scholarly journals Murine interferon lambdas (type III interferons) exhibit potent antiviral activity in vivo in a poxvirus infection model

2005 ◽  
Vol 86 (6) ◽  
pp. 1589-1596 ◽  
Author(s):  
Nathan W. Bartlett ◽  
Karen Buttigieg ◽  
Sergei V. Kotenko ◽  
Geoffrey L. Smith
Keyword(s):  
Virus Infection ◽  
Antiviral Activity ◽  
Janus Kinase ◽  
Human Interferon ◽  
Infection Model ◽  
Type I ◽  
Type Iii ◽  
Potent Antiviral Activity ◽  
Cell Extracts

Human interferon lambdas (IFN-λs) (type III IFNs) exhibit antiviral activity in vitro by binding to a receptor complex distinct from that used by type I and type II IFNs, and subsequent signalling through the Janus kinase signal transducers and activators of transcription (STAT) pathway. However, evidence for a function of type III IFNs during virus infection in vivo is lacking. Here, the expression of murine IFN-λs by recombinant vaccinia virus (VACV) is described and these proteins are shown to have potent antiviral activity in vivo. VACV expressing murine IFN-λ2 (vIFN-λ2) and IFN-λ3 (vIFN-λ3) showed normal growth in tissue culture and expressed N-glycosylated IFN-λ in infected cell extracts and culture supernatants. The role that murine IFN-λs play during virus infection was assessed in two different mouse models. vIFN-λ2 and vIFN-λ3 were avirulent for mice infected intranasally and induced no signs of illness or weight loss, in contrast to control viruses. Attenuation of vIFN-λ2 was associated with increases in lymphocytes in bronchial alveolar lavages and CD4+ T cells in total-lung lymphocyte preparations. In addition, vIFN-λ2 was cleared more rapidly from infected lungs and, in contrast to control viruses, did not disseminate to the brain. Expression of IFN-λ2 also attenuated VACV in an intradermal-infection model, characterized by a delay in lesion onset and reduced lesion size. Thus, by characterizing murine IFN-λs within a mouse infection model, the potent antiviral and immunostimulatory activity of IFN-λs in response to poxvirus infection has been demonstrated.

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.

The In Vivo Source of Type I and Type III IFNs is Pathogen Dependent

2021 ◽  
Author(s):  
Marvin J. Sandoval ◽  
Hsiang-Chi Tseng ◽  
Heidi P. Risman ◽  
Sergey Smirnov ◽  
Qing Li ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Virus Infection ◽  
Respiratory Tract ◽  
Influenza A ◽  
Influenza Infection ◽  
Type I ◽  
Protective Effects ◽  
Type Iii

Type I (-α, β) and type III (-λ) interferons (IFNs) are produced in response to virus infection and upregulate a largely overlapping set of IFN stimulated genes which mediate the protective effects of these antiviral cytokines. In vitro studies have demonstrated the redundancy of these two cytokine families which activate the same transcription factor, IFN stimulated gene factor 3 (ISGF3), via distinct ligands and receptors. However, in vivo, these IFN types do have distinct functions based on receptor distribution, but also ligand availability. Using a newly generated IFN-λ reporter mouse strain we have observed that both type I and type III IFNs are produced in response to respiratory tract infection by Newcastle disease virus (NDV) and influenza A virus (IAV). In the case of NDV these IFNs are synthesized by different cell types. Type I IFNs are produced primarily by alveolar macrophages, type III IFNs are made only by epithelial cells, and production of either is dependent on MAVS. While epithelial cells of the respiratory tract represent the primary target of IAV infection, we found that they did not significantly contribute to IFN-λ production, and IFN-λ protein levels were largely unaffected in the absence of MAVS. Instead we found that pDCs, a cell type known for robust IFN-α production via TLR/MyD88 signaling, were the major producers of IFN-λ during IAV infection, with pDC depletion during influenza infection resulting in significantly reduced levels of both IFN-α and IFN-λ. In addition, we were able to demonstrate that pDCs rely on type I IFN for optimal IFN-λ production. These studies therefore demonstrate that the in vivo producers of Type III IFNs in response to respiratory virus infection are pathogen dependent, a finding which may explain the varying levels of cytokine production induced by different viral pathogens.

scholarly journals Lambda Interferon (IFN-λ), a Type III IFN, Is Induced by Viruses and IFNs and Displays Potent Antiviral Activity against Select Virus Infections In Vivo

2006 ◽  
Vol 80 (9) ◽  
pp. 4501-4509 ◽  
Author(s):  
Nina Ank ◽  
Hans West ◽  
Christina Bartholdy ◽  
Kristina Eriksson ◽  
Allan R. Thomsen ◽  
...  
Keyword(s):  
Viral Load ◽  
Antiviral Activity ◽  
Encephalomyocarditis Virus ◽  
In Vitro Assays ◽  
Vaginal Mucosa ◽  
Virus Infections ◽  
Type Iii ◽  
Potent Antiviral Activity

ABSTRACT Type III interferons (IFNs) (interleukin-28/29 or lambda interferon [IFN-λ]) are cytokines with IFN-like activities. Here we show that several classes of viruses induce expression of IFN-λ1 and -λ2/3 in similar patterns. The IFN-λs were—unlike alpha/beta interferon (IFN-α/β)—induced directly by stimulation with IFN-α or -λ, thus identifying type III IFNs as IFN-stimulated genes. In vitro assays revealed that IFN-λs have appreciable antiviral activity against encephalomyocarditis virus (EMCV) but limited activity against herpes simplex virus type 2 (HSV-2), whereas IFN-α potently restricted both viruses. Using three murine models for generalized virus infections, we found that while recombinant IFN-α reduced the viral load after infection with EMCV, lymphocytic choriomeningitis virus (LCMV), and HSV-2, treatment with recombinant IFN-λ in vivo did not affect viral load after infection with EMCV or LCMV but did reduce the hepatic viral titer of HSV-2. In a model for a localized HSV-2 infection, we further found that IFN-λ completely blocked virus replication in the vaginal mucosa and totally prevented development of disease, in contrast to IFN-α, which had a more modest antiviral activity. Finally, pretreatment with IFN-λ enhanced the levels of IFN-γ in serum after HSV-2 infection. Thus, type III IFNs are expressed in response to most viruses and display potent antiviral activity in vivo against select viruses. The discrepancy between the observed antiviral activity in vitro and in vivo may suggest that IFN-λ exerts a significant portion of its antiviral activity in vivo via stimulation of the immune system rather than through induction of the antiviral state.

scholarly journals Oyster viperin retains direct antiviral activity and its transcription occurs via a signalling pathway involving a heat-stable haemolymph protein

2015 ◽  
Vol 96 (12) ◽  
pp. 3587-3597 ◽  
Author(s):  
Timothy J. Green ◽  
Peter Speck ◽  
Lu Geng ◽  
David Raftos ◽  
Michael R. Beard ◽  
...  
Keyword(s):  
Immune System ◽  
Virus Infection ◽  
Antiviral Activity ◽  
Innate Immune System ◽  
Innate Immune ◽  
Type I ◽  
Regulatory Factor ◽  
Antiviral Protein ◽  
Caveolin 1 ◽  
Heat Stable

Little is known about the response of non-model invertebrates, such as oysters, to virus infection. The vertebrate innate immune system detects virus-derived nucleic acids to trigger the type I IFN pathway, leading to the transcription of hundreds of IFN-stimulated genes (ISGs) that exert antiviral functions. Invertebrates were thought to lack the IFN pathway based on the absence of IFN or ISGs encoded in model invertebrate genomes. However, the oyster genome encodes many ISGs, including the well-described antiviral protein viperin. In this study, we characterized oyster viperin and showed that it localizes to caveolin-1 and inhibits dengue virus replication in a heterologous model. In a second set of experiments, we have provided evidence that the haemolymph from poly(I : C)-injected oysters contains a heat-stable, protease-susceptible factor that induces haemocyte transcription of viperin mRNA in conjunction with upregulation of IFN regulatory factor. Collectively, these results support the concept that oysters have antiviral systems that are homologous to the vertebrate IFN pathway.

scholarly journals Novel Mode of ISG15-Mediated Protection against Influenza A Virus and Sendai Virus in Mice

2014 ◽  
Vol 89 (1) ◽  
pp. 337-349 ◽  
Author(s):  
David J. Morales ◽  
Kristen Monte ◽  
Lulu Sun ◽  
Jessica J. Struckhoff ◽  
Eugene Agapov ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Virus Replication ◽  
Influenza A ◽  
Type I Interferon ◽  
Sendai Virus ◽  
Type I ◽  
Induced Genes

ABSTRACTISG15 is a diubiquitin-like modifier and one of the most rapidly induced genes upon type I interferon stimulation. Hundreds of host proteins and a number of viral proteins have been shown to be ISGylated, and understanding how these modifications affect the interferon response and virus replication has been of considerable interest. ISG15−/−mice exhibit increased susceptibility to viral infection, and in the case of influenza B virus and vaccinia virus, ISG15 conjugation has been shown to restrict virus replicationin vivo. A number of studies have also found that ISG15 is capable of antagonizing replication of some viruses in tissue culture. However, recent findings have demonstrated that ISG15 can protect mice from Chikungunya virus infection without affecting the virus burden. In order to better understand the function of ISG15in vivo, we characterized the pathogenesis of influenza A virus and Sendai virus in ISG15−/−mice. We found that ISG15 protects mice from virus induced lethality by a conjugation-dependent mechanism in both of these models. However, surprisingly, we found that ISG15 had minimal effect on virus replication and did not have an obvious role in the modulation of the acute immune response to infection. Instead, we observed an increase in the number of diseased small airways in mice lacking ISG15. This ability of ISG15 to protect mice in a conjugation-dependent, but nonantiviral, manner from respiratory virus infection represents a previously undescribed role for ISG15 and demonstrates the importance of further characterization of ISG15in vivo.IMPORTANCEIt has previously been demonstrated that ISG15−/−mice are more susceptible to a number of viral infections. Since ISG15 is one of the most strongly induced genes after type I interferon stimulation, analysis of ISG15 function has largely focused on its role as an antiviral molecule during acute infection. Although a number of studies have shown that ISG15 does have a small effect on virus replication in tissue culture, few studies have confirmed this mechanism of protectionin vivo. In these studies we have found that while ISG15−/−mice are more susceptible to influenza A virus and Sendai virus infections, ISGylation does not appear to mediate this protection through the direct inhibition of virus replication or the modulation of the acute immune response. Thus, in addition to showing a novel mode of ISG15 mediated protection from virus infection, this study demonstrates the importance of studying the role of ISG15in vivo.

Type VI collagen induces cardiac myofibroblast differentiation: implications for postinfarction remodeling

2006 ◽  
Vol 290 (1) ◽  
pp. H323-H330 ◽  
Author(s):  
Jennifer E. Naugle ◽  
Erik R. Olson ◽  
Xiaojin Zhang ◽  
Sharon E. Mase ◽  
Charles F. Pilati ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Type I Collagen ◽  
In Vivo Model ◽  
Type Iii Collagen ◽  
Type I ◽  
Myofibroblast Differentiation ◽  
Type Vi Collagen ◽  
Collagen Substrate ◽  
Type Iii

Cardiac fibroblast (CF) proliferation and differentiation into hypersecretory myofibroblasts can lead to excessive extracellular matrix (ECM) production and cardiac fibrosis. In turn, the ECM produced can potentially activate CFs via distinct feedback mechanisms. To assess how specific ECM components influence CF activation, isolated CFs were plated on specific collagen substrates (type I, III, and VI collagens) before functional assays were carried out. The type VI collagen substrate potently induced myofibroblast differentiation but had little effect on CF proliferation. Conversely, the type I and III collagen substrates did not affect differentiation but caused significant induction of proliferation (type I, 240.7 ± 10.3%, and type III, 271.7 ± 21.8% of basal). Type I collagen activated ERK1/2, whereas type III collagen did not. Treatment of CFs with angiotensin II, a potent mitogen of CFs, enhanced the growth observed on types I and III collagen but not on the type VI collagen substrate. Using an in vivo model of myocardial infarction (MI), we measured changes in type VI collagen expression and myofibroblast differentiation after post-MI remodeling. Concurrent elevations in type VI collagen and myofibroblast content were evident in the infarcted myocardium 20-wk post-MI. Overall, types I and III collagen stimulate CF proliferation, whereas type VI collagen plays a potentially novel role in cardiac remodeling through facilitation of myofibroblast differentiation.

Establishment of Full-length cDNA Clones and an Efficient Oral Infection Model for Feline Coronavirus in Cats

2021 ◽  
Author(s):  
Gang Wang ◽  
Guangli Hu ◽  
Rui Liang ◽  
Jiale Shi ◽  
Xiuxiu Qiu ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Full Length ◽  
Infection Model ◽  
Type I ◽  
Feline Infectious Peritonitis ◽  
Spike Gene ◽  
Full Length Cdna ◽  
Adult Cats

Feline infectious peritonitis virus (FIPV) is the etiologic agent of feline infectious peritonitis (FIP) and causes fatal disease in cats of almost all ages. Currently, there are no clinically approved drugs or effective vaccines for FIP. Furthermore, the pathogenesis of FIP is still not fully understood. There is an urgent need for an effective infection model of feline infectious peritonitis induced by FIPV. Here, we constructed a field type I FIPV full-length cDNA clone, pBAC-QS, corresponding to the isolated FIPV QS. By replacing the FIPV QS spike gene with the commercially available type II FIPV 79-1146 (79-1146_CA) spike gene, we established and rescued a recombinant virus, designated rQS-79. Moreover, we constructed 79-1146_CA infectious full-length cDNA pBAC-79-1146_CA, corresponding to recombinant FCoV 79-1146_CA (r79-1146_CA). In animal experiments with one- to two-year-old adult cats orally infected with the recombinant virus, rQS-79 induced typical FIP signs and 100% mortality. In contrast to cats infected with rQS-79, cats infected with 79-1146_CA did not show obvious signs. Furthermore, by rechallenging rQS-79 in surviving cats previously infected with 79-1146_CA, we found that there was no protection against rQS-79 with different titers of neutralizing antibodies. However, high titers of neutralizing antibodies may help prolong the cat survival time. Overall, we report the first reverse genetics of virulent recombinant FCoV (causing 100% mortality in adult cats) and attenuated FCoV (causing no mortality in adult cats), which will be powerful tools to study the pathogenesis, antiviral drugs and vaccines for FCoV. Importance Tissue- or cell culture-adapted feline infectious peritonitis virus (FIPV) usually loses pathogenicity. To develop a highly virulent FIPV, we constructed a field isolate type I FIPV full-length clone with the spike gene replaced by the 79-1146 spike gene, corresponding to a virus named rQS-79, which induces high mortality in adult cats. rQS-79 represents the first described reverse genetics system for highly pathogenic FCoV. By further constructing the cell culture-adapted FCoV 79-1146_CA, we obtained infectious clones of virulent and attenuated FCoV. By in vitro and in vivo experiments, we established a model that can serve to study the pathogenic mechanisms of FIPV. Importantly, the wild-type FIPV replicase skeleton of serotype I will greatly facilitate the screening of antiviral drugs, both in vivo and in vitro.

scholarly journals Autophagy Contributes to Host Immunity and Protection against Zika Virus Infection via Type I IFN Signaling

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Yuyi Huang ◽  
Yujie Wang ◽  
Shuhui Meng ◽  
Zhuohang Chen ◽  
Haifan Kong ◽  
...  
Keyword(s):  
Virus Infection ◽  
Cell Line ◽  
Zika Virus ◽  
Fetal Brain ◽  
Host Immunity ◽  
Type I ◽  
Type I Ifn ◽  
Zikv Infection

Recent studies have indicated that the Zika virus (ZIKV) has a significant impact on the fetal brain, and autophagy is contributing to host immune response and defense against virus infection. Here, we demonstrate that ZIKV infection triggered increased LC3 punctuation in mouse monocyte-macrophage cell line (RAW264.7), mouse microglial cell line (BV2), and hindbrain tissues, proving the occurrence of autophagy both in vitro and in vivo. Interestingly, manual intervention of autophagy, like deficiency inhibited by 3-MA, can reduce viral clearance in RAW264.7 cells upon ZIKV infection. Besides, specific siRNA strategy confirmed that autophagy can be activated through Atg7-Atg5 and type I IFN signaling pathway upon ZIKV infection, while knocking down of Atg7 and Atg5 effectively decreased the ZIKV clearance in phagocytes. Furthermore, we analyzed that type I IFN signaling could contribute to autophagic clearance of invaded ZIKV in phagocytes. Taken together, our findings demonstrate that ZIKV-induced autophagy is favorable to activate host immunity, particularly through type I IFN signaling, which participates in host protection and defense against ZIKV infection.

scholarly journals Heavily Armed Ancestors: CRISPR Immunity and Applications in Archaea with a Comparative Analysis of CRISPR Types in Sulfolobales

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1523
Author(s):  
Isabelle Anna Zink ◽  
Erika Wimmer ◽  
Christa Schleper
Keyword(s):  
Comparative Analysis ◽  
Molecular Mechanisms ◽  
Model Organisms ◽  
Special Focus ◽  
Natural Environments ◽  
Type I ◽  
Accessory Proteins ◽  
Type Iii

Prokaryotes are constantly coping with attacks by viruses in their natural environments and therefore have evolved an impressive array of defense systems. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is an adaptive immune system found in the majority of archaea and about half of bacteria which stores pieces of infecting viral DNA as spacers in genomic CRISPR arrays to reuse them for specific virus destruction upon a second wave of infection. In detail, small CRISPR RNAs (crRNAs) are transcribed from CRISPR arrays and incorporated into type-specific CRISPR effector complexes which further degrade foreign nucleic acids complementary to the crRNA. This review gives an overview of CRISPR immunity to newcomers in the field and an update on CRISPR literature in archaea by comparing the functional mechanisms and abundances of the diverse CRISPR types. A bigger fraction is dedicated to the versatile and prevalent CRISPR type III systems, as tremendous progress has been made recently using archaeal models in discerning the controlled molecular mechanisms of their unique tripartite mode of action including RNA interference, DNA interference and the unique cyclic-oligoadenylate signaling that induces promiscuous RNA shredding by CARF-domain ribonucleases. The second half of the review spotlights CRISPR in archaea outlining seminal in vivo and in vitro studies in model organisms of the euryarchaeal and crenarchaeal phyla, including the application of CRISPR-Cas for genome editing and gene silencing. In the last section, a special focus is laid on members of the crenarchaeal hyperthermophilic order Sulfolobales by presenting a thorough comparative analysis about the distribution and abundance of CRISPR-Cas systems, including arrays and spacers as well as CRISPR-accessory proteins in all 53 genomes available to date. Interestingly, we find that CRISPR type III and the DNA-degrading CRISPR type I complexes co-exist in more than two thirds of these genomes. Furthermore, we identified ring nuclease candidates in all but two genomes and found that they generally co-exist with the above-mentioned CARF domain ribonucleases Csx1/Csm6. These observations, together with published literature allowed us to draft a working model of how CRISPR-Cas systems and accessory proteins cross talk to establish native CRISPR anti-virus immunity in a Sulfolobales cell.

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