SARS-CoV-2 meta-interactome suggests disease-specific, autoimmune pathophysiologies and therapeutic targets

Background: Severe coronavirus disease 2019 (COVID-19) is associated with multiple comorbidities and is characterized by an auto-aggressive inflammatory state leading to massive collateral damage. To identify preventive and therapeutic strategies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is important to ascertain the molecular interactions between virus and host, and how they translate into disease pathophysiology. Methods: We matched virus-human protein interactions of human coronaviruses and other respiratory viruses with lists of genes associated with autoimmune diseases and comorbidities associated to worse COVID-19 course. We then selected the genes included in the statistically significant intersection between SARS-CoV-2 network and disease associated gene sets, identifying a meta-interactome. We analyzed the meta-interactome genes expression in samples derived from lungs of infected humans, and their regulation by IFN-β. Finally, we performed a drug repurposing screening to target the network’s most critical nodes. Results: We found a significant enrichment of SARS-CoV-2 interactors in immunological pathways and a strong association with autoimmunity and three prognostically relevant conditions (type 2 diabetes, coronary artery diseases, asthma), that present more independent physiopathological subnetworks. We observed a reduced expression of meta-interactome genes in human lungs after SARS-CoV-2 infection, and a regulatory potential of type I interferons. We also underscored multiple repurposable drugs to tailor the therapeutic strategies. Conclusions: Our data underscored a plausible genetic background that may contribute to the distinct observed pathophysiologies of severe COVID-19. Also, these results may help identify the most promising therapeutic targets and treatments for this condition.

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TRIM22. A Multitasking Antiviral Factor

Cells ◽

10.3390/cells10081864 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1864

Author(s):

Isabel Pagani ◽

Guido Poli ◽

Elisa Vicenzi

Keyword(s):

Protein Interactions ◽

Influenza A ◽

Direct Interaction ◽

Type I Interferons ◽

Viral Gene ◽

Target Cells ◽

Type I ◽

Protein Protein Interactions ◽

Viral Genomes ◽

Dna And Rna

Viral invasion of target cells triggers an immediate intracellular host defense system aimed at preventing further propagation of the virus. Viral genomes or early products of viral replication are sensed by a number of pattern recognition receptors, leading to the synthesis and production of type I interferons (IFNs) that, in turn, activate a cascade of IFN-stimulated genes (ISGs) with antiviral functions. Among these, several members of the tripartite motif (TRIM) family are antiviral executors. This article will focus, in particular, on TRIM22 as an example of a multitarget antiviral member of the TRIM family. The antiviral activities of TRIM22 against different DNA and RNA viruses, particularly human immunodeficiency virus type 1 (HIV-1) and influenza A virus (IAV), will be discussed. TRIM22 restriction of virus replication can involve either direct interaction of TRIM22 E3 ubiquitin ligase activity with viral proteins, or indirect protein–protein interactions resulting in control of viral gene transcription, but also epigenetic effects exerted at the chromatin level.

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The activation of bystander CD8+ T cells and their roles in viral infection

Experimental & Molecular Medicine ◽

10.1038/s12276-019-0316-1 ◽

2019 ◽

Vol 51 (12) ◽

pp. 1-9 ◽

Cited By ~ 12

Author(s):

Tae-Shin Kim ◽

Eui-Cheol Shin

Keyword(s):

T Cells ◽

Viral Infections ◽

Hepatitis A Virus ◽

Tissue Injury ◽

Strong Association ◽

Killer Cell ◽

Type I Interferons ◽

Type I ◽

Dependent Manner ◽

Bystander Activation

AbstractDuring viral infections, significant numbers of T cells are activated in a T cell receptor-independent and cytokine-dependent manner, a phenomenon referred to as “bystander activation.” Cytokines, including type I interferons, interleukin-18, and interleukin-15, are the most important factors that induce bystander activation of T cells, each of which plays a somewhat different role. Bystander T cells lack specificity for the pathogen, but can nevertheless impact the course of the immune response to the infection. For example, bystander-activated CD8+ T cells can participate in protective immunity by secreting cytokines, such as interferon-γ. They also mediate host injury by exerting cytotoxicity that is facilitated by natural killer cell-activating receptors, such as NKG2D, and cytolytic molecules, such as granzyme B. Interestingly, it has been recently reported that there is a strong association between the cytolytic function of bystander-activated CD8+ T cells and host tissue injury in patients with acute hepatitis A virus infection. The current review addresses the induction of bystander CD8+ T cells, their effector functions, and their potential roles in immunity to infection, immunopathology, and autoimmunity.

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Type I Interferons Triggered through the Toll-Like Receptor 3–TRIF Pathway Control Coxsackievirus A16 Infection in Young Mice

Journal of Virology ◽

10.1128/jvi.01627-15 ◽

2015 ◽

Vol 89 (21) ◽

pp. 10860-10867 ◽

Cited By ~ 13

Author(s):

Juhao Yang ◽

Chunfu Yang ◽

Nining Guo ◽

Kai Zhu ◽

Kaiming Luo ◽

...

Keyword(s):

Protective Immunity ◽

Foot And Mouth Disease ◽

Therapeutic Strategies ◽

Mouth Disease ◽

Type I Interferons ◽

Type I ◽

Toll Like Receptor ◽

Coxsackievirus A16 ◽

Foot And Mouth ◽

Young Mice

ABSTRACTCoxsackievirus A16 (CVA16) is one of the major etiological agents of hand, foot, and mouth disease (HFMD) in children. The host defense mechanisms against CVA16 infection remain almost entirely unknown. Unlike previous observations with enterovirus 71 (EV71) infection, here we show that gamma interferon (IFN-γ) or invariant NK T cell deficiency does not affect disease development or the survival of CVA16-infected mice. In contrast, type I interferon receptor deficiency resulted in the development of more severe disease in mice, and the mice had a lower survival rate than wild-type mice. Similarly, a deficiency of Toll-like receptor 3 (TLR3) and TRIF, but not other pattern recognition receptors, led to the decreased survival of CVA16-infected mice. TLR3-TRIF signaling was indispensable for the induction of type I interferons during CVA16 infection in mice and protected young mice from disease caused by the infection. In particular, TRIF-mediated immunity was critical for preventing CVA16 replication in the neuronal system before disease occurred. IFN-β treatment was also found to compensate for TRIF deficiency in mice and decreased the disease severity in and mortality of CVA16-infected mice. Altogether, type I interferons induced by TLR3-TRIF signaling mediate protective immunity against CVA16 infection. These findings may shed light on therapeutic strategies to combat HFMD caused by CVA16 infection.IMPORTANCEHand, foot, and mouth disease (HFMD) is a major threat to public health in the Asia-Pacific region. Both CVA16 and EV71 are major pathogens that are responsible for HFMD. The majority of research efforts have focused on the more virulent EV71, but little has been done with CVA16. Thus far, host immune responses to CVA16 infection have not yet been elucidated. The present study discovered an initial molecular mechanism underlying host protective immunity against CVA16 infection, providing the first explanation for why CVA16 and EV71 cause different clinical outcomes upon infection of humans. Therefore, different therapeutic strategies should be developed to treat HFMD cases caused by these two viruses.

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Evaluation of safety, efficacy, tolerability, and treatment-related outcomes of type I interferons for human coronaviruses (HCoVs) infection in clinical practice: An updated critical systematic review and meta-analysis

International Immunopharmacology ◽

10.1016/j.intimp.2020.106740 ◽

2020 ◽

Vol 86 ◽

pp. 106740 ◽

Cited By ~ 3

Author(s):

Chengjun Yu ◽

Lian Kang ◽

Jiadong Chen ◽

Na Zang

Keyword(s):

Systematic Review ◽

Clinical Practice ◽

Meta Analysis ◽

Type I Interferons ◽

Type I ◽

Human Coronaviruses

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Remarkable Role of Indoleamine 2,3-Dioxygenase and Tryptophan Metabolites in Infectious Diseases: Potential Role in Macrophage-Mediated Inflammatory Diseases

Mediators of Inflammation ◽

10.1155/2013/391984 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 33

Author(s):

Yuki Murakami ◽

Masato Hoshi ◽

Yukio Imamura ◽

Yuko Arioka ◽

Yasuko Yamamoto ◽

...

Keyword(s):

Infectious Diseases ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Therapeutic Strategies ◽

Type I Interferons ◽

Regulatory Function ◽

Type I ◽

Indoleamine 2,3 Dioxygenase ◽

Tryptophan Metabolites

Indoleamine 2,3-dioxygenase 1 (IDO1), the L-tryptophan-degrading enzyme, plays a key role in the immunomodulatory effects on several types of immune cells. Originally known for its regulatory function during pregnancy and chronic inflammation in tumorigenesis, the activity of IDO1 seems to modify the inflammatory state of infectious diseases. The pathophysiologic activity of L-tryptophan metabolites, kynurenines, is well recognized. Therefore, an understanding of the regulation of IDO1 and the subsequent biochemical reactions is essential for the design of therapeutic strategies in certain immune diseases. In this paper, current knowledge about the role of IDO1 and its metabolites during various infectious diseases is presented. Particularly, the regulation of type I interferons (IFNs) production via IDO1 in virus infection is discussed. This paper offers insights into new therapeutic strategies in the modulation of viral infection and several immune-related disorders.

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