 proteins from human and avian origin. We 
      found that these viruses induced a clearly distinct phenotype in DCs. 
      Specifically, viruses expressing NS1 from human IAV (either H1N1 or H3N2) induced 
      higher levels of expression of type I (IFN-alpha and IFN-beta) and type III (IFN-lambda1 to 
      IFNlambda3) IFNs than viruses expressing avian IAV NS1 proteins (H5N1, H7N9, and 
      H7N2), but the differences observed in the expression levels of proinflammatory 
      cytokines like tumor necrosis factor alpha (TNF-alpha) or interleukin-6 (IL-6) were 
      not significant. In addition, using imaging flow cytometry, we found that human 
      and avian NS1 proteins segregate based on their subcellular trafficking dynamics, 
      which might be associated with the different innate immune profile induced in DCs 
      by viruses expressing those NS1 proteins. Innate immune responses induced by our 
      panel of IAV recombinant viruses were also characterized in normal human 
      bronchial epithelial cells, and the results were consistent with those in DCs. 
      Altogether, our results reveal an increased ability of NS1 from avian viruses to 
      antagonize innate immune responses in human primary cells compared to the ability 
      of NS1 from human viruses, which could contribute to the severe disease induced 
      by avian IAV in humans.IMPORTANCE Influenza A viruses (IAVs) cause seasonal 
      epidemics which result in an important health and economic burden. Wild aquatic 
      birds are the natural host of IAV. However, IAV can infect diverse hosts, 
      including humans, domestic poultry, pigs, and others. IAVs circulating in animals 
      occasionally cross the species barrier, infecting humans, which results in mild 
      to very severe disease. In some cases, these viruses can acquire the ability to 
      be transmitted among humans and initiate a pandemic. The nonstructural 1 (NS1) 
      protein of IAV is an important antagonist of the innate immune response. In this 
      study, using recombinant viruses and primary human cells, we show that NS1 
      proteins from human and avian hosts show intrinsic differences in the modulation 
      of the innate immunity in human dendritic cells and epithelial cells, as well as 
      different cellular localization dynamics in infected cells.
CI  - Copyright (c) 2019 Monteagudo et al.
FAU - Monteagudo, Paula L
AU  - Monteagudo PL
AUID- ORCID: 0000-0001-7843-6849
AD  - Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, 
      New York, USA.
FAU - Munoz-Moreno, Raquel
AU  - Munoz-Moreno R
AD  - Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, 
      New York, USA.
FAU - Fribourg, Miguel
AU  - Fribourg M
AD  - Department of Medicine Division of Infectious Diseases, Icahn School of Medicine 
      at Mount Sinai, New York, New York, New York, USA.
FAU - Potla, Uma
AU  - Potla U
AD  - Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, 
      New York, USA.
FAU - Mena, Ignacio
AU  - Mena I
AD  - Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, 
      New York, USA.
FAU - Marjanovic, Nada
AU  - Marjanovic N
AD  - Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New 
      York, USA.
FAU - Hartmann, Boris M
AU  - Hartmann BM
AD  - Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New 
      York, USA.
FAU - Sealfon, Stuart C
AU  - Sealfon SC
AD  - Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New 
      York, USA.
FAU - Garcia-Sastre, Adolfo
AU  - Garcia-Sastre A
AD  - Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, 
      New York, USA.
AD  - Department of Medicine Division of Infectious Diseases, Icahn School of Medicine 
      at Mount Sinai, New York, New York, New York, USA.
AD  - Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount 
      Sinai, New York, New York, USA.
FAU - Ramos, Irene
AU  - Ramos I
AUID- ORCID: 0000-0002-0223-0120
AD  - Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, 
      New York, USA irene.ramos-lopez@mssm.edu ana.sesma@mssm.edu.
FAU - Fernandez-Sesma, Ana
AU  - Fernandez-Sesma A
AUID- ORCID: 0000-0002-3405-6702
AD  - Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, 
      New York, USA irene.ramos-lopez@mssm.edu ana.sesma@mssm.edu.
AD  - Department of Medicine Division of Infectious Diseases, Icahn School of Medicine 
      at Mount Sinai, New York, New York, New York, USA.
AD  - The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount 
      Sinai, New York, New York, USA.
LA  - eng
GR  - HHSN272201400008C/AI/NIAID NIH HHS/United States
GR  - U19 AI117873/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20191212
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (IL6 protein, human)
RN  - 0 (INS1 protein, influenza virus)
RN  - 0 (Interferon-alpha)
RN  - 0 (Interleukin-6)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Viral Nonstructural Proteins)
RN  - 77238-31-4 (Interferon-beta)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Animals
MH  - Birds
MH  - Dendritic Cells/immunology/virology
MH  - Dogs
MH  - Epithelial Cells/*immunology/virology
MH  - Gene Expression Regulation
MH  - Host Specificity
MH  - Host-Pathogen Interactions/*genetics/immunology
MH  - Humans
MH  - *Immunity, Innate
MH  - Influenza A Virus, H1N1 Subtype/classification/*genetics/immunology
MH  - Influenza A Virus, H3N2 Subtype/classification/genetics/immunology
MH  - Influenza A Virus, H5N1 Subtype/classification/*genetics/immunology
MH  - Influenza A Virus, H7N2 Subtype/classification/genetics/immunology
MH  - Influenza A Virus, H7N9 Subtype/classification/genetics/immunology
MH  - Interferon-alpha/genetics/immunology
MH  - Interferon-beta/genetics/immunology
MH  - Interferon-gamma/genetics/immunology
MH  - Interleukin-6/genetics/immunology
MH  - Madin Darby Canine Kidney Cells
MH  - Phylogeny
MH  - Primary Cell Culture
MH  - Reassortant Viruses/genetics/immunology
MH  - Tumor Necrosis Factor-alpha/genetics/immunology
MH  - Viral Nonstructural Proteins/classification/*genetics/immunology
PMC - PMC6912104
OTO - NOTNLM
OT  - NS1 protein
OT  - dendritic cells
OT  - epithelial cells
OT  - influenza
OT  - innate immunity
OT  - interferons
EDAT- 2019/10/11 06:00
MHDA- 2020/06/12 06:00
PMCR- 2019/12/12
CRDT- 2019/10/11 06:00
PHST- 2019/07/10 00:00 [received]
PHST- 2019/09/29 00:00 [accepted]
PHST- 2019/10/11 06:00 [pubmed]
PHST- 2020/06/12 06:00 [medline]
PHST- 2019/10/11 06:00 [entrez]
PHST- 2019/12/12 00:00 [pmc-release]
AID - JVI.00999-19 [pii]
AID - 00999-19 [pii]
AID - 10.1128/JVI.00999-19 [doi]
PST - epublish
SO  - J Virol. 2019 Dec 12;94(1):e00999-19. doi: 10.1128/JVI.00999-19. Print 2019 Dec 
      12.