Type I IFNs: A Blessing in Disguise or Partner in Crime in MERS-CoV-, SARS-CoV-, and SARS-CoV-2-Induced Pathology and Potential Use of Type I IFNs in Synergism with IFN-<i>γ</i>as a Novel Antiviral Approach Against COVID-19

Anjum, Faisal Rasheed; Anam, Sidra; Abbas, Ghazanfar; Mahmood, Muhammad Shahid; Rahman, Sajjad Ur; Goraya, Mohsan Ullah; Abdullah, Rana Muhammad; Luqman, Muhammad; Ali, Asad; Kamran, Muhammad; Chaudhry, Tamoor Hamid

doi:10.1089/vim.2020.0085

Cited by 12 publications

(6 citation statements)

References 108 publications

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“…Indeed, we did not rule out the possibility that low levels of IFN-I produced by a TLR3-and TRIF-negative epithelial layer could provide exacerbated HSE progression. The direct antiviral functions of IFN-I have been documented in various viral diseases [46,47]. In particular, IFN-β was reported to enhance systemic cytokine secretion and elevate cytotoxic responses, which negatively correlated with viral loads in inflamed tissues [48].…”

Section: Discussionmentioning

confidence: 99%

TLR3/TRIF pathway confers protection against herpes simplex encephalitis through NK cell activation mediated by a loop of type I IFN and IL‐15 from epithelial and dendritic cells

et al. 2023

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Autosomal recessive (AR) and dominant (AD) deficiencies of TLR3 and TRIF are believed to be crucial genetic causes of herpes simplex encephalitis (HSE), which is a fatal disease causing focal or global cerebral dysfunction following infection with herpes simplex virus type 1 (HSV‐1). However, few studies have been conducted on the immunopathological networks of HSE in the context of TLR3 and TRIF defects at the cellular and molecular levels. In this work, we deciphered the crosstalk between type I IFN (IFN‐I)‐producing epithelial layer and IL‐15‐producing dendritic cells (DC) to activate NK cells for the protective role of TLR3/TRIF pathway in HSE progression after vaginal HSV‐1 infection. TLR3‐ and TRIF‐ablated mice showed enhanced susceptibility to HSE progression, along with high HSV‐1 burden in vaginal tract, lymphoid tissues and CNS. The increased HSV‐1 burden in TLR3‐ and TRIF‐ablated mice did not correlate with increased infiltration of Ly‐6C+ monocytes, but it was closely associated with impaired NK cell activation in vaginal tract. Furthermore, using delicate ex vivo experiments and bone marrow transplantation, TRIF deficiency in tissue‐resident cells, such as epithelial cells in vaginal tract, was found to cause impaired NK cell activation by means of low IFN‐I production, whereas IFN‐I receptor in DC was required for NK cell activation via IL‐15 production in response to IFN‐I produced from epithelial layer. These results provide new information about IFN‐I‐ and IL‐15‐mediated crosstalk between epithelial cells and DC at the primary infection site, which suppresses HSE progression in a TLR3‐ and TRIF‐dependent manner.

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Section: Discussionmentioning

confidence: 99%

TLR3/TRIF pathway confers protection against herpes simplex encephalitis through NK cell activation mediated by a loop of type I IFN and IL‐15 from epithelial and dendritic cells

et al. 2023

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“…Type I interferons bind the receptor complex consisting of interferon α and β receptor subunit 1 and 2 (IFNAR1/IFNAR2), leading to the activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. This promotes the expression of ISGs [ 108 ], which play an important role in the inhibition of viral transcription and replication [ 106 , 108 ]. Although the TLR-mediated production of ISGs has a protective effect against SARS-CoV-2 [ 108 ], the ISGs resulting from activation of the TLR4 pathway have been proposed to increase surface ACE2 expression, therefore, amplifying the ACE2-mediated pathways of myocardial inflammation [ 23 , 109 ].…”

Section: Role Of Immune System Components (Toll-like Receptors)mentioning

confidence: 99%

“…This promotes the expression of ISGs [ 108 ], which play an important role in the inhibition of viral transcription and replication [ 106 , 108 ]. Although the TLR-mediated production of ISGs has a protective effect against SARS-CoV-2 [ 108 ], the ISGs resulting from activation of the TLR4 pathway have been proposed to increase surface ACE2 expression, therefore, amplifying the ACE2-mediated pathways of myocardial inflammation [ 23 , 109 ]. In this context, ACE2 has been suggested to act as an ISG; therefore, the type I interferon-induced expression of ACE2 may further aggravate SARS-CoV-2 manifestations, including myocarditis [ 109 , 110 ].…”

Section: Role Of Immune System Components (Toll-like Receptors)mentioning

confidence: 99%

COVID-19-Induced Myocarditis: Pathophysiological Roles of ACE2 and Toll-like Receptors

Pannucci

Jefferson

Hampshire

et al. 2023

IJMS

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The clinical manifestations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection responsible for coronavirus disease 2019 (COVID-19) commonly include dyspnoea and fatigue, and they primarily involve the lungs. However, extra-pulmonary organ dysfunctions, particularly affecting the cardiovascular system, have also been observed following COVID-19 infection. In this context, several cardiac complications have been reported, including hypertension, thromboembolism, arrythmia and heart failure, with myocardial injury and myocarditis being the most frequent. These secondary myocardial inflammatory responses appear to be associated with a poorer disease course and increased mortality in patients with severe COVID-19. In addition, numerous episodes of myocarditis have been reported as a complication of COVID-19 mRNA vaccinations, especially in young adult males. Changes in the cell surface expression of angiotensin-converting enzyme 2 (ACE2) and direct injury to cardiomyocytes resulting from exaggerated immune responses to COVID-19 are just some of the mechanisms that may explain the pathogenesis of COVID-19-induced myocarditis. Here, we review the pathophysiological mechanisms underlying myocarditis associated with COVID-19 infection, with a particular focus on the involvement of ACE2 and Toll-like receptors (TLRs).

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“…Using different in vitro and in vivo models, both protective and pathogenic functions of IFN-I were proposed in COVID-19 disease (Anjum et al, 2021; Boudewijns et al, 2020; Domizio et al, 2022; Israelow et al, 2020; King & Sprent, 2021; Mao et al, 2022). Using a mouse model based on adeno-associated virus (AAV)–mediated expression of human angiotensin I-converting enzyme 2 (hACE2), Israelow et al concluded that IFN-I does not control SARS-CoV-2 replication but drives pathological responses (Israelow et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Transgenic Mouse Models Establish a Protective Role of Type 1 IFN Response in SARS-CoV-2 infection-related Immunopathology

Chauhan

Kundu

Bal

et al. 2022

Preprint

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Type 1 interferon (IFN-I) response is the first line of host defense against invading viruses. In the absence of definite mouse models, however, the role of IFN-I in SARS-CoV-2 infections remained to be perplexing. Here, we developed two mouse models, one with constitutively high IFN-I response (hACE2; Irgm1-/-) and the other with dampened IFN-I response (hACE2; Ifnar1-/-) to comprehend the role of IFN-I response during SARS-CoV-2 invasion. We found that hACE2; Irgm1-/- mice were resistant to lethal SARS-CoV-2 (including delta variant) infection with substantially reduced cytokine storm and immunopathology in the lungs and brain. In striking contrast, a severe SARS-CoV-2 infection along with immune cell infiltration, inflammatory response, and enhanced pathology was observed in the lungs of hACE2; Ifnar1-/- mice. Additionally, hACE2; Ifnar1-/- mice were highly susceptible to SARS-CoV-2 neuroinvasion in the brain accompanied by immune cell infiltration, microglia/astrocytes activation, cytokine response, and demyelination of neurons. The hACE2; Irgm1-/- Ifnar1-/- double knockout mice or hACE2; Irgm1-/- mice treated with STING or RIPK2 pharmacological inhibitors displayed loss of the protective phenotypes observed in hACE2; Irgm1-/- mice suggesting that heightened IFN-I response accounts for the observed immunity. Taken together, we explicitly demonstrate that IFN-I protects from lethal SARS-CoV-2 infection, and Irgm1 (IRGM) could be an excellent therapeutic target against COVID-19.

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Type I IFNs: A Blessing in Disguise or Partner in Crime in MERS-CoV-, SARS-CoV-, and SARS-CoV-2-Induced Pathology and Potential Use of Type I IFNs in Synergism with IFN-γas a Novel Antiviral Approach Against COVID-19

Cited by 12 publications

References 108 publications

TLR3/TRIF pathway confers protection against herpes simplex encephalitis through NK cell activation mediated by a loop of type I IFN and IL‐15 from epithelial and dendritic cells

TLR3/TRIF pathway confers protection against herpes simplex encephalitis through NK cell activation mediated by a loop of type I IFN and IL‐15 from epithelial and dendritic cells

COVID-19-Induced Myocarditis: Pathophysiological Roles of ACE2 and Toll-like Receptors

Transgenic Mouse Models Establish a Protective Role of Type 1 IFN Response in SARS-CoV-2 infection-related Immunopathology

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