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IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes.

ABSTRACT: Type 1 IFNs (IFN-I) generally protect mammalian hosts from virus infections, but in some cases, IFN-I is pathogenic. Because IFN-I is protective, it is commonly used to treat virus infections for which no specific approved drug or vaccine is available. The Middle East respiratory syndrome-coronavirus (MERS-CoV) is such an infection, yet little is known about the role of IFN-I in this setting. Here, we show that IFN-I signaling is protective during MERS-CoV infection. Blocking IFN-I signaling resulted in delayed virus clearance, enhanced neutrophil infiltration, and impaired MERS-CoV-specific T cell responses. Notably, IFN-I administration within 1 day after infection (before virus titers peak) protected mice from lethal infection, despite a decrease in IFN-stimulated gene (ISG) and inflammatory cytokine gene expression. In contrast, delayed IFN-β treatment failed to effectively inhibit virus replication, increased infiltration and activation of monocytes, macrophages, and neutrophils in the lungs, and enhanced proinflammatory cytokine expression, resulting in fatal pneumonia in an otherwise sublethal infection. Together, these results suggest that the relative timing of the IFN-I response and maximal virus replication is key in determining outcomes, at least in infected mice. By extension, IFN-αβ or combination therapy may need to be used cautiously to treat viral infections in clinical settings.

SUBMITTER: Channappanavar R

PROVIDER: S-EPMC6715373 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Relative timing of type I interferon response and virus replication determines disease outcome during MERS-CoV infection

Project description:Type 1 interferons (IFN-I) generally protect mammalian hosts from virus infections, but in some cases, IFN-I is pathogenic. Because IFN-I is protective, it is commonly used to treat virus infections for which no specific approved drug or vaccine is available. The Middle East respiratory syndrome-coronavirus (MERS-CoV) is such an infection, yet little is known about the role of IFN-I in this setting. Here we show that IFN-I signaling is protective during MERS-CoV infection. Blocking IFN-I signaling resulted in delayed virus clearance, enhanced neutrophil infiltration and impaired MERS-CoV-specific T cell responses. Notably, IFN-I administration within 1-day post infection (before virus titers peak) protected mice from lethal infection, despite a decrease in ISG (interferon stimulated gene) and inflammatory cytokine gene expression. In contrast, delayed IFN-I treatment failed to effectively inhibit virus replication, increased infiltration and activation of monocyte-macrophages and neutrophils into the lungs and enhanced pro-inflammatory cytokine expression, resulting in fatal pneumonia in an otherwise sub-lethal infection. Together, these results suggest that the relative timing of the IFN-I response and maximal virus replication is key in determining outcomes, at least in infected mice. By extension, IFN-I or combination therapy may need to be used cautiously to treat virus infections in clinical settings.

2019-05-30 | GSE131936 | GEO

Relative timing of type I interferon response and virus replication determines disease outcome during MERS-CoV infection

Project description:Relative timing of type I interferon response and virus replication determines disease outcome during MERS-CoV infection

| PRJNA545350 | ENA

Alisporivir inhibits MERS- and SARS-coronavirus replication in cell culture, but not SARS-coronavirus infection in a mouse model.

Project description:Currently, there is no registered treatment for infections with emerging zoonotic coronaviruses like SARS- and MERS-coronavirus. We here report that in cultured cells low-micromolar concentrations of alisporivir, a non-immunosuppressive cyclosporin A-analog, inhibit the replication of four different coronaviruses, including MERS- and SARS-coronavirus. Ribavirin was found to further potentiate the antiviral effect of alisporivir in these cell culture-based infection models, but this combination treatment was unable to improve the outcome of SARS-CoV infection in a mouse model. Nevertheless, our data provide a basis to further explore the potential of Cyp inhibitors as host-directed, broad-spectrum inhibitors of coronavirus replication.

| S-EPMC7114565 | biostudies-literature

IFN-gamma production during initial infection determines the outcome of reinfection with respiratory syncytial virus.

Project description:RationaleSevere respiratory syncytial virus (RSV) bronchiolitis has been associated with deficient IFN-gamma production in humans, but the role of this cytokine in determining the outcome of reinfection is unknown.ObjectivesTo define the role of IFN-gamma in the development of RSV-mediated airway hyperresponsiveness (AHR) and lung histopathology in mice.MethodsWild-type (WT) and IFN-gamma knockout mice were infected with RSV in the newborn or weaning stages and reinfected 5 weeks later. Airway responses were assessed on Day 6 after the primary or secondary infection.Measurements and main resultsBoth WT and IFN-gamma knockout mice developed similar levels of AHR and airway inflammation after primary infection. After reinfection, IFN-gamma knockout mice, but not WT mice, developed AHR, airway eosinophilia, and mucus hyperproduction. Intranasal administration of IFN-gamma during primary infection but not during reinfection prevented the development of these altered airway responses on reinfection in IFN-gamma knockout mice. Adoptive transfer of WT T cells into IFN-gamma knockout mice before primary infection restored IFN-gamma production in the lungs and prevented the development of altered airway responses on reinfection. Treatment of mice with IFN-gamma during primary neonatal infection prevented the enhancement of AHR and the development of airway eosinophilia and mucus hyperproduction on reinfection.ConclusionsIFN-gamma production during primary RSV infection is critical to the development of protection against AHR and lung histopathology on reinfection. Provision of IFN-gamma during primary infection in infancy may be a potential therapeutic approach to alter the course of RSV-mediated long-term sequelae.

| S-EPMC2204078 | biostudies-literature

The timing of IFN? production affects early innate responses to Listeria monocytogenes and determines the overall outcome of lethal infection.

Project description:Dendritic cells (DCs) and natural killer (NK) cells are essential components of the innate immunity and play a crucial role in the first phase of host defense against infections and tumors. Listeria monocytogenes (Lm) is an intracellular pathogen that colonizes the cytosol of eukaryotic cells. Recent findings have shown Lm specifically in splenic CD8a(+) DCs shortly after intravenous infection. We examined gene expression profiles of mouse DCs exposed to Lm to elucidate the molecular mechanisms underlying DCs interaction with Lm. Using a functional genomics approach, we found that Lm infection induced a cluster of late response genes including type I IFNs and interferon responsive genes (IRGs) in DCs. Type I INFs were produced at the maximal level only at 24 h post infection indicating that the regulation of IFNs in the context of Lm infection is delayed compared to the rapid response observed with viral pathogens. We showed that during Lm infection, IFN? production and cytotoxic activity were severely impaired in NK cells compared to E. coli infection. These defects were restored by providing an exogenous source of IFN? during the initial phase of bacterial challenge. Moreover, when treated with IFN? during early infection, NK cells were able to reduce bacterial titer in the spleen and significantly improve survival of infected mice. These findings show that the timing of IFN? production is fundamental to the efficient control of the bacterium during the early innate phase of Lm infection.

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CRISPR screens identify candidate host factors for SARS and MERS coronavirus infection

Project description:Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are zoonotic pathogens that can cause severe respiratory disease in humans. Identification of the host factors that are necessary for viral infection and virus-induced cell death is critical to our understanding of the viral life cycle and can potentially aid the development of new treatment options. Here, we report CRISPR screen results of both SARS-CoV and MERS-CoV infections in derivatives of the human hepatoma cell line Huh7. Our screens identified the known entry receptors ACE2 for SARS-CoV and DPP4 for MERS-CoV. Additionally, the SARS-CoV screen uncovered several components of the NF-κB signaling pathway (CARD10, BCL10, MALT1, MAP3K7, IKBKG), while the MERS-CoV screen revealed the polypyrimidine tract-binding protein PTBP1, the ER scramblase TMEM41B, furin protease and several transcriptional and chromatin regulators as candidate factors for viral replication and/or virus-induced cell death. Together, we present several known and unknown coronavirus host factors that are of interest for further investigation.

2024-01-08 | GSE252396 | GEO

DNA Replication Determines Timing of Mitosis by Restricting CDK1 and PLK1 Activation.

Project description:To maintain genome stability, cells need to replicate their DNA before dividing. Upon completion of bulk DNA synthesis, the mitotic kinases CDK1 and PLK1 become active and drive entry into mitosis. Here, we have tested the hypothesis that DNA replication determines the timing of mitotic kinase activation. Using an optimized double-degron system, together with kinase inhibitors to enforce tight inhibition of key proteins, we find that human cells unable to initiate DNA replication prematurely enter mitosis. Preventing DNA replication licensing and/or firing causes prompt activation of CDK1 and PLK1 in S phase. In the presence of DNA replication, inhibition of CHK1 and p38 leads to premature activation of mitotic kinases, which induces severe replication stress. Our results demonstrate that, rather than merely a cell cycle output, DNA replication is an integral signaling component that restricts activation of mitotic kinases. DNA replication thus functions as a brake that determines cell cycle duration.

| S-EPMC6039720 | biostudies-literature

The coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression.

Project description:ADP-ribosylation is a ubiquitous post-translational addition of either monomers or polymers of ADP-ribose to target proteins by ADP-ribosyltransferases, usually by interferon-inducible diphtheria toxin-like enzymes known as PARPs. While several PARPs have known antiviral activities, these activities are mostly independent of ADP-ribosylation. Consequently, less is known about the antiviral effects of ADP-ribosylation. Several viral families, including Coronaviridae, Togaviridae, and Hepeviridae, encode for macrodomain proteins that bind to and hydrolyze ADP-ribose from proteins and are critical for optimal replication and virulence. These results suggest that macrodomains counter cellular ADP-ribosylation, but whether PARPs or, alternatively, other ADP-ribosyltransferases cause this modification is not clear. Here we show that pan-PARP inhibition enhanced replication and inhibited interferon production in primary macrophages infected with macrodomain-mutant but not wild-type coronavirus. Specifically, knockdown of two abundantly expressed PARPs, PARP12 and PARP14, led to increased replication of mutant but did not significantly affect wild-type virus. PARP14 was also important for the induction of interferon in mouse and human cells, indicating a critical role for this PARP in the regulation of innate immunity. In summary, these data demonstrate that the macrodomain is required to prevent PARP-mediated inhibition of coronavirus replication and enhancement of interferon production.

| S-EPMC6521996 | biostudies-literature

Inhibiting coronavirus replication by chemical ER stress, including SARS-CoV-2 and MERS-CoV

Project description:Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. We found that the ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replication in different cell types, (partially) restores the virus-induced translational shut-down, and counteracts the CoV-mediated downregulation of IRE1α and the ER chaperone BiP. Proteome-wide data sets revealed specific pathways, protein networks and components that likely mediate the thapsigargin-induced antiviral state, including HERPUD1, an essential factor of ER quality control, and ER-associated protein degradation complexes. The data show that thapsigargin hits a central mechanism required for CoV replication, suggesting that thapsigargin (or derivatives thereof) may be developed into broad-spectrum anti-CoV drugs.

2021-06-24 | PXD021222 | Pride

Timing of Intubation and Its Implications on Outcomes in Critically Ill Patients With Coronavirus Disease 2019 Infection.

Project description:In critically ill patients with coronavirus disease 2019, there has been considerable debate about when to intubate patients with acute respiratory failure. Early expert recommendations supported early intubation. However, as we learned more about this disease, the risks versus benefits of early intubation are less clear. We report our findings from an observational study aimed to compare the difference in outcomes of critically ill patients with coronavirus disease 2019 who were intubated early versus later in the disease course. Early need for intubation was defined as intubation either at admission or within 2 days of having a documented Fio2 greater than or equal to 0.5. In the final sample of 111 patients, 76 (68%) required early intubation. The mean age among those who received early intubation was significantly higher (69.79 ± 12.15 vs 65.03 ± 8.37 years; p = 0.038). Also, the patients who required early intubation had significantly higher Sequential Organ Failure Assessment scores at admission (6.51 vs 3.48; p ≤ 0.0001). The outcomes were equivocal among both groups. In conclusion, we suggest that the timing of intubation has no impact on clinical outcomes among patients with coronavirus disease 2019 pneumonia.

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