antiviral gene
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Biology ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 143
Author(s):  
Mithun Das ◽  
Monique L. Smith ◽  
Tomomi Furihata ◽  
Subir Sarker ◽  
Ross O’Shea ◽  
...  

Zika virus (ZIKV) is a pathogenic neurotropic virus that infects the central nervous system (CNS) and results in various neurological complications. Astrocytes are the dominant CNS cell producer of the antiviral cytokine IFN-β, however little is known about the factors involved in their ability to mediate viral infection control. Recent studies have displayed differential responses in astrocytes to ZIKV infection, and this study sought to elucidate astrocyte cell-specific responses to ZIKV using a variety of cell models infected with either the African (MR766) or Asian (PRVABC59) ZIKV strains. Expression levels of pro-inflammatory (TNF-α and IL-1β) and inflammatory (IL-8) cytokines following viral infection were low and mostly comparable within the ZIKV-resistant and ZIKV-susceptible astrocyte models, with better control of proinflammatory cytokines displayed in resistant astrocyte cells, synchronising with the viral infection level at specific timepoints. Astrocyte cell lines displaying ZIKV-resistance also demonstrated early upregulation of multiple antiviral genes compared with susceptible astrocytes. Interestingly, pre-stimulation of ZIKV-susceptible astrocytes with either poly(I:C) or poly(dA:dT) showed efficient protection against ZIKV compared with pre-stimulation with either recombinant IFN-β or IFN-λ, perhaps indicating that a more diverse antiviral gene expression is necessary for astrocyte control of ZIKV, and this is driven in part through interferon-independent mechanisms.


2021 ◽  
Author(s):  
Carlos F. Estevez-Castro ◽  
Murillo F. Rodrigues ◽  
Antinéa Babarit ◽  
Flávia Viana Ferreira ◽  
Eric Marois ◽  
...  

Mosquito borne viruses such as dengue, Zika, yellow fever and Chikungunya cause millions of infections every year. These viruses are mostly transmitted by two urban-adapted mosquito species, Aedes aegypti and Aedes albopictus, that appear to be more permissive to arbovirus infections compared to closely related species. Although mechanistic understanding remains, Aedes mosquitoes may have evolved specialized antiviral mechanisms that potentially contribute to the low impact of viral infection. Recently, we reported the identification of an Aedes specific double-stranded RNA binding protein (dsRBP), named Loqs2, that is involved in the control of infection by dengue and Zika viruses in Ae. aegypti. Loqs2 interacts with two important co-factors of the RNA interference (RNAi) pathway, Loquacious (Loqs) and R2D2, and seems to be a strong regulator of the antiviral defense. However, the origin and evolution of loqs2 remains unclear. Here, we describe that loqs2 likely originated from two independent duplications of the first dsRNA binding domain (dsRBD) of loquacious that occurred before the radiation of the Aedes Stegomya subgenus. After its origin, our analyses suggest that loqs2 evolved by relaxed positive selection towards neofunctionalization. In fact, loqs2 is evolving at a faster pace compared to other RNAi components such as loquacious, r2d2 and Dicer-2 in Aedes mosquitoes. Unlike loquacious, transcriptomic analysis showed that loqs2 expression is tightly regulated, almost restricted to reproductive tissues in Ae. aegypti and Ae. albopictus. Transgenic mosquitoes engineered to ubiquitously express loqs2 show massive dysregulation of stress response genes and undergo developmental arrest at larval stages. Overall, our results uncover the possible origin and neofunctionalization of a novel antiviral gene, loqs2, in Aedes mosquitoes that ultimately may contribute to their effectiveness as vectors for arboviruses.


2021 ◽  
Vol 12 ◽  
Author(s):  
Rui Zhang ◽  
Jun Tang

Type I interferon (IFN-I) mediated innate immunity serves as the first line of host defense against viral infection, ranging from IFN-I production upon viral detection, IFN-I triggered signaling pathway that induces antiviral gene transcription the antiviral effects of IFN-I induced gene products. During coevolution, herpesviruses have developed multiple countermeasures to inhibit the various steps involved to evade the IFN response. This mini-review focuses on the strategies used by the alphaherpesvirus Pseudorabies virus (PRV) to antagonize IFN-I mediated innate immunity, with a particular emphasis on the mechanisms inhibiting IFN-I induced gene transcription through the JAK-STAT pathway. The knowledge obtained from PRV enriches the current understanding of the alphaherpesviral immune evasion mechanisms and provides insight into the vaccine development for PRV control.


2021 ◽  
Vol 22 (22) ◽  
pp. 12097
Author(s):  
Rebecca Harris ◽  
Jianjun Yang ◽  
Kassandra Pagan ◽  
Soo Jung Cho ◽  
Heather Stout-Delgado

Influenza is a respiratory virus that alone or in combination with secondary bacterial pathogens can contribute to the development of acute pneumonia in persons >65 years of age. Host innate immune antiviral signaling early in response to influenza is essential to inhibit early viral replication and guide the initiation of adaptive immune responses. Using young adult (3 months) and aged adult mice infected with mouse adapted H1N1 or H3N2, the results of our study illustrate dysregulated and/or diminished activation of key signaling pathways in aged lung contribute to increased lung inflammation and morbidity. Specifically, within the first seven days of infection, there were significant changes in genes associated with TLR and RIG-I signaling detected in aged murine lung in response to H1N1 or H3N2. Taken together, the results of our study expand our current understanding of age-associated changes in antiviral signaling in the lung.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 960-960
Author(s):  
Sergei Nekhai ◽  
Namita Kumari ◽  
Songping Wang ◽  
Sharmin Diaz ◽  
Marina Jerebtsova

Abstract Introduction Patients with Sickle cell disease (SCD) have lower risk for HIV-1 infection. We showed that ex vivo HIV-1 replication is blocked in SCD PBMCs in part because of the increased expression of ferroportin (FPN) and activation of SAMHD1, a host antiviral restriction factor. We hypothesized that rupture of sickling red blood cells releases sickle cell hemoglobin (HbS) that is phagocyted by macrophages leading to upregulation of innate antiviral response and inhibition of HIV-1 replication. We accessed changes in antiviral gene expression in PBMCs obtained from SCD patients compared to healthy controls. We also analyzed antiviral gene expression in macrophages treated with HbS compared to the HbA treatment. Methods The study was approved by Howard University review board (IRB) and all subjects consented to sample collection. Whole blood was collected from 9 SCA patients and 9 age and gender- matched healthy controls. PBMCs were activated with PHA (0.5 μg/ml) for 24-48 hrs followed by IL-2 (10 U/ml) for 24 hrs. Human THP-1 cells were differentiated into macrophages with PMA (25nM) for 72 hrs and treated with purified HbS or HbA (5µM). RNA strand-specific libraries were constructed using TruSeq Stranded Total RNA Gold kit (Illumina) and sequenced on an Illumina NextSeq 500 using 75 bp paired-end sequencing on two v2.5 150 cycle High-Output kits, generating 40-50 million paired-end reads per sample. The sequencing data were mapped using Dragen RNA and compared using Dragen differential expression software (Illumina). Ingenuity Pathway analysis (IPA, Qiagen) was used for pathway analysis. Results In activated SCD PBMCs compared to control PBMCs, 40432 genes were detected including 2230 differentially expressed genes (5.5%, 1.5-fold difference, 287 down and 1943 up) at 5% false discovery rate. In non-activated SCD PBMCs compared to control PBMCs, 33119 genes were detected including 5299 differentially expressed genes (16%, 923 down and 4376 up). In THP-1-differentiated macrophages treated with HbS versus HbA, 28362 genes were detected including 322 differentially expressed genes (1.1%, 187 down and 135 up). We focused our analysis on 61 genes including viral restriction factors and iron regulatory genes. In activated SCD PBMCs, four genes had highest upregulation: APOBEC3A (23-fold, p=2 x 10 -5), CH25H (11-fold, p=4 x 10 -5), heme oxygenase-1 (HMOX1, 13-fold, p=1.5 x 10 -12) and FPN (SLC40A1, 5-fold, p = 9 x 10 -8) (Fig.1). Several additional genes were upregulated with 1.5-3-fold increase and high significance including APOBEC3B, BRD4, CD40, CDKN1A (p21), GDR1, IFIT3, IFITM3 and SAMHD1. In non-activated SCD PBMCs, the most upregulated gene was PKR (EIF2AK2, 15-fold, p=1 x 10 -11) and genes with 1.5-3 fold upregulation included APOBEC3B, BST2, CPSF6, IFI16, IFITM3, ISG15, LGALS3BP, PML and RTF1 (Fig.1). Of these genes, only IFITM3 overlapped between activated and non-activated PBMCs. To test whether circulating HbS leads to the upregulation of antiviral response, we analyzed HbS-treated macrophages and found upregulation of several antiviral restriction factors (1.5-2.3 fold): IFIT3, LGALS3BP, MX2 and RTF1 (Fig.1). Unsupervised IPA showed upregulation of IRF-7 signaling pathway and down regulation of viral infection and replication (Fig.2). We validated the CH25 and HO-1 antiviral role in activated SCD PBMCs using small molecule inhibitors. We also confirmed overexpression of CH25H and HO-1 by western blot and ELISA. We observed higher levels of IRF7 in the activated SCD PBMCs confirming that it may play a role in the induction of antiviral response. Conclusion We propose that HbS released by hemolysis and uptaken by macrophages leads to the IRF-7-triggered induction of antiviral state in macrophages that will induced antiviral state in non-activated circulating PBMCs likely though the cytokines and interferons secretion known to be elevated in SCD patients. Upregulation of PKR (EIFAK2) levels in non-activated PBMCs strongly argue toward this possibility. Upon activation of PBMCs, additional factors are expressed including CH25H, HO-1, APOBEC3A and FPN that facilitated stronger and more robust anti-HIV-1 effect and block viral replication. Taken together, our study point to novel mechanism of upregulation of antiviral factors mediated by sickle cell hemoglobin that included induction of antiviral, heme- and iron- regulatory pathways. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.


2021 ◽  
Vol 98 ◽  
pp. 310-316
Author(s):  
Danny Rahal ◽  
Sarah M. Tashjian ◽  
Maira Karan ◽  
Naomi Eisenberger ◽  
Adriana Galván ◽  
...  

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2032
Author(s):  
Pengfei Diao ◽  
Hongyu Sun ◽  
Zhuo Bao ◽  
Wenxia Li ◽  
Niu Niu ◽  
...  

Most of R (resistance) genes encode the protein containing NBS-LRR (nucleotide binding site and leucine-rich repeat) domains. Here, N. benthamiana plants were used for transient expression assays at 3–4 weeks of age. We identified a TNL (TIR-NBS-LRR) encoding gene GmRUN1 that was resistant to both soybean mosaic virus (SMV) and tobacco mosaic virus (TMV). Truncation analysis indicated the importance of all three canonical domains for GmRUN1-mediated antiviral activity. Promoter-GUS analysis showed that GmRUN1 expression is inducible by both salicylic acid (SA) and a transcription factor GmDREB3 via the cis-elements as-1 and ERE (ethylene response element), which are present in its promoter region. Interestingly, GmRUN1 gDNA (genomic DNA) shows higher viral resistance than its cDNA (complementary DNA), indicating the existence of intron-mediated enhancement (IME) for GmRUN1 regulation. We provided evidence that intron2 of GmRUN1 increased the mRNA level of native gene GmRUN1, a soybean antiviral gene SRC7 and also a reporter gene Luciferase, indicating the general transcriptional enhancement of intron2 in different genes. In summary, we identified an antiviral TNL type soybean gene GmRUN1, expression of which was regulated at different layers. The investigation of GmRUN1 gene regulatory network would help to explore the mechanism underlying soybean-SMV interactions.


FEBS Letters ◽  
2021 ◽  
Author(s):  
Shawn M. Freed ◽  
Danielle S. Baldi ◽  
Jason A. Snow ◽  
Sierra Athen ◽  
Zachary P. Guinn ◽  
...  

2021 ◽  
Author(s):  
Danny Rahal ◽  
Sarah M Tashjian ◽  
Maira Karan ◽  
Naomi Eisenberger ◽  
Adriana Galván ◽  
...  

Parasympathetic nervous system activity can downregulate inflammation, but it remains unclear how parasympathetic nervous system activity relates to antiviral activity. The present study examined associations between parasympathetic nervous system activity and cellular antiviral gene regulation in 90 adolescents (Mage = 16.3, SD = 0.7; 51.1% female) who provided blood samples and measures of cardiac respiratory sinus arrhythmia (RSA), twice, five weeks apart. Using a multilevel analytic framework, we found that higher RSA (an indicator of higher parasympathetic nervous system activity) - both at rest and during paced breathing - was associated with higher expression of Type I interferon (IFN) response genes in circulating leukocytes, even after adjusting for demographic and biological covariates. RSA was not associated with a parallel measure of inflammatory gene expression. These results identify a previously unrecognized immunoregulatory aspect of autonomic nervous system function and highlight a potential biological pathway by which parasympathetic nervous system activity may relate to health.


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