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Influenza versus Host: The Role of Novel Copper‐Related Host Factors in Antiviral Immunity
Author(s) -
Dagdag Ralf P.,
Burkhead Jason L.,
Bortz Eric
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06545
Subject(s) - irf3 , virology , interferon , influenza a virus , biology , nucleoprotein , innate immune system , immune system , virus , rna , luciferase , antiviral protein , plasmid , immunity , rna interference , microbiology and biotechnology , transfection , gene , immunology , genetics
Influenza A virus is a respiratory orthomyxovirus that causes 3–5 million cases of severe illness and 250,000–500,000 deaths annually in humans. The NS1 protein antagonizes RIG‐I and IRF3‐induced IFN‐β responses during an influenza infection. Some influenza strains also contain nucleoproteins (NP) variants that impart resistance to the antiviral protein Mx. To better understand roles of NP in antagonizing interferon responses, NP plasmids from H1N1, H5N1, or H7N9 influenza subtypes were transfected into A549 human lung adenocarcinoma and HEK293T IFN‐β luciferase reporter cells. The viral RNA mimic poly‐I:C was used to induce a type‐I IFN response. Quantitative measures of normalized luciferase values (RLUs) reveal that viral NPs significant decrease the expression of both IFN‐β and the antiviral gene ISG56, indicating antagonism of host innate immune responses by NP. On the host side, copper handling machinery has been recently recognized as regulating influenza infection. RNA interference experiments showed that copper transporter ATP7A, a protein that imports [Cu1+] into trans‐Golgi derived compartments, is required for influenza viral RNA and protein syntheses. The trafficking‐regulatory Commander complex includes the 10‐member COMMD protein family, first identified in regulation of copper export. Preliminary experiments reveal that a type I IFN response induced by both low and high molecular weight variants of poly‐I:C in A549 cells also results in dose‐dependent upregulation of COMMD5 (13‐fold) and COMMD7 (24‐fold), but not COMMD1. Viral mixed infections using A/WSN/33 (H1N1) and A/PR/8/34 (H1N1) result in the upregulation of COMMD5 and no significant change in COMMD1 or COMMD5, which may be a result of immunosuppression by the viral proteins NS1 and NP. While simultaneous knockdown of COMMD5 and COMMD7 did not enhance influenza infection of A549 cells, knockdown of the copper‐binding protein ATOX1 licensed viral replication in a limiting dilution assay. Taken together, these results suggest a previously unrecognized interplay between viral NP, antiviral proteins and copper‐binding proteins to regulate influenza A virus infection in mammals, providing novel targets for antiviral therapy. Support or Funding Information Alaska INBRE