scholarly journals Prominent Amphibian (Xenopus laevis) Tadpole Type III Interferon Response to the Frog Virus 3 Ranavirus

2015 ◽  
Vol 89 (9) ◽  
pp. 5072-5082 ◽  
Author(s):  
Leon Grayfer ◽  
Francisco De Jesús Andino ◽  
Jacques Robert
Keyword(s):  
Gene Expression ◽  
Xenopus Laevis ◽  
Receptor Gene ◽  
Type I ◽  
Type I Ifn ◽  
Content Type ◽  
Frog Virus ◽  
Type Iii ◽  
Type Iii Ifn ◽  
Type Iii Interferon

ABSTRACTRanaviruses (Iridoviridae) are posing an increasing threat to amphibian populations, with anuran tadpoles being particularly susceptible to these viral infections. Moreover, amphibians are the most basal phylogenetic class of vertebrates known to possess both type I and type III interferon (IFN)-mediated immunity. Moreover, little is known regarding the respective roles of the IFN mediators in amphibian antiviral defenses. Accordingly, we transcriptionally and functionally compared the amphibianXenopus laevistype I (IFN) and III (IFN-λ) IFNs in the context of infections by the ranavirus frog virus 3 (FV3).X. laevisIFN and IFN-λ displayed distinct tissue expression profiles. In contrast to our previous findings thatX. laevistadpoles exhibit delayed and modest type I IFN responses to FV3 infections compared to the responses of adults, here we report that tadpoles mount timely and robust type III IFN gene responses. Recombinant forms of these cytokines (recombinantX. laevisIFN [rXlIFN] and rXlIFN-λ) elicited antiviral gene expression in the kidney-derived A6 cell line as well as in tadpole leukocytes and tissues. However, rXlIFN-λ was less effective than rXlIFN in preventing FV3 replication in A6 cells and tadpoles and inferior at promoting tadpole survival. Intriguingly, FV3 impaired A6 cell and tadpole kidney type III IFN receptor gene expression. Furthermore, in A6 cultures rXlIFN-λ conferred equal or greater protection than rXlIFN against recombinant viruses deficient for the putative immune evasion genes, the viral caspase activation and recruitment domain (vCARD) or a truncated vIF-2α gene. Thus, in contrast to previous assumptions, tadpoles possess intact antiviral defenses reliant on type III IFNs, which are overcome by FV3 pathogens.IMPORTANCEAnuran tadpoles, including those ofXenopus laevis, are particularly susceptible to infection by ranavirus such as FV3. We investigated the respective roles ofX. laevistype I and type III interferons (IFN and IFN-λ, respectively) during FV3 infections. Notably, tadpoles mounted timely and more robust IFN-λ gene expression responses to FV3 than adults, contrasting with the poorer tadpole type I IFN responses. However, a recombinantX. laevisIFN-λ (rXlIFN-λ) conferred less protection to tadpoles and the A6 cell line than rXlIFN, which may be explained by the FV3 impairment of IFN-λ receptor gene expression. The importance of IFN-λ in tadpole anti-FV3 defenses is underlined by the critical involvement of two putative immune evasion genes in FV3 resistance to IFN- and IFN-λ-mediated responses. These findings challenge the view that tadpoles have defective antiviral immunity and suggest, rather, that their antiviral responses are predominated by IFN-λ responses, which are overcome by FV3.

scholarly journals Amphibian (Xenopus laevis) Tadpoles and Adult Frogs Differ in Their Use of Expanded Repertoires of Type I and Type III Interferon Cytokines

Viruses ◽  
2018 ◽  
Vol 10 (7) ◽  
pp. 372 ◽  
Author(s):  
Emily Wendel ◽  
Amulya Yaparla ◽  
Mattie Melnyk ◽  
Daphne Koubourli ◽  
Leon Grayfer
Keyword(s):  
Xenopus Laevis ◽  
Antiviral Immunity ◽  
Distinct Pattern ◽  
Receptor Expression ◽  
Type I ◽  
Isolated Cells ◽  
Frog Virus ◽  
Type Iii ◽  
Adult Frog ◽  
Type Iii Interferon

While amphibians around the globe are facing catastrophic declines, in part because of infections with pathogens such as the Frog Virus 3 (FV3) ranavirus; the mechanisms governing amphibian susceptibility and resistance to such pathogens remain poorly understood. The type I and type III interferon (IFN) cytokines represent a cornerstone of vertebrate antiviral immunity, while our recent work indicates that tadpoles and adult frogs of the amphibian Xenopus laevis may differ in their IFN responses to FV3. In this respect, it is notable that anuran (frogs and toads) tadpoles are significantly more susceptible to FV3 than adult frogs, and thus, gaining greater insight into the differences in the tadpole and adult frog antiviral immunity would be invaluable. Accordingly, we examined the FV3-elicited expression of a panel of type I and type III IFN genes in the skin (site of FV3 infection) and kidney (principal FV3 target) tissues and isolated cells of X. laevis tadpoles and adult frogs. We also examined the consequence of tadpole and adult frog skin and kidney cell stimulation with hallmark pathogen-associated molecular patterns (PAMPs) on the IFN responses of these cells. Together, our findings indicate that tadpoles and adult frogs mount drastically distinct IFN responses to FV3 as well as to viral and non-viral PAMPs, while these expression differences do not appear to be the result of a distinct pattern recognition receptor expression by tadpoles and adults.

scholarly journals Type III Interferon (IFN) Induces a Type I IFN-Like Response in a Restricted Subset of Cells through Signaling Pathways Involving both the Jak-STAT Pathway and the Mitogen-Activated Protein Kinases

2007 ◽  
Vol 81 (14) ◽  
pp. 7749-7758 ◽  
Author(s):  
Zhangle Zhou ◽  
Ole J. Hamming ◽  
Nina Ank ◽  
Søren R. Paludan ◽  
Anders L. Nielsen ◽  
...  
Keyword(s):  
Map Kinases ◽  
Detailed Comparison ◽  
Family Type ◽  
Type I ◽  
Type I Ifn ◽  
Expression Array ◽  
Type Iii ◽  
Mitogen Activated Protein ◽  
Type Iii Ifn ◽  
Type Iii Interferon

ABSTRACT Type III interferon (IFN) is a novel member of the interferon family. Type III IFN utilizes a receptor complex different from that of type I IFN, but both types of IFN induce STAT1, STAT2, and STAT3 activation. Here we describe a detailed comparison of signal transduction initiated by type I and type III IFN. Gene expression array analysis showed that IFN types I and III induced a similar subset of genes. In particular, no genes were induced uniquely by type III IFN. Next, we used chromatin immunoprecipitation (ChIP) analysis to investigate the promoter activation by types I and III IFN. The ChIP assays demonstrated that stimulation of cells with both type I and type III IFN resulted in the recruitment of ISGF3 transcription factor components to the promoter region of responsive genes and in an increase of polymerase II loading and histone acetylation. Whereas IFN type I signaling was observed for a broad spectrum of cell lines, type III IFN signaling was more restricted. The lack of IFN type III signaling was correlated with a low expression of the IL28Ra component of the IFN type III receptor, and IL28Ra overexpression was sufficient to restore IFN type III signaling. We also tested the activation of mitogen-activated protein (MAP) kinases by type III IFN and found that type III IFN relies strongly upon both p38 and JNK MAP kinases for gene induction.

scholarly journals 975. Roles of Type I and III Interferon in Severe Pathogenesis of Human Metapneumovirus

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S34-S35
Author(s):  
John V Williams ◽  
Yu Zhang ◽  
Jiuyang Xu ◽  
Margot Miranda-Katz ◽  
Helen Rich ◽  
...  
Keyword(s):  
Weight Loss ◽  
Disease Severity ◽  
Severe Disease ◽  
Human Metapneumovirus ◽  
Mouse Strains ◽  
Type I ◽  
Viral Titer ◽  
Type I Ifn ◽  
Type Iii ◽  
Type Iii Ifn

Abstract Background Human metapneumovirus (HMPV) is a leading cause of respiratory tract infection in children and adults. However, mechanisms of pathogenesis are not fully understood. Methods We tested HMPV clinical and laboratory isolates in an established C57BL/6 mouse model and measured weight loss, airway function, and viral titers. Immune responses were determined using cytokine quantitation and flow cytometry. Results HMPV clinical isolates induced variable disease severity ranging from mild to fatal disease. Laboratory strain TN/94-49 did not cause weight loss, but mice infected with clinical isolate C2-202 showed dramatic weight loss and 40% mortality within 5 days post-infection (Figure 1). These findings were confirmed in other inbred mouse strains. C2-202-infected mice also suffered from impaired pulmonary function post-recovery. Lung viral titer did not correlate with disease severity, suggesting immune-mediated pathogenesis. C2-202-infected mice exhibited increased production of type I and III interferons (IFN) and pro-inflammatory cytokines, and lung neutrophil infiltration. However, neutrophil depletion or inflammasome inactivation did not reduce disease. Stat1/Stat2 double knockout (KO) mice lacking type I and III IFN signaling exhibited reduced weight loss but increased lung viral titer after C2-202 infection (Figure 2). Type I IFN receptor (IFNAR) KO mice infected with C2-202 had reduced weight loss but unchanged lung viral titer (Figure 3), while the addition of type III IFN blockade to C2-202-infected IFNAR mice had no effect on disease but increased lung viral titer (Figure 4). Conclusion These results suggest that severe disease caused by virulent HMPV was due to exuberant IFN response. Moreover, type I IFN was primarily associated with disease, while type III IFN was associated with viral clearance. These data suggest that IFN signaling plays an important role in HMPV pathogenesis, and thus serves as a potential therapeutic target. Disclosures All Authors: No reported Disclosures.

scholarly journals A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection

2017 ◽  
Vol 114 (4) ◽  
pp. E570-E579 ◽  
Author(s):  
Kapil Saxena ◽  
Lukas M. Simon ◽  
Xi-Lei Zeng ◽  
Sarah E. Blutt ◽  
Sue E. Crawford ◽  
...  
Keyword(s):  
Enteric Virus ◽  
Type I ◽  
Type I Ifn ◽  
Type Iii ◽  
Specific Pathogen ◽  
Type Iii Ifn ◽  
Ifn Treatment ◽  
Transcriptional Pathway ◽  
Interferon Responses

The intestinal epithelium can limit enteric pathogens by producing antiviral cytokines, such as IFNs. Type I IFN (IFN-α/β) and type III IFN (IFN-λ) function at the epithelial level, and their respective efficacies depend on the specific pathogen and site of infection. However, the roles of type I and type III IFN in restricting human enteric viruses are poorly characterized as a result of the difficulties in cultivating these viruses in vitro and directly obtaining control and infected small intestinal human tissue. We infected nontransformed human intestinal enteroid cultures from multiple individuals with human rotavirus (HRV) and assessed the host epithelial response by using RNA-sequencing and functional assays. The dominant transcriptional pathway induced by HRV infection is a type III IFN-regulated response. Early after HRV infection, low levels of type III IFN protein activate IFN-stimulated genes. However, this endogenous response does not restrict HRV replication because replication-competent HRV antagonizes the type III IFN response at pre- and posttranscriptional levels. In contrast, exogenous IFN treatment restricts HRV replication, with type I IFN being more potent than type III IFN, suggesting that extraepithelial sources of type I IFN may be the critical IFN for limiting enteric virus replication in the human intestine.

scholarly journals Combined action of type I and type III interferon restricts initial replication of severe acute respiratory syndrome coronavirus in the lung but fails to inhibit systemic virus spread

2012 ◽  
Vol 93 (12) ◽  
pp. 2601-2605 ◽  
Author(s):  
Tanel Mahlakõiv ◽  
Daniel Ritz ◽  
Markus Mordstein ◽  
Marta L. DeDiego ◽  
Luis Enjuanes ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Decisive Role ◽  
Type I ◽  
Double Knockout ◽  
Type Iii ◽  
Viral Spread ◽  
Combined Action ◽  
Type Iii Ifn ◽  
Type Iii Interferon ◽  
Deficient Mice

STAT1-deficient mice are more susceptible to infection with severe acute respiratory syndrome coronavirus (SARS-CoV) than type I interferon (IFN) receptor-deficient mice. We used mice lacking functional receptors for both type I and type III IFN (double knockout, dKO) to evaluate the possibility that type III IFN plays a decisive role in SARS-CoV protection. We found that viral peak titres in lungs of dKO and STAT1-deficient mice were similar, but significantly higher than in wild-type mice. The kinetics of viral clearance from the lung were also comparable in dKO and STAT1-deficient mice. Surprisingly, however, infected dKO mice remained healthy, whereas infected STAT1-deficient mice developed liver pathology and eventually succumbed to neurological disease. Our data suggest that the failure of STAT1-deficient mice to control initial SARS-CoV replication efficiently in the lung is due to impaired type I and type III IFN signalling, whereas the failure to control subsequent systemic viral spread is due to unrelated defects in STAT1-deficient mice.

scholarly journals Importance of Type I and III Interferons at Respiratory and Intestinal Barrier Surfaces

2020 ◽  
Vol 11 ◽  
Author(s):  
Megan L. Stanifer ◽  
Cuncai Guo ◽  
Patricio Doldan ◽  
Steeve Boulant
Keyword(s):  
Epithelial Cells ◽  
Intestinal Barrier ◽  
The Body ◽  
Type I ◽  
Type I Ifn ◽  
Type Iii ◽  
Interferon Stimulated Genes ◽  
Mucosal Surfaces ◽  
Microbial Infections ◽  
Type Iii Ifn

Interferons (IFNs) constitute the first line of defense against microbial infections particularly against viruses. They provide antiviral properties to cells by inducing the expression of hundreds of genes known as interferon-stimulated genes (ISGs). The two most important IFNs that can be produced by virtually all cells in the body during intrinsic innate immune response belong to two distinct families: the type I and type III IFNs. The type I IFN receptor is ubiquitously expressed whereas the type III IFN receptor’s expression is limited to epithelial cells and a subset of immune cells. While originally considered to be redundant, type III IFNs have now been shown to play a unique role in protecting mucosal surfaces against pathogen challenges. The mucosal specific functions of type III IFN do not solely rely on the restricted epithelial expression of its receptor but also on the distinct means by which type III IFN mediates its anti-pathogen functions compared to the type I IFN. In this review we first provide a general overview on IFNs and present the similarities and differences in the signal transduction pathways leading to the expression of either type I or type III IFNs. By highlighting the current state-of-knowledge of the two archetypical mucosal surfaces (e.g. the respiratory and intestinal epitheliums), we present the differences in the signaling cascades used by type I and type III IFNs to uniquely induce the expression of ISGs. We then discuss in detail the role of each IFN in controlling pathogen infections in intestinal and respiratory epithelial cells. Finally, we provide our perspective on novel concepts in the field of IFN (stochasticity, response heterogeneity, cellular polarization/differentiation and tissue microenvironment) that we believe have implications in driving the differences between type I and III IFNs and could explain the preferences for type III IFNs at mucosal surfaces.

scholarly journals Selective interferon responses of intestinal epithelial cells minimize TNFα cytotoxicity

2020 ◽  
Author(s):  
Jacob A. Van Winkle ◽  
David A. Constant ◽  
Lena Li ◽  
Timothy J. Nice
Keyword(s):  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Neonatal Mouse ◽  
Type I ◽  
Intestinal Epithelial ◽  
Type I Ifn ◽  
Type Iii ◽  
Apoptotic Genes ◽  
Type Iii Ifn

ABSTRACTInterferon (IFN) family cytokines stimulate genes (ISGs) that are integral to antiviral host defense. Type I IFNs act systemically whereas type III IFNs act preferentially at epithelial barriers. Among barrier cells, intestinal epithelial cells (IECs) are particularly dependent on type III IFN for control and clearance of virus infection, but the physiological basis of this selective IFN response is not well understood. Here, we confirm that type III IFN treatment elicits robust and uniform ISG expression in neonatal mouse IECs and inhibits replication of IEC-tropic rotavirus. In contrast, type I IFN elicits a marginal ISG response in neonatal mouse IECs and does not inhibit rotavirus replication. In vitro treatment of IEC organoids with type III IFN results in ISG expression that mirrors the in vivo type III IFN response. However, the response of IEC organoids to type I IFN is strikingly increased relative to type III IFN in magnitude and scope. The expanded type I IFN-specific response includes pro-apoptotic genes and potentiates toxicity triggered by tumor necrosis factor alpha (TNFα). The ISGs stimulated in common by types I and III IFN have strong interferon-stimulated response element (ISRE) promoter motifs, whereas the expanded set of type I IFN-specific ISGs, including pro-apoptotic genes, have weak ISRE motifs. Thus, preferential responsiveness of IECs to type III IFN in vivo enables selective ISG expression during infection that confers antiviral protection but minimizes disruption of intestinal homeostasis.

scholarly journals Differential Gene Expression in Mice Infected with Distinct Toxoplasma Strains

2011 ◽  
Vol 80 (3) ◽  
pp. 968-974 ◽  
Author(s):  
Rachel D. Hill ◽  
Julia S. Gouffon ◽  
Arnold M. Saxton ◽  
Chunlei Su
Keyword(s):  
Gene Expression ◽  
Parasite Burden ◽  
Type I ◽  
Type Ii ◽  
Gene Expression Response ◽  
Content Type ◽  
Type Iii ◽  
Clonal Type ◽  
Expression Response ◽  
Macrophage Populations

Toxoplasma gondiiis the causative agent of toxoplasmosis in human and animals. In a mouse model,T. gondiistrains can be divided into three groups, including the virulent, intermediately virulent, and nonvirulent. The clonal type I, II, and IIIT. gondiistrains belong to these three groups, respectively. To better understand the basis of virulence phenotypes, we investigated mouse gene expression responses to the infection of differentT. gondiistrains at day 5 after intraperitoneal inoculation with 500 tachyzoites. The transcriptomes of mouse peritoneal cells showed that 1,927, 1,573, and 1,009 transcripts were altered more than 2-fold by type I, II, and III infections, respectively, and that the majority of altered transcripts were shared. Overall transcription patterns were similar in type I and type II infections, and both had greater changes than infection with type III. Quantification of parasite burden in mouse spleens showed that the burden with type I infection was 1,000 times higher than that of type II and that the type II burden was 20 times higher than that of type III. Fluorescence-activated cell sorting revealed that type I and II infections had comparable macrophage populations, and both were higher than the population with type III infection. In addition, type I infection had a higher percentage of neutrophils than type II and III infections. Taken together, these results suggested that there is a common gene expression response toT. gondiiinfection in mice. This response is further modified by parasite strain-specific factors that determine their distinct virulence phenotypes.

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