scholarly journals Efficient Replication of the Novel Human Betacoronavirus EMC on Primary Human Epithelium Highlights Its Zoonotic Potential

mBio ◽  
2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Eveline Kindler ◽  
Hulda R. Jónsdóttir ◽  
Doreen Muth ◽  
Ole J. Hamming ◽  
Rune Hartmann ◽  
...  
Keyword(s):  
Airway Epithelium ◽  
Respiratory Viruses ◽  
Innate Immune ◽  
Type I ◽  
Target Tissue ◽  
Primary Target ◽  
Human Coronavirus ◽  
Type Iii ◽  
Human Airway Epithelium ◽  
Type Iii Interferon

ABSTRACT The recent emergence of a novel human coronavirus (HCoV-EMC) in the Middle East raised considerable concerns, as it is associated with severe acute pneumonia, renal failure, and fatal outcome and thus resembles the clinical presentation of severe acute respiratory syndrome (SARS) observed in 2002 and 2003. Like SARS-CoV, HCoV-EMC is of zoonotic origin and closely related to bat coronaviruses. The human airway epithelium (HAE) represents the entry point and primary target tissue for respiratory viruses and is highly relevant for assessing the zoonotic potential of emerging respiratory viruses, such as HCoV-EMC. Here, we show that pseudostratified HAE cultures derived from different donors are highly permissive to HCoV-EMC infection, and by using reverse transcription (RT)-PCR and RNAseq data, we experimentally determined the identity of seven HCoV-EMC subgenomic mRNAs. Although the HAE cells were readily responsive to type I and type III interferon (IFN), we observed neither a pronounced inflammatory cytokine nor any detectable IFN responses following HCoV-EMC, SARS-CoV, or HCoV-229E infection, suggesting that innate immune evasion mechanisms and putative IFN antagonists of HCoV-EMC are operational in the new host. Importantly, however, we demonstrate that both type I and type III IFN can efficiently reduce HCoV-EMC replication in HAE cultures, providing a possible treatment option in cases of suspected HCoV-EMC infection. IMPORTANCE A novel human coronavirus, HCoV-EMC, has recently been described to be associated with severe respiratory tract infection and fatalities, similar to severe acute respiratory syndrome (SARS) observed during the 2002-2003 epidemic. Closely related coronaviruses replicate in bats, suggesting that, like SARS-CoV, HCoV-EMC is of zoonotic origin. Since the animal reservoir and circumstances of zoonotic transmission are yet elusive, it is critically important to assess potential species barriers of HCoV-EMC infection. An important first barrier against invading respiratory pathogens is the epithelium, representing the entry point and primary target tissue of respiratory viruses. We show that human bronchial epithelia are highly susceptible to HCoV-EMC infection. Furthermore, HCoV-EMC, like other coronaviruses, evades innate immune recognition, reflected by the lack of interferon and minimal inflammatory cytokine expression following infection. Importantly, type I and type III interferon treatment can efficiently reduce HCoV-EMC replication in the human airway epithelium, providing a possible avenue for treatment of emerging virus infections.

Type-III interferon, not type-I, is the predominant interferon induced by respiratory viruses in nasal epithelial cells

2011 ◽  
Vol 160 (1-2) ◽  
pp. 360-366 ◽  
Author(s):  
Tamaki Okabayashi ◽  
Takashi Kojima ◽  
Tomoyuki Masaki ◽  
Shin-ichi Yokota ◽  
Tadaatsu Imaizumi ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Respiratory Viruses ◽  
Type I ◽  
Nasal Epithelial Cells ◽  
Type Iii ◽  
Type Iii Interferon

scholarly journals Coronavirus Endoribonuclease Activity in Porcine Epidemic Diarrhea Virus Suppresses Type I and Type III Interferon Responses

2019 ◽  
Vol 93 (8) ◽  
Author(s):  
Xufang Deng ◽  
Albert van Geelen ◽  
Alexandra C. Buckley ◽  
Amornrat O’Brien ◽  
Angela Pillatzki ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Virulence Factor ◽  
Vero Cells ◽  
Innate Immune ◽  
Interferon Response ◽  
Type I ◽  
Diarrhea Virus ◽  
Type Iii ◽  
Porcine Epidemic Diarrhea ◽  
Type Iii Interferon

ABSTRACTIdentifying viral antagonists of innate immunity and determining if they contribute to pathogenesis are critical for developing effective strategies to control emerging viruses. Previously, we reported that an endoribonuclease (EndoU) encoded by murine coronavirus plays a pivotal role in evasion of host innate immune defenses in macrophages. Here, we asked if the EndoU activity of porcine epidemic diarrhea coronavirus (PEDV), which causes acute diarrhea in swine, plays a role in antagonizing the innate response in porcine epithelial cells and macrophages, the sites of viral replication. We constructed an infectious clone of PEDV-Colorado strain (icPEDV-wt) and an EndoU-mutant PEDV (icPEDV-EnUmt) by changing the codon for a catalytic histidine residue of EndoU to alanine (His226Ala). We found that both icPEDV-wt and icPEDV-EnUmt propagated efficiently in interferon (IFN)-deficient Vero cells. In contrast, the propagation of icPEDV-EnUmt was impaired in porcine epithelial cells (LLC-PK1), where we detected an early and robust transcriptional activation of type I and type III IFNs. Infection of piglets with the parental Colorado strain, icPEDV-wt, or icPEDV-EnUmt revealed that all viruses replicated in the gut and induced diarrhea; however, there was reduced viral shedding and mortality in the icPEDV-EnUmt-infected animals. These results demonstrate that EndoU activity is not required for PEDV replication in immortalized, IFN-deficient Vero cells, but is important for suppressing the IFN response in epithelial cells and macrophages, which facilitates replication, shedding, and pathogenesisin vivo. We conclude that PEDV EndoU activity is a key virulence factor that suppresses both type I and type III IFN responses.IMPORTANCECoronaviruses (CoVs) can emerge from an animal reservoir into a naive host species to cause pandemic respiratory or gastrointestinal diseases with significant mortality in humans or domestic animals. Porcine epidemic diarrhea virus (PEDV), an alphacoronavirus (alpha-CoV), infects gut epithelial cells and macrophages, inducing diarrhea and resulting in high mortality in piglets. How PEDV suppresses the innate immune response was unknown. We found that mutating a viral endoribonuclease, EndoU, results in a virus that activates both the type I interferon response and the type III interferon response in macrophages and epithelial cells. This activation of interferon resulted in limited viral replication in epithelial cell cultures and was associated with reduced virus shedding and mortality in piglets. This study reveals a role for EndoU activity as a virulence factor in PEDV infection and provides an approach for generating live-attenuated vaccine candidates for emerging coronaviruses.

scholarly journals The Emergence of Human Coronavirus EMC: How Scared Should We Be?

mBio ◽  
2013 ◽  
Vol 4 (2) ◽  
Author(s):  
Renee W. Y. Chan ◽  
Leo L. M. Poon
Keyword(s):  
Airway Epithelial Cells ◽  
Type I ◽  
Airway Epithelial ◽  
Human Coronavirus ◽  
Angiotensin Converting Enzyme 2 ◽  
Human Airway Epithelium ◽  
Mammalian Cell Lines ◽  
Physiological Relevance

ABSTRACT A novel betacoronavirus, human coronavirus (HCoV-EMC), has recently been detected in humans with severe respiratory disease. Further characterization of HCoV-EMC suggests that this virus is different from severe acute respiratory syndrome coronavirus (SARS-CoV) because it is able to replicate in multiple mammalian cell lines and it does not use angiotensin-converting enzyme 2 as a receptor to achieve infection. Additional research is urgently needed to better understand the pathogenicity and tissue tropism of this virus in humans. In their recent study published in mBio, Kindler et al. shed some light on these important topics (E. Kindler, H. R. Jónsdóttir, M. Muth, O. J. Hamming, R. Hartmann, R. Rodriguez, R. Geffers, R. A. Fouchier, C. Drosten, M. A. Müller, R. Dijkman, and V. Thiel, mBio 4[1]:e00611-12, 2013). These authors report the use of differentiated pseudostratified human primary airway epithelial cells, an in vitro model with high physiological relevance to the human airway epithelium, to characterize the cellular tropism of HCoV-EMC. More importantly, the authors demonstrate the potential use of type I and type III interferons (IFNs) to control viral infection.

scholarly journals Early nasal type I IFN immunity against SARS-CoV-2 is compromised in patients with autoantibodies against type I IFNs

2021 ◽  
Vol 218 (10) ◽  
Author(s):  
Jonathan Lopez ◽  
Marine Mommert ◽  
William Mouton ◽  
Andrés Pizzorno ◽  
Karen Brengel-Pesce ◽  
...  
Keyword(s):  
Airway Epithelium ◽  
Type I ◽  
Nasal Type ◽  
Viral Loads ◽  
Functional Assays ◽  
Human Airway Epithelium ◽  
Type I Ifns ◽  
Antiviral Effects ◽  
Nasopharyngeal Mucosa

IFN-I and IFN-III immunity in the nasal mucosa is poorly characterized during SARS-CoV-2 infection. We analyze the nasal IFN-I/III signature, namely the expression of ISGF-3–dependent IFN-stimulated genes, in mildly symptomatic COVID-19 patients and show its correlation with serum IFN-α2 levels, which peak at symptom onset and return to baseline from day 10 onward. Moreover, the nasal IFN-I/III signature correlates with the nasopharyngeal viral load and is associated with the presence of infectious viruses. By contrast, we observe low nasal IFN-I/III scores despite high nasal viral loads in a subset of critically ill COVID-19 patients, which correlates with the presence of autoantibodies (auto-Abs) against IFN-I in both blood and nasopharyngeal mucosa. In addition, functional assays in a reconstituted human airway epithelium model of SARS-CoV-2 infection confirm the role of such auto-Abs in abrogating the antiviral effects of IFN-I, but not those of IFN-III. Thus, IFN-I auto-Abs may compromise not only systemic but also local antiviral IFN-I immunity at the early stages of SARS-CoV-2 infection.

scholarly journals Limited In Vivo Production of Type I or Type III Interferon After Infection of Macaques with Vaccine or Wild-Type Strains of Measles Virus

2015 ◽  
Vol 35 (4) ◽  
pp. 292-301 ◽  
Author(s):  
Rupak Shivakoti ◽  
Debra Hauer ◽  
Robert J. Adams ◽  
Wen-Hsuan W. Lin ◽  
William Paul Duprex ◽  
...  
Keyword(s):  
Measles Virus ◽  
Type I ◽  
Wild Type ◽  
Type Iii ◽  
Type Iii Interferon ◽  
Type Strains

scholarly journals Infection with human coronavirus NL63 enhances streptococcal adherence to epithelial cells

2011 ◽  
Vol 92 (6) ◽  
pp. 1358-1368 ◽  
Author(s):  
Anna Golda ◽  
Natalia Malek ◽  
Bartosz Dudek ◽  
Slawomir Zeglen ◽  
Jacek Wojarski ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Airway Epithelium ◽  
Viral Infections ◽  
Platelet Activating Factor ◽  
Virus Infected Cell ◽  
Human Coronavirus ◽  
Bacterial Pathogenicity ◽  
Human Airway Epithelium ◽  
Detailed Evaluation ◽  
Respiratory Tract Illnesses

Understanding the mechanisms of augmented bacterial pathogenicity in post-viral infections is the first step in the development of an effective therapy. This study assessed the effect of human coronavirus NL63 (HCoV-NL63) on the adherence of bacterial pathogens associated with respiratory tract illnesses. It was shown that HCoV-NL63 infection resulted in an increased adherence of Streptococcus pneumoniae to virus-infected cell lines and fully differentiated primary human airway epithelium cultures. The enhanced binding of bacteria correlated with an increased expression level of the platelet-activating factor receptor (PAF-R), but detailed evaluation of the bacterium–PAF-R interaction revealed a limited relevance of this process.

scholarly journals The Role of Type III Interferons in Hepatitis C Virus Infection and Therapy

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Janina Bruening ◽  
Bettina Weigel ◽  
Gisa Gerold
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Infection ◽  
Current Knowledge ◽  
Tissue Expression ◽  
Innate Immune ◽  
Human Interferon ◽  
Classical Type ◽  
Type I ◽  
Type Iii

The human interferon (IFN) response is a key innate immune mechanism to fight virus infection. IFNs are host-encoded secreted proteins, which induce IFN-stimulated genes (ISGs) with antiviral properties. Among the three classes of IFNs, type III IFNs, also called IFN lambdas (IFNLs), are an essential component of the innate immune response to hepatitis C virus (HCV). In particular, human polymorphisms in IFNL gene loci correlate with hepatitis C disease progression and with treatment response. To date, the underlying mechanisms remain mostly elusive; however it seems clear that viral infection of the liver induces IFNL responses. As IFNL receptors show a more restricted tissue expression than receptors for other classes of IFNs, IFNL treatment has reduced side effects compared to the classical type I IFN treatment. In HCV therapy, however, IFNL will likely not play an important role as highly effective direct acting antivirals (DAA) exist. Here, we will review our current knowledge on IFNL gene expression, protein properties, signaling, ISG induction, and its implications on HCV infection and treatment. Finally, we will discuss the lessons learnt from the HCV and IFNL field for virus infections beyond hepatitis C.

PS1-53 Analysis of Type I and Type III interferon in sera from autoimmune diseases

Cytokine ◽  
2010 ◽  
Vol 52 (1-2) ◽  
pp. 28
Author(s):  
Thomas B. Lavoie ◽  
Yognandan Pandya ◽  
Michael Skawinski ◽  
Sara Crisafulli Cabatu ◽  
Jessica Esposito ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Type I ◽  
Type Iii ◽  
Type Iii Interferon

scholarly journals Rotavirus susceptibility of antibiotic-treated mice ascribed to diminished expression of interleukin-22

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0247738
Author(s):  
Daniel Schnepf ◽  
Pedro Hernandez ◽  
Tanel Mahlakõiv ◽  
Stefania Crotta ◽  
Meagan E. Sullender ◽  
...  
Keyword(s):  
Antiviral Effect ◽  
Innate Immune ◽  
Fine Tuning ◽  
Type I ◽  
Innate Immune Responses ◽  
Wild Type ◽  
Interleukin 22 ◽  
Commensal Microbiota ◽  
Type Iii Interferon ◽  
Deficient Mice

The commensal microbiota regulates susceptibility to enteric pathogens by fine-tuning mucosal innate immune responses, but how susceptibility to enteric viruses is shaped by the microbiota remains incompletely understood. Past reports have indicated that commensal bacteria may either promote or repress rotavirus replication in the small intestine of mice. We now report that rotavirus replicated more efficiently in the intestines of germ-free and antibiotic-treated mice compared to animals with an unmodified microbiota. Antibiotic treatment also facilitated rotavirus replication in type I and type III interferon (IFN) receptor-deficient mice, revealing IFN-independent proviral effects. Expression of interleukin-22 (IL-22) was strongly diminished in the intestine of antibiotic-treated mice. Treatment with exogenous IL-22 blocked rotavirus replication in microbiota-depleted wild-type and Stat1-/- mice, demonstrating that the antiviral effect of IL-22 in animals with altered microbiome is not dependent on IFN signaling. In antibiotic-treated animals, IL-22-induced a specific set of genes including Fut2, encoding fucosyl-transferase 2 that participates in the biosynthesis of fucosylated glycans which can mediate rotavirus binding. Interestingly, IL-22 also blocked rotavirus replication in antibiotic-treated Fut2-/- mice. Furthermore, IL-22 inhibited rotavirus replication in antibiotic-treated mice lacking key molecules of the necroptosis or pyroptosis pathways of programmed cell death. Taken together, our results demonstrate that IL-22 determines rotavirus susceptibility of antibiotic-treated mice, yet the IL-22-induced effector molecules conferring rotavirus resistance remain elusive.

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