Demarcation of Viral Shelters Results in Destruction by Membranolytic GTPases: Antiviral Function of Autophagy Proteins and Interferon‐Inducible GTPases

Brown, Hailey; Biering, Scott B.; Zhu, Allen; Choi, Jayoung; Hwang, Seungmin

doi:10.1002/bies.201700231

Cited by 8 publications

(14 citation statements)

References 101 publications

(201 reference statements)

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“…However, a lesson may be learned from recent studies identifying a parallel function of IFNG in the defense against a protozoan parasite Toxoplasma gondii and a positive-sense single-stranded RNA virus MNV ( 71 96 97 98 99 ). Despite the dissimilarity of these 2 pathogens, a common IFNG-dependent mechanism underlies both the anti-protozoan and antiviral response ( 100 ). In this line of thinking, well-known anti-pathogen and immunomodulatory mechanisms of IFNG may guide the discovery of lesser-known antiviral mechanisms of IFNG.…”

Section: Discussionmentioning

confidence: 99%

Direct Antiviral Mechanisms of Interferon-Gamma

2018

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Interferon-gamma (IFNG) is a pleiotropic cytokine that modulates both innate and adaptive immune networks; it is the most potent activator of macrophages and a signature cytokine of activated T lymphocytes. Though IFNG is now appreciated to have a multitude of roles in immune modulation and broad-spectrum pathogen defense, it was originally discovered, and named, as a secretory factor that interferes with viral replication. In contrast to the prototypical type I interferons produced by any cells upon viral infection, only specific subsets of immune cells can produce IFNG upon infection or stimulation with antigen or mitogen. Still, virtually all cells can respond to both types of interferons. This makes IFNG a versatile anti-microbial cytokine and also gives it a unique position in the antiviral defense system. The goal of this review is to highlight the direct antiviral mechanisms of IFNG, thereby clarifying its antiviral function in the effective control of viral infections.

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Section: Discussionmentioning

confidence: 99%

Direct Antiviral Mechanisms of Interferon-Gamma

2018

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“…GBPs are recruited to pathogen-containing compartments, including viral replication sites, by autophagy related proteins (43). Once recruited, they exert a variety of antiviral activities that interfere with various steps of the viral replication cycle within these compartments, coordinate lysis or lysosomal fusion, and activate the inflammasome (44,45). For example, GBP1 inhibits the delivery of Kaposi's sarcoma-associated herpesvirus virions to the nucleus by interfering with actin filament organization (46).…”

Section: Discussionmentioning

confidence: 99%

Egyptian Rousette IFN-ω Subtypes Elicit Distinct Antiviral Effects and Transcriptional Responses in Conspecific Cells

et al. 2020

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Bats host a number of viruses that cause severe disease in humans without experiencing overt symptoms of disease themselves. While the mechanisms underlying this ability to avoid sickness are not known, deep sequencing studies of bat genomes have uncovered genetic adaptations that may have functional importance in the antiviral response of these animals. Egyptian rousette bats (Rousettus aegyptiacus) are the natural reservoir hosts of Marburg virus (MARV). In contrast to humans, these bats do not become sick when infected with MARV. A striking difference to the human genome is that Egyptian rousettes have an expanded repertoire of IFNW genes. To probe the biological implications of this expansion, we synthesized IFN-ω4 and IFN-ω9 proteins and tested their antiviral activity in Egyptian rousette cells. Both IFN-ω4 and IFN-ω9 showed antiviral activity against RNA viruses, including MARV, with IFN-ω9 being more efficient than IFN-ω4. Using RNA-Seq, we examined the transcriptional response induced by each protein. Although the sets of genes induced by the two IFNs were largely overlapping, IFN-ω9 induced a more rapid and intense response than did IFN-ω4. About 13% of genes induced by IFN-ω treatment are not found in the Interferome or other ISG databases, indicating that they may be uniquely IFN-responsive in this bat.

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“…Autophagy pathways can be specifically targeted, according to the type of virus infection. Inhibitors of autophagy may inhibit the growth of RNA viruses that rely on the associated membranes for replication, such as Picornaviruses and Dengue .…”

Section: Finding New Uses For Approved Drugsmentioning

confidence: 99%

Repurposing approved drugs on the pathway to novel therapies

Schein

2019

Medicinal Research Reviews

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The time and cost of developing new drugs have led many groups to limit their search for therapeutics to compounds that have previously been approved for human use. Many “repurposed” drugs, such as derivatives of thalidomide, antibiotics, and antivirals have had clinical success in treatment areas well beyond their original approved use. These include applications in treating antibiotic‐resistant organisms, viruses, cancers and to prevent burn scarring. The major theoretical justification for reusing approved drugs is that they have known modes of action and controllable side effects. Coadministering antibiotics with inhibitors of bacterial toxins or enzymes that mediate multidrug resistance can greatly enhance their activity. Drugs that control host cell pathways, including inflammation, tumor necrosis factor, interferons, and autophagy, can reduce the “cytokine storm” response to injury, control infection, and aid in cancer therapy. An active compound, even if previously approved for human use, will be a poor clinical candidate if it lacks specificity for the new target, has poor solubility or can cause serious side effects. Synergistic combinations can reduce the dosages of the individual components to lower reactivity. Preclinical analysis should take into account that severely ill patients with comorbidities will be more sensitive to side effects than healthy trial subjects. Once an active, approved drug has been identified, collaboration with medicinal chemists can aid in finding derivatives with better physicochemical properties, specificity, and efficacy, to provide novel therapies for cancers, emerging and rare diseases.

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Demarcation of Viral Shelters Results in Destruction by Membranolytic GTPases: Antiviral Function of Autophagy Proteins and Interferon‐Inducible GTPases

Cited by 8 publications

References 101 publications

Direct Antiviral Mechanisms of Interferon-Gamma

Direct Antiviral Mechanisms of Interferon-Gamma

Egyptian Rousette IFN-ω Subtypes Elicit Distinct Antiviral Effects and Transcriptional Responses in Conspecific Cells

Repurposing approved drugs on the pathway to novel therapies

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