New Mechanism by Which Human Cytomegalovirus MicroRNAs Negate the Proinflammatory Response to Infection.

Andrew D Yurochko

doi:10.1128/mbio.00505-17

Andrew D Yurochko

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https://doi.org/10.1128/mbio.00505-17

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ABSTRACTViruses have evolved many novel mechanisms to promote infection and to mitigate the host cell response to that infection. In the article by M. H. Hancock et al. (mBio 8:e00109-17, 2017, https://doi.org/10.1128/mBio.00109-17), the authors describe a new mechanism by which human cytomegalovirus (HCMV) microRNAs (miRNAs; miR-US5-1 and miR-UL112-3p) negate the proinflammatory response to infection. The authors document that these two viral miRNAs downregulate the NF-κB response through direct targeting of the IKKα and IKKβ mRNAs, which in turn, through diminished IκB kinases (IKKs), block production of proinflammatory cytokines (interleukin-6 [IL-6], CCL5, and tumor necrosis factor alpha [TNF-α]). Because most signaling pathways that promote NF-κB activation and nuclear translocation ultimately converge on the activation of the IKK complex, this new study documents that HCMV can strongly dictate how infected cells respond to internal and/or external stimuli and thus positively influence the outcome of both lytic and latent infection.

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The authors document that these two viral miRNAs downregulate the NF-␬B response through direct targeting of the IKK␣ and IKK␤ mRNAs, which in turn, through diminished I␬B kinases (IKKs), block production of proinflammatory cytokines
Via cytokines, chemokines, growth factors, viral infection, etc., a downstream signaling pathway is initiated from the receptor-ligand engagement that usually culminates in the activation of the appropriate I␬B kinase (IKK) complex (IKK␣ and IKK␤ are the catalytic subunits, and IKK␥/NEMO is a structural regulator) and the phosphorylation of the critical serines, S32 and S36, on the I␬B␣ molecules
Through the use of various mutant viruses that were engineered to lack the miRNAs, the authors showed an increase in the protein levels of the two IKKs, as well as a loss of control of late NF-␬B signaling and loss of control of proinflammatory cytokine production, in cells infected with mutant human cytomegalovirus (HCMV)

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Introduction

The authors document that these two viral miRNAs downregulate the NF-␬B response through direct targeting of the IKK␣ and IKK␤ mRNAs, which in turn, through diminished I␬B kinases (IKKs), block production of proinflammatory cytokines (interleukin-6 [IL-6], CCL5, and tumor necrosis factor alpha [TNF-␣]). Because most signaling pathways that promote NF-␬B activation and nuclear translocation converge on the activation of the IKK complex, this new study documents that HCMV can strongly dictate how infected cells respond to internal and/or external stimuli and positively influence the outcome of both lytic and latent infection.

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