Παρασκευή 10 Φεβρουαρίου 2023

SARS‐CoV‐2 NSP7 inhibits type I and III IFN production by targeting the RIG‐I/MDA5, TRIF, and STING signaling pathways

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Abstract

SARS-CoV-2 is a poor inducer of innate antiviral immunity, and the underlying mechanism still needs further investigation. Here, we reported that SARS-CoV-2 NSP7 inhibited the production of type I and III IFNs by targeting the RIG-I/MDA5, TLR3-TRIF, and cGAS-STING signaling pathways. SARS-CoV-2 NSP7 suppressed the expression of IFNs and IFN-stimulated genes induced by poly (I:C) transfection and infection with Sendai virus or SARS-CoV-2 virus-like particles. NSP7 impaired type I and III IFN production activated by components of the cytosolic dsRNA-sensing pathway, including RIG-I, MDA5, and MAVS, but not TBK1, IKKε, and IRF3-5D, an active form of IRF3. In addition, NSP7 also suppressed TRIF- and STING-induced IFN responses. Mechanistically, NSP7 associated with RIG-I and MDA5 prevented the formation of the RIG-I/MDA5−MAVS signalosome and interacted with TRIF and STING to inhibit TRIF-TBK1 and STING-TBK1 complex formation, thus reducing the subsequent IRF3 phosphorylation and nu clear translocation that are essential for IFN induction. In addition, ectopic expression of NSP7 impeded innate immune activation and facilitated virus replication. Taken together, SARS-CoV-2 NSP7 dampens type I and III IFN responses via disruption of the signal transduction of the RIG-I/MDA5−MAVS, TLR3-TRIF, and cGAS-STING signaling pathways, thus providing novel insights into the interactions between SARS-CoV-2 and innate antiviral immunity.

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The Long Outer-Hair-Cell RC Time Constant: A Feature, Not a Bug, of the Mammalian Cochlea

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AbstractThe cochlea of the mammalian inner ear includes an active, hydromechanical amplifier thought to arise via the piezoelectric action of the outer hair cells (OHCs). A classic problem of cochlear biophysics is that theRC (resistance-capacitance) time constant of the hair-cell membrane appears inconveniently long, producing an effective cut-off frequency much lower than that of most audible sounds. The longRC time constant implies that the OHC receptor potential —and hence its electromotile response—decreases by roughly two orders of magnitude over the frequency range of mammalian hearing, casting doubt on the hypothesized role of cycle-by-cycle OHC-based amplification in mammalian hearing. Here, we review published data and basic physics to show that t he "RC problem " has bee...
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Analysis of Unmet Information Needs Among Patients With Thyroid Cancer

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This survey study uses mixed-methods analysis to assess p retreatment counseling experiences of survivors of thyroid cancer and to identify their unmet information needs.
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Patterns of Infectious Disease Associated with Injection Drug Use

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
Since 2014, multiple outbreaks of HIV among people who inject drugs (PWID) have occurred across the United States along with hepatitis C (HCV), skin and soft tissue infections (SSTI) and infective endocarditis (IE), creating a converging public health crisis.
Methods
We analyzed the temporal patterns of infectious disease and overdose (OD) using a hierarchical Bayesian distributed lag logistic regression model examining the probability that a given geographic area experienced at least one HIV case in a given month as a function of the counts/rates of OD, HCV, SSTI, IE and associated medical procedures at different lagged time periods.
Results
Current-month HIV is associated with increasing HCV cases; abscess incision and drainage, and SSTI cases, in distinct temporal patterns. For example, one additional HCV case occurring 5 and 7 months previously is associated with a 4% increase in the odds of observing at least one current-month HIV case in a given locale (odds ratios: 1.04, 1.04; 90% credible intervals: 1.01-1.10, 1.00-1.09). No such associations were observed for echocardiograms, IE, or OD.
Conclusion
Lagged associations in other infections preceding rises in current-month HIV counts cannot be described as predictive of HIV outbreaks but may point towards newly discovered epidemics of injection drug use and associated clinical sequalae, prompting clinicians to screen patients more carefully for substance use disorder and associated infections.
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