A multi-tissue study of immune gene expression profiling highlights the key role of the nasal epithelium in COVID-19 severity

Background: COVID-19 symptoms range from mild to severe illness; the cause for this differential response to infection remains unknown. Unravelling the immune mechanisms acting at different levels of the colonization process might be key to understand these differences. Methods and findings: We carried out a multi-tissue (nasal, buccal and blood; n = 156) gene expression analysis of immune-related genes from patients affected by different COVID-19 severities, and healthy controls through the nCounter technology. We then used a differential expression approach and pathways analysis to detect tissue specific immune severity signals in COVID-19 patients. Mild and asymptomatic cases showed a powerful innate antiviral response in nasal epithelium, characterized by activation of interferon (IFN) pathway and downstream cascades, successfully controlling the infection at local level. In contrast, weak macrophage/monocyte driven innate antiviral response and lack of IFN signalling activity were shown in severe cases. Consequently, oral mucosa from severe patients showed signals of viral activity, cell arresting and viral dissemination to the lower respiratory tract, which ultimately could explain the exacerbated innate immune response and impaired adaptative immune responses observed at systemic level. Results from saliva transcriptome suggest that the buccal cavity might play a key role in SARS-CoV-2 infection and dissemination in patients with worse prognosis. Conclusions: We found severity-related signatures in patient tissues mainly represented by genes involved in the innate immune system and cytokine/chemokine signalling. Local immune response could be key to determine the course of the systemic response and thus COVID-19 severity. Our findings provide a framework to investigate severity host gene biomarkers and pathways that might be relevant to diagnosis, prognosis, and therapy.

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Reduced severe acute respiratory syndrome coronavirus 2 entry factors and enhanced innate immune gene expression in the nasal epithelium of pregnant rats

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2020.10.010 ◽

2021 ◽

Vol 224 (1) ◽

pp. 118-120

Author(s):

Arvind Palanisamy ◽

Tusar Giri

Keyword(s):

Gene Expression ◽

Severe Acute Respiratory Syndrome ◽

Innate Immune ◽

Nasal Epithelium ◽

Immune Gene ◽

Pregnant Rats ◽

Immune Gene Expression ◽

Innate Immune Gene

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IFN-I Independent Antiviral Immune Response to Vesicular Stomatitis Virus Challenge in Mouse Brain

Vaccines ◽

10.3390/vaccines8020326 ◽

2020 ◽

Vol 8 (2) ◽

pp. 326

Author(s):

Anurag R. Mishra ◽

Siddappa N. Byrareddy ◽

Debasis Nayak

Keyword(s):

Gene Expression ◽

Immune Response ◽

Vesicular Stomatitis Virus ◽

Antiviral Response ◽

Type I ◽

Immune Gene ◽

Antiviral Immune Response ◽

Virus Challenge ◽

Vesicular Stomatitis ◽

Ifn Γ

Type I interferon (IFN-I) plays a pivotal role during viral infection response in the central nervous system (CNS). The IFN-I can orchestrate and regulate most of the innate immune gene expression and myeloid cell dynamics following a noncytopathic virus infection. However, the role of IFN-I in the CNS against viral encephalitis is not entirely clear. Here we have implemented the combination of global differential gene expression profiling followed by bioinformatics analysis to decipher the CNS immune response in the presence and absence of the IFN-I signaling. We observed that vesicular stomatitis virus (VSV) infection induced 281 gene changes in wild-type (WT) mice primarily associated with IFN-I signaling. This was accompanied by an increase in antiviral response through leukocyte vascular patrolling and leukocyte influx along with the expression of potent antiviral factors. Surprisingly, in the absence of the IFN-I signaling (IFNAR−/− mice), a significantly higher (1357) number of genes showed differential expression compared to the WT mice. Critical candidates such as IFN-γ, CCL5, CXCL10, and IRF1, which are responsible for the recruitment of the patrolling leukocytes, are also upregulated in the absence of IFN-I signaling. The computational network analysis suggests the presence of the IFN-I independent pathway that compensates for the lack of IFN-I signaling in the brain. The analysis shows that TNF-α is connected maximally to the networked candidates, thus emerging as a key regulator of gene expression and recruitment of myeloid cells to mount antiviral action. This pathway could potentiate IFN-γ release; thereby, synergistically activating IRF1-dependent ISG expression and antiviral response.

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The RNA-binding protein LUC7L2 mediates MITA/STING intron retention to negatively regulate innate antiviral response

Cell Discovery ◽

10.1038/s41421-021-00277-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Chen Li ◽

Lu Feng ◽

Wei-Wei Luo ◽

Cao-Qi Lei ◽

Mi Li ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Adaptor Protein ◽

Antiviral Response ◽

Innate Immune ◽

Innate Antiviral Response ◽

Hsv 1

AbstractMITA (also known as STING) is an ER-located adaptor protein, which mediates DNA-triggered innate immune response and is critically involved in autoimmune diseases and tumorigenesis. MITA is regulated by post-translational modifications, but how post-transcriptional mechanisms are involved in the regulation of MITA is still largely unknown. Here, we identified the RNA-binding protein LUC7L2 as a negative regulator of DNA virus-triggered innate immune response. LUC7L2-deficient mice exhibited resistance to lethal herpes simplex virus 1 (HSV-1) infection and reduced HSV-1 loads in the brain. Mechanistically, LUC7L2 directly bound to intron 3 of MITA precursor messenger RNA, inhibited its splicing and promoted its nonsense-mediated decay, leading to its downregulation at protein level. LUC7L2-deficient cells had markedly increased MITA level, leading to heightened innate antiviral response. Finally, LUC7L2 was induced following HSV-1 infection. Our findings reveal a feedback negative post-transcriptional regulatory mechanism for regulation of MITA-mediated innate immune response to viral and aberrant cellular DNA.

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SARS-CoV-2 membrane glycoprotein M antagonizes the MAVS-mediated innate antiviral response

Cellular and Molecular Immunology ◽

10.1038/s41423-020-00571-x ◽

2020 ◽

Author(s):

Yu-Zhi Fu ◽

Su-Yun Wang ◽

Zhou-Qin Zheng ◽

Yi Huang ◽

Wei-Wei Li ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Adaptor Protein ◽

Antiviral Response ◽

Innate Immune ◽

Negative Regulator ◽

M Protein ◽

High Morbidity ◽

Membrane Glycoprotein ◽

Innate Antiviral Response

Abstract A novel SARS-related coronavirus (SARS-CoV-2) has recently emerged as a serious pathogen that causes high morbidity and substantial mortality. However, the mechanisms by which SARS-CoV-2 evades host immunity remain poorly understood. Here, we identified SARS-CoV-2 membrane glycoprotein M as a negative regulator of the innate immune response. We found that the M protein interacted with the central adaptor protein MAVS in the innate immune response pathways. This interaction impaired MAVS aggregation and its recruitment of downstream TRAF3, TBK1, and IRF3, leading to attenuation of the innate antiviral response. Our findings reveal a mechanism by which SARS-CoV-2 evades the innate immune response and suggest that the M protein of SARS-CoV-2 is a potential target for the development of SARS-CoV-2 interventions.

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PTPN1/2-mediated dephosphorylation of MITA/STING promotes its 20S proteasomal degradation and attenuates innate antiviral response

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1906431116 ◽

2019 ◽

Vol 116 (40) ◽

pp. 20063-20069 ◽

Cited By ~ 14

Author(s):

Tian Xia ◽

Xue-Mei Yi ◽

Xin Wu ◽

Jun Shang ◽

Hong-Bing Shu

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Adaptor Protein ◽

Antiviral Response ◽

Innate Immune ◽

Viral Dna ◽

Intrinsically Disordered ◽

Antiviral Genes ◽

Associated Proteins ◽

Innate Antiviral Response

Upon cytosolic viral DNA stimulation, cGMP-AMP synthase (cGAS) catalyzes synthesis of 2′3′cGMP-AMP (cGAMP), which binds to the adaptor protein MITA (mediator of IRF3 activation, also called STING, stimulator of IFN genes) and induces innate antiviral response. How the activity of MITA/STING is regulated to avoid excessive innate immune response is not fully understood. Here we identified the tyrosine-protein phosphatase nonreceptor type (PTPN) 1 and 2 as MITA/STING-associated proteins. PTPN1 and PTPN2 are associated with MITA/STING following viral infection and dephosphorylate MITA/STING at Y245. Dephosphorylation of MITA/STING leads to its degradation via the ubiquitin-independent 20S proteasomal pathway, which is dependent on the intrinsically disordered region (IDR) of MITA/STING. Deficiencies of PTPN1 and PTPN2 enhance viral DNA-induced transcription of downstream antiviral genes and innate antiviral response. Our findings reveal that PTPN1/2-mediated dephosphorylation of MITA/STING and its degradation by the 20S proteasomal pathway is an important regulatory mechanism of innate immune response to DNA virus.

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The immune response in rohu,Labeo rohita(Actinopterygii: Cyprinidae) toArgulus siamensis(Branchiura: Argulidae) infection: kinetics of immune gene expression and innate immune response

Aquaculture Research ◽

10.1111/are.12279 ◽

2013 ◽

Vol 46 (6) ◽

pp. 1292-1308 ◽

Cited By ~ 27

Author(s):

Banya Kar ◽

Jyotirmaya Mohanty ◽

K P Hemaprasanth ◽

Pramoda Kumar Sahoo

Keyword(s):

Gene Expression ◽

Immune Response ◽

Innate Immune Response ◽

Labeo Rohita ◽

Innate Immune ◽

Immune Gene ◽

Immune Gene Expression ◽

Kinetics Of

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Global transcriptomics analyses reveal specialized roles for splicing regulatory proteins in the macrophage innate immune response

10.1101/2020.12.06.413690 ◽

2020 ◽

Author(s):

KO West ◽

AR Wagner ◽

HM Scott ◽

KJ Vail ◽

K Carter ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Innate Immune Response ◽

Innate Immune ◽

Regulatory Proteins ◽

Raw 264.7 ◽

Immune Gene ◽

Post Translational Modification ◽

Immune Genes ◽

Innate Immune Genes

ABSTRACTWhile the signaling cascades and transcription factors that activate gene expression in macrophages following pattern recognition receptor engagement are well known, the role of post-transcriptional RNA processing in modulating innate immune gene expression remains understudied. Recent phosphoproteomics analyses revealed that members of the SR and hnRNP families of splicing regulatory proteins undergo dynamic post-translational modification in infected macrophages. To begin to test if these splicing factors play a privileged role in controlling the innate immune transcriptome, we analyzed steady state gene expression and alternatively spliced isoform production in ten SR/hnRNP knockdown RAW 264.7 macrophage cell lines following infection with the bacterial pathogen Salmonella enterica serovar Typhimurium (Salmonella). We observed that thousands of genes were up or downregulated in SR/hnRNP knockdown cells and differentially expressed genes (DEGs) varied significantly depending on the SR/hnRNP examined. We discovered that a subset of critical innate immune genes (Nos2, Mx1, Il1a) rely heavily on SR/hnRNPs for proper induction and/or repression, while others (Tnf, Il1b) are generally unaffected by splicing factor knockdown. We also discovered that many key immune sensors and signaling molecules are subject to regulation by alternative splicing. While our data does not provide evidence for positive correlation between a transcripts’ reliance of SR/hnRNPs for proper expression and the gene’s induction level, length, or intron/exon architecture, we found that many rapidly induced primary response genes are repressed by SR/hnRNPs. Consistent with SR/hnRNP proteins contributing to innate immune outcomes, knockdown of hnRNP K and U significantly enhanced the ability of RAW 264.7 macrophages to control viral replication. Based on these collective findings, we conclude that many innate immune genes have evolved to rely on one or more splicing regulatory factors to ensure the proper timing and magnitude of their induction, supporting a model wherein pre-splicing is a critical regulatory node in the innate immune response.

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