Common and species-specific molecular signatures, networks, and regulators of influenza virus infection in mice, ferrets, and humans

Forst, Christian V.; Martin-Sancho, Laura; Tripathi, Shashank; Wang, Guojun; Borges, Luiz Gustavo dos Anjos; Wang, Minghui; Geber, Adam; Lashua, Lauren; Ding, Tao; Zhou, Xianxiao; Carter, Chalise E.; Metreveli, Giorgi; Rodríguez-Frandsen, Ariel; Urbanowski, Matthew; White, Kris M.; Stein, David A.; Moulton, Hong M.; Chanda, Sumit K.; Pache, Lars; Shaw, Megan L.; Ross, Ted M.; Ghedin, Elodie; García‐Sastre, Adolfo; Zhang, Bin

doi:10.1126/sciadv.abm5859

Cited by 7 publications

(5 citation statements)

References 63 publications

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“…Studies reported herein provide the first key insights regarding the regulation, localisation and antiviral activity of fMx1, noting that previous studies have performed comprehensive transcriptional analyses of ISGs, including fMx1 and fMx2, in the blood and lungs of IAV-infected ferrets 42 . Our finding that fMx1 can inhibit IAV infection and replication, despite its similarity to canine Mx1 (which does not inhibit IAV), provides avenues for further research to determine the influence of specific Mx1 regions and residues which modulate the potency of anti-IAV activity.…”

Section: Discussionmentioning

confidence: 87%

Induction and antiviral activity of ferret myxovirus resistance (Mx) protein 1 against influenza A viruses

Farrukee,

Schwab,

Barnes

et al. 2024

Sci Rep

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Myxovirus resistance (Mx) proteins are products of interferon stimulated genes (ISGs) and Mx proteins of different species have been reported to mediate antiviral activity against a number of viruses, including influenza A viruses (IAV). Ferrets are widely considered to represent the ‘gold standard’ small animal model for studying pathogenesis and immunity to human IAV infections, however little is known regarding the antiviral activity of ferret Mx proteins. Herein, we report induction of ferret (f)Mx1/2 in a ferret lung cell line and in airway tissues from IAV-infected ferrets, noting that fMx1 was induced to higher levels that fMx2 both in vitro and in vivo. Overexpression confirmed cytoplasmic expression of fMx1 as well as its ability to inhibit infection and replication of IAV, noting that this antiviral effect of fMx1was modest when compared to cells overexpressing either human MxA or mouse Mx1. Together, these studies provide the first insights regarding the role of fMx1 in cell innate antiviral immunity to influenza viruses. Understanding similarities and differences in the antiviral activities of human and ferret ISGs provides critical context for evaluating results when studying human IAV infections in the ferret model.

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Section: Discussionmentioning

confidence: 87%

Induction and antiviral activity of ferret myxovirus resistance (Mx) protein 1 against influenza A viruses

Farrukee,

Schwab,

Barnes

et al. 2024

Sci Rep

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“…To investigate the role of BAG6 during IAV infection in vivo , BAG6-knockdown mice were generated using a peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) before PR8 virus (100 TCID 50 ) or mock infection ( Fig 3A ). PPMOs are sequence-specific antisense agents that can be administered intranasally to elicit a transient reduction in the expression of the targeted gene product in the lungs of treated mice [ 25 – 28 ]. The successful depletion of BAG6 in lung by BAG6-targeting PPMO (PPMO-BAG6) was confirmed by western blotting compared with PPMO control (PPMO-NC) before and after virus infection ( Fig 3B ).…”

Section: Resultsmentioning

confidence: 99%

BAG6 inhibits influenza A virus replication by inducing viral polymerase subunit PB2 degradation and perturbing RdRp complex assembly

Zhou,

Li,

Zhang

et al. 2024

PLoS Pathog

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The interaction between influenza A virus (IAV) and host proteins is an important process that greatly influences viral replication and pathogenicity. PB2 protein is a subunit of viral ribonucleoprotein (vRNP) complex playing distinct roles in viral transcription and replication. BAG6 (BCL2-associated athanogene 6) as a multifunctional host protein participates in physiological and pathological processes. Here, we identify BAG6 as a new restriction factor for IAV replication through targeting PB2. For both avian and human influenza viruses, overexpression of BAG6 reduced viral protein expression and virus titers, whereas deletion of BAG6 significantly enhanced virus replication. Moreover, BAG6-knockdown mice developed more severe clinical symptoms and higher viral loads upon IAV infection. Mechanistically, BAG6 restricted IAV transcription and replication by inhibiting the activity of viral RNA-dependent RNA polymerase (RdRp). The co-Immunoprecipitation assays showed BAG6 specifically interacted with the N-terminus of PB2 and competed with PB1 for RdRp complex assembly. The ubiquitination assay indicated that BAG6 promoted PB2 ubiquitination at K189 residue and targeted PB2 for K48-linked ubiquitination degradation. The antiviral effect of BAG6 necessitated its N-terminal region containing a ubiquitin-like (UBL) domain (17-92aa) and a PB2-binding domain (124-186aa), which are synergistically responsible for viral polymerase subunit PB2 degradation and perturbing RdRp complex assembly. These findings unravel a novel antiviral mechanism via the interaction of viral PB2 and host protein BAG6 during avian or human influenza virus infection and highlight a potential application of BAG6 for antiviral drug development.

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“…Exposure of mice to normoxic hypercapnia downregulated AMØ expression of genes involved in multiple GO processes that are likely relevant to host defense against IAV, including innate immune response, cell migration, chemotaxis, inflammatory response, response to IFN-β, complement activation, regulation of IFN-γ production, and response to virus. Specific genes with documented roles in host defense against influenza and other viral infections that were downregulated in AMØs include Ripk3 (30), Msr1 (31), Cxcl17 (32), C1q (33), C4a (34), C4b (35), Cfh (36), Ch25h (37), Ccl17 (38), Cd200 (39), Gbp6 (40), Iigp1 (41), Pyhin1 (42), and the IFN-stimulated antiviral effector Oasl2 (43). Myeloid Zfhx3 deficiency abrogated hypercapnic downregulation of GO processes in AMØs associated with antiviral host defense, including innate immune response, complement activation, inflammatory response, and chemotaxis.…”

Section: Discussionmentioning

confidence: 99%

Myeloid Zfhx3 deficiency protects against hypercapnia-induced suppression of host defense against influenza A virus

Casalino-Matsuda,

Chen,

Gonzalez-Gonzalez

et al. 2024

JCI Insight

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of hypercapnic immune suppression in vivo. Like Drosophila Zfh2, its mammalian ortholog, zinc finger homeobox 3 (Zfhx3), also known as AT-binding transcription factor 2 (Atbf1), is a very large zinc-finger homeodomain transcription factor. Two isoforms, Zfhx3-A (MW 404 kD) and Zfhx3-B (MW 306 kD), are expressed as a result of alternative promoter usage combined with alternative splicing (20). Zfhx3 regulates neuronal differentiation (21), functions as a tumor suppressor ( 22), and sequence variants of the gene associated with atrial fibrillation (23). In the mouse, homozygous germline deletion of Zfhx3 is embryonic lethal, and heterozygosity results in partial fetal loss and high neonatal and preweaning mortality (24). Lung MØs are critical for resistance to influenza virus infection (25)(26)(27)(28). This, along with our findings that hypercapnia downregulates MØ antiviral gene and protein expression (18) and that Zfh2 deficiency abrogates hypercapnic suppression of resistance to bacterial infection in Drosophila (19), led us to hypothesize that Zfhx3 might mediate the effects of elevated CO 2 on lung MØs and host defense against IAV. Here we show that Zfhx3 is highly expressed in mouse and human MØs. We thus bred a mouse selectively lacking Zfhx3 in the myeloid lineage, which in the unstressed state grows without apparent phenotypic abnormalities. We now report that deletion of Zfhx3 abrogates hypercapnia-induced suppression of antiviral and innate immune gene expression in murine MØs and that myeloid Zfhx3 deficiency attenuates CO 2 -induced increases in viral replication, lung injury, and mortality in mice infected with IAV. Our results define Zfhx3 as the first known component, to our knowledge, of a CO 2 response pathway affecting the immune system and host defense in a mammalian system.

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Common and species-specific molecular signatures, networks, and regulators of influenza virus infection in mice, ferrets, and humans

Cited by 7 publications

References 63 publications

Induction and antiviral activity of ferret myxovirus resistance (Mx) protein 1 against influenza A viruses

Induction and antiviral activity of ferret myxovirus resistance (Mx) protein 1 against influenza A viruses

BAG6 inhibits influenza A virus replication by inducing viral polymerase subunit PB2 degradation and perturbing RdRp complex assembly

Myeloid Zfhx3 deficiency protects against hypercapnia-induced suppression of host defense against influenza A virus

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