MXD1 regulates the H9N2 and H1N1 influenza A virus–induced chemokine expression and their replications in human macrophage

Abstract

Human infection with influenza A/Hong Kong/156/97 (H5N1) avian influenza virus is associated with a high mortality rate of 60%. This virus is originated from influenza A/Quail/Hong Kong/G1/97 (H9N2/G1) avian influenza virus. Since the 1990s, four lineages of H9N2 viruses have been circulating in poultry and cause occasional infection in humans in different countries. Due to its zoonotic and genetic reassortment potential, H9N2/G1 and H5N1 viruses are believed to be the next pandemic candidates. Previous reports, including ours, showed that the virulence of avian virus strains correlates with their ability to dysregulate cytokine expression, including TNF-, CXCL10, and related chemokines in the virus-infected cells. However, the transcriptional factors required for this cytokine dysregulation remains undefined. In light of our previous report showing the unconventional role of MYC, an onco-transcriptional factor, for regulating the antibacterial responses, we hypothesize that the influenza virus-induced cytokine productions may be governed by MYC/MAX/MXD1 network members. Here, we demonstrated that the influenza A/Hong Kong/54/98 (H1N1)-or H9N2/G1 virus-induced CXCL10 expressions can be significantly attenuated by knocking down the MXD1 expression in primary human blood macrophages. Indeed, only the MXD1 expression was up-regulated by both H1N1 and H9N2/G1 viruses, but not other MYC/MAX/MXD1 members. The MXD1 expression and the CXCL10 hyperinduction were dependent on MEK1/2 activation. By using EMSAs, we revealed that MXD1 directly binds to the CXCL10 promoter-derived oligonucleotides upon infection of both viruses. Furthermore, silencing of MXD1 decreased the replication of H9N2 but not H1N1 viruses. Our results provide a new insight into the role of MXD1 for the pathogenicity of avian influenza viruses. K E Y W O R D S cytokine, influenza virus, MXD1 1 INTRODUCTION Although the influenza A/Hong Kong/54/98 (H1N1) influenza virus transmits efficiently among humans in 2009 pandemic, its virulence is mild compared with the highly pathogenic influenza A/Hong Kong/156/97 (H5N1) avian influenza virus. 1 The six internal RNA segments of this H5N1 avian influenza were donated by influenza A/Quail/Hong Kong/G1/97 (H9N2) avian influenza virus in Asian poultry in early 1990s. 2 Since then, four different poultry lineages of H9N2 avian influenza viruses have been circulated in the poultry Abbreviations: IRF3, IFN regulatory factor 3; MDCK, Madin-Darby canine kidney cells; PBMac, human blood macrophages; TCID, tissue culture infectious dose assay. in Asia, the Middle East, Africa, and Europe without causing any symptoms in these animals. 3 Of these, only two lineages, including the G1 and the Y280, are linked to human infections. 3 These viruses are zoonotic, highly prevalent in poultry in endemic countries, and have the ability to reassert their gene segments in other intermediate host such as pigs to acquire more human-like receptor binding ability. 3 Hence, these factors make these viruses a potential pandemic threat to hu...

Genetic Exchange of Lung-Derived Exosome to Brain Causing Neuronal Changes on COVID-19 Infection

“…Recently, Mamoor et al demonstrate the role of MXD1 in host cells’ response to COVID-19 infection [ 55 ]. Also, Howard et al reported the influence of MXD1 expression upon H1N1 and H9N2/G1 viral infection in the host [ 56 ]. Furthermore, silencing of MXD1 decreases the H9N2 replication process [ 56 ].…”

“…Also, Howard et al reported the influence of MXD1 expression upon H1N1 and H9N2/G1 viral infection in the host [ 56 ]. Furthermore, silencing of MXD1 decreases the H9N2 replication process [ 56 ]. Similarly, PHF11 is one of the interferon-stimulated genes expressed by a host on viral infections that regulates cytokine genes in T lymphocytes [ 57 , 58 ].…”

Targeting Macrophage Dysregulation for Viral Infections: Novel Targets for Immunomodulators

“…H5N1 and H9N2 are highly pathogenic. H9N2 induces CXCL10, RANTES, TNF-α, MIP-1α, and CCL2 expression ( 68 ). H5N1 induces TNF-α, CCL2, RANTES, CXCL10, IL-6, IL-8, and TGF-β3 ( 68 , 69 ).…”

“…H9N2 induces CXCL10, RANTES, TNF-α, MIP-1α, and CCL2 expression ( 68 ). H5N1 induces TNF-α, CCL2, RANTES, CXCL10, IL-6, IL-8, and TGF-β3 ( 68 , 69 ). H7N9 induces heightened IL-6, TNF-α, and IL-8 expression ( 69 ).…”

“…H7N9 induces heightened IL-6, TNF-α, and IL-8 expression ( 69 ). H1N1 induces elevated TNF-α, IL-8, TGF-β3, CXCL10, RANTES, and MIP-1α expression ( 68 , 69 ).…”