scholarly journals Establishment of a Poliovirus Oral Infection System in Human Poliovirus Receptor-Expressing Transgenic Mice That Are Deficient in Alpha/Beta Interferon Receptor

2007 ◽  
Vol 81 (15) ◽  
pp. 7902-7912 ◽  
Author(s):  
Seii Ohka ◽  
Hiroko Igarashi ◽  
Noriyo Nagata ◽  
Mai Sakai ◽  
Satoshi Koike ◽  
...  
Keyword(s):  
Small Intestine ◽  
Transgenic Mice ◽  
Alimentary Tract ◽  
Oral Route ◽  
Oral Infection ◽  
Infection Model ◽  
Oral Infections ◽  
Beta Interferon ◽  
Interferon Receptor ◽  
Alpha Beta

ABSTRACT Poliovirus (PV) is easily transferred to humans orally; however, no rodent model for oral infections has been developed because of the alimentary tract's low sensitivity to the virus. Here we showed that PV is inactivated by the low pH of the gastric contents in mice. The addition of 3% NaHCO3 to the viral inoculum increased the titer of virus reaching the small intestine through the stomach after intragastric inoculation of PV. Transgenic mice (Tg) carrying the human PV receptor (hPVR/CD155) gene and lacking the alpha/beta interferon receptor (IFNAR) gene (hPVR-Tg/IfnarKO) were sensitive to the oral administration of PV with 3% NaHCO3, whereas hPVR-Tg expressing IFNAR were much less sensitive. The virus was detected in the epithelia of the small intestine and proliferated in the alimentary tract of hPVR-Tg/IfnarKO. By the ninth day after the administration of a virulent PV, the mice had died. These results suggest that IFNAR plays an important role in determining permissivity in the alimentary tract as well as the generation of virus-specific immune responses to PV via the oral route. Thus, hPVR-Tg/IfnarKO are considered to be the first oral infection model for PV, although levels of anti-PV antibodies were not elevated dramatically in serum and intestinal secretions of surviving mice when hPVR-Tg/IfnarKO were administered an attenuated PV.

scholarly journals Establishment of a Bluetongue Virus Infection Model in Mice that Are Deficient in the Alpha/Beta Interferon Receptor

PLoS ONE ◽  
2009 ◽  
Vol 4 (4) ◽  
pp. e5171 ◽  
Author(s):  
Eva Calvo-Pinilla ◽  
Teresa Rodríguez-Calvo ◽  
Juan Anguita ◽  
Noemí Sevilla ◽  
Javier Ortego
Keyword(s):  
Virus Infection ◽  
Bluetongue Virus ◽  
Infection Model ◽  
Beta Interferon ◽  
Interferon Receptor ◽  
Alpha Beta ◽  
Virus Infection Model

A recombinant DNA vaccine protects mice deficient in the alpha/beta interferon receptor against lethal challenge with Usutu virus

Vaccine ◽  
2016 ◽  
Vol 34 (18) ◽  
pp. 2066-2073 ◽  
Author(s):  
Miguel A. Martín-Acebes ◽  
Ana-Belén Blázquez ◽  
Rodrigo Cañas-Arranz ◽  
Ángela Vázquez-Calvo ◽  
Teresa Merino-Ramos ◽  
...  
Keyword(s):  
Dna Vaccine ◽  
Recombinant Dna ◽  
Lethal Challenge ◽  
Usutu Virus ◽  
Beta Interferon ◽  
Interferon Receptor ◽  
Alpha Beta

scholarly journals The Alpha/Beta Interferon Receptor Provides Protection against Influenza Virus Replication but Is Dispensable for Inflammatory Response Signaling

2009 ◽  
Vol 84 (4) ◽  
pp. 2027-2037 ◽  
Author(s):  
Alan G. Goodman ◽  
Hui Zeng ◽  
Sean C. Proll ◽  
Xinxia Peng ◽  
Cristian Cillóniz ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Viral Replication ◽  
Cellular Response ◽  
Viral Infections ◽  
Expression Profiles ◽  
Gamma Interferon ◽  
Interferon Production ◽  
Beta Interferon ◽  
Interferon Receptor ◽  
Alpha Beta

ABSTRACT The innate immune response provides the first line of defense against foreign pathogens by responding to molecules that are a signature of a pathogenic infection. Certain RNA viruses, such as influenza virus, produce double-stranded RNA as an intermediate during the replication life cycle, which activates pathogen recognition receptors capable of inducing interferon production. By engaging interferon receptors, interferon activates the JAK-STAT pathway and results in the positive feedback of interferon production, amplifying the response to viral infection. To examine how deficiencies in interferon signaling affect the cellular response to infection, we performed influenza virus infections of mouse embryonic fibroblasts lacking the alpha/beta interferon receptor, the gamma interferon receptor, or both. In the absence of the alpha/beta interferon receptor, we observed increased viral replication but decreased activation of PKR, Stat1, and NF-κB; the presence or absence of the gamma interferon receptor did not exhibit discernible differences in these readouts. Analysis of gene expression profiles showed that while cells lacking the alpha/beta interferon receptor exhibited decreased levels of transcription of antiviral genes, genes related to inflammatory and apoptotic responses were transcribed to levels similar to those of cells containing the receptor. These results indicate that while the alpha/beta interferon receptor is needed to curb viral replication, it is dispensable for the induction of certain inflammatory and apoptotic genes. We have identified potential pathways, via interferon regulatory factor 3 (IRF3) activation or Hoxa13, Polr2a, Nr4a1, or Ing1 induction, that contribute to this redundancy. This study illustrates another way in which the host has evolved to establish several overlapping mechanisms to respond to viral infections.

scholarly journals Human MxA Protein Protects Mice Lacking a Functional Alpha/Beta Interferon System against La Crosse Virus and Other Lethal Viral Infections

1999 ◽  
Vol 73 (8) ◽  
pp. 6984-6991 ◽  
Author(s):  
Hans Peter Hefti ◽  
Michael Frese ◽  
Heinrich Landis ◽  
Claudio Di Paolo ◽  
Adriano Aguzzi ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Semliki Forest Virus ◽  
Viral Infections ◽  
Antiviral Agent ◽  
Virus Multiplication ◽  
La Crosse Virus ◽  
Beta Interferon ◽  
Alpha Beta ◽  
Induced Proteins

ABSTRACT The human MxA protein is part of the antiviral state induced by alpha/beta interferon (IFN-α/β). MxA inhibits the multiplication of several RNA viruses in cell culture. However, its antiviral potential in vivo has not yet been fully explored. We have generated MxA-transgenic mice that lack a functional IFN system by crossing MxA-transgenic mice constitutively expressing MxA with genetically targeted (knockout) mice lacking the β subunit of the IFN-α/β receptor (IFNAR-1−/− mice). These mice are an ideal animal model to investigate the unique antiviral activity of human MxA in vivo, because they are unable to express other IFN-induced proteins. Here, we show that MxA confers resistance to Thogoto virus, La Crosse virus, and Semliki Forest virus. No Thogoto virus progeny was detectable in MxA-transgenic mice, indicating an efficient block of virus replication at the primary site of infection. In the case of La Crosse virus, MxA restricted invasion of the central nervous system. In contrast, Semliki Forest virus multiplication in the brain was detectable in both MxA-expressing and nonexpressing IFNAR-1−/− mice. However, viral titers were clearly reduced in MxA-transgenic mice. Our results demonstrate that MxA does not need the help of other IFN-induced proteins for activity but is a powerful antiviral agent on its own. Moreover, the results suggest that MxA may protect humans from potential fatal infections by La Crosse virus and other viral pathogens.

scholarly journals The serology of experimental Salmonella dublin infections of cattle

1978 ◽  
Vol 81 (1) ◽  
pp. 31-41 ◽  
Author(s):  
G. A. Hall ◽  
P. W. Jones ◽  
Maureen M. Aitken ◽  
K. R. Parsons
Keyword(s):  
No Value ◽  
Alimentary Tract ◽  
Oral Route ◽  
Oral Infection ◽  
Agglutination Test ◽  
Faecal Excretion ◽  
Salmonella Dublin ◽  
Fetal Infection ◽  
Antibody Titres ◽  
Serum Agglutination

SUMMARYAgglutinating antibodies to somatic ‘O’ and flagellar ‘H’ antigens of S. dublin were measured in the serum of 43 pregnant heifers before intravenous or oral infection with S. dublin and in the serum of 21 uninfected control animals. The data from these animals were analysed statistically and a titre of 1/80, to both antigens, has been interpreted as of doubtful significance and a titre of 1/160 to both antigens, has been interpreted as significantly raised. Animals in which fetal infection occurred after challenge by either the intravenous or oral route developed significant increases in ‘H‘O’ titres indicating the value of measuring ‘H’ titres in the diagnosis of S. dublin abortion. In animals which were infected orally and in which infection appeared to be confined to the alimentary tract the ‘H’ titre did not become significantly raised. Lack of correlation between antibody titres and faecal excretion of S. dublin and persistence of infection in carcasses confirms that the serum agglutination test is of no value in detecting latent carriers.

Enterovirus A71 Induces Neurological Diseases and Dynamic Variants in Oral Infection of Human SCARB2-Transgenic Weaned Mice

2021 ◽  
Author(s):  
Jing-Yi Lin ◽  
Kuo-Feng Weng ◽  
Chih-Kuang Chang ◽  
Yu-Nong Gong ◽  
Guo-Jen Huang ◽  
...  
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Transgenic Mice ◽  
Public Health Problem ◽  
Viral Pathogenesis ◽  
Oral Route ◽  
Oral Infection ◽  
Viral Spread ◽  
Enterovirus A71 ◽  
Positive Strand Rna

Enterovirus A71 (EV-A71) and many members of the Picornaviridae family are neurotropic pathogens of global concern. These viruses are primarily transmitted through the fecal-oral route, and thus suitable animal models of oral infection are needed to investigate viral pathogenesis. An animal model of oral infection was developed using transgenic mice expressing human SCARB2 (hSCARB2 Tg), murine-adapted EV-A71/MP4 virus, and EV-A71/MP4 virus with an engineered nanoluciferase gene that allows imaging of viral replication and spread in infected mice. Next-generation sequencing of EV-A71 genomes in the tissues and organs of infected mice was also performed. Oral inoculation of EV-A71/MP4 or nanoluciferase-carrying MP4 virus stably induced neurological symptoms and death in infected 21-day-old weaned mice. In vivo bioluminescence imaging of infected mice and tissue immunostaining of viral antigens indicated that orally-inoculated virus can spread to the central nervous system and other tissues. Next-generating sequencing further identified diverse mutations in viral genomes that can potentially contribute to viral pathogenesis. This study presents an EV-A71 oral infection murine model that efficiently infects weaned mice and allows tracking of viral spread, features that can facilitate research into viral pathogenesis and neuroinvasion via the natural route of infection. Importance Enterovirus A71 (EV-A71), a positive-strand RNA virus of the Picornaviridae , poses a persistent global public health problem. EV-A71 is primarily transmitted through the fecal-oral route, and thus suitable animal models of oral infection are needed to investigate viral pathogenesis. We present an animal model of EV-A71 infection that enables the natural route of oral infection in weaned and non-immunocompromised 21-day-old hSCARB2 transgenic mice. Our results demonstrate that severe disease and death could be stably induced and viral invasion of the CNS could be replicated in this model, similar to severe real-world EV-A71 infections. We also developed a nanoluciferase-containing EV-A71 virus that can be used with this animal model to track viral spread after oral infection in real-time. Such a model offers several advantages over existing animal models, and can facilitate future research into viral spread, tissue tropism, and viral pathogenesis, all pressing issues that remain unaddressed for EV-A71 infections.

Cell-mediated immunity to intestinal infection

1980 ◽  
Vol 28 (2) ◽  
pp. 516-523 ◽  
Author(s):  
T T MacDonald ◽  
P B Carter
Keyword(s):  
Small Intestine ◽  
Lymph Node ◽  
Listeria Monocytogenes ◽  
Mesenteric Lymph Node ◽  
Oral Route ◽  
Oral Infection ◽  
Cell Mediated Immunity ◽  
Intestinal Infection ◽  
Tissue Invasion ◽  
Mesenteric Lymph

Specified pathogen-free B6D2F1 mice were orally infected with various doses of Listeria monocytogenes. Oral inocula containing more than 2.5 X 10(8) live organisms consistently initiated infection in the Peyer's patches (PP) of the small intestine. At lower doses the infection was sporadic, with many mice showing no apparent infection in the PP. The PP appeared to be the only site of tissue invasion and L. monocytogenes survival in the intestinal tissues, as no organisms were recovered from mucosa dissected free of all visible PP. Within the PP, the bacteria multiplied and the infection then disseminated to the mesenteric lymph node (MLN), liver, and spleen. However, bacteria were almost completely eliminated from all tissues, both systemic and gut-associated by 6 days postinfection. Mice given a primary L. monocytogenes infection by the oral route were highly resistant to subsequent intravenous or oral challenge. Likewise, sublethal intravenous infection rendered mice highly resistant to subsequent oral infection. In addition, lymphocytes from the PP, MLN, and spleens of mice recovering from a primary oral infection were able to adoptively transfer immunity to normal recipients. Finally, after oral infection, mice did not display peripheral delayed hypersensitivity to L. monocytogenes antigens until the organisms had penetrated to the spleen.

scholarly journals The Alpha/Beta Interferon Response Controls Tissue Tropism and Pathogenicity of Poliovirus

2005 ◽  
Vol 79 (7) ◽  
pp. 4460-4469 ◽  
Author(s):  
Miki Ida-Hosonuma ◽  
Takuya Iwasaki ◽  
Tomoki Yoshikawa ◽  
Noriyo Nagata ◽  
Yuko Sato ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Knockout Mice ◽  
Receptor Gene ◽  
Differential Susceptibility ◽  
Interferon Response ◽  
Tissue Tropism ◽  
Poliovirus Infection ◽  
Beta Interferon ◽  
Poliovirus Receptor ◽  
Alpha Beta

ABSTRACT Poliovirus selectively replicates in neurons in the spinal cord and brainstem, although poliovirus receptor (PVR) expression is observed in both the target and nontarget tissues in humans and transgenic mice expressing human PVR (PVR-transgenic mice). We assessed the role of alpha/beta interferon (IFN) in determining tissue tropism by comparing the pathogenesis of the virulent Mahoney strain in PVR-transgenic mice and PVR-transgenic mice deficient in the alpha/beta IFN receptor gene (PVR-transgenic/Ifnar knockout mice). PVR-transgenic/Ifnar knockout mice showed increased susceptibility to poliovirus. After intravenous inoculation, severe lesions positive for the poliovirus antigen were detected in the liver, spleen, and pancreas in addition to the central nervous system. These results suggest that the alpha/beta IFN system plays an important role in determining tissue tropism by protecting nontarget tissues that are potentially susceptible to infection. We subsequently examined the expression of IFN and IFN-stimulated genes (ISGs) in the PVR-transgenic mice. In the nontarget tissues, ISGs were expressed even in the noninfected state, and the expression level increased soon after poliovirus infection. On the contrary, in the target tissues, ISG expression was low in the noninfected state and sufficient response after poliovirus infection was not observed. The results suggest that the unequal IFN response is one of the important determinants for the differential susceptibility of tissues to poliovirus. We consider that poliovirus replication was observed in the nontarget tissues of PVR-transgenic/Ifnar knockout mice because the IFN response was null in all tissues.

scholarly journals Both Viral and Host Factors Contribute to Neurovirulence of Bovine Herpesviruses 1 and 5 in Interferon Receptor-Deficient Mice

2004 ◽  
Vol 78 (7) ◽  
pp. 3644-3653 ◽  
Author(s):  
Carlos Abril ◽  
Monika Engels ◽  
Anne Liman ◽  
Monika Hilbe ◽  
Sarah Albini ◽  
...  
Keyword(s):  
Immune System ◽  
Protective Effect ◽  
Neurological Disease ◽  
Adaptive Immune System ◽  
Gamma Interferon ◽  
Beta Interferon ◽  
Interferon Receptor ◽  
Interferon System ◽  
Alpha Beta ◽  
Simplex Virus

ABSTRACT Herpes simplex virus (HSV) type 1 and bovine herpesviruses 1 and 5 (BHV-1 and BHV-5) can use the same cellular receptor for entry, but only HSV is known to cause disease in mice. We hypothesized that components of either the innate or the adaptive immune system, or a combination of both, were responsible for curbing replication of BHVs in mice. Therefore, wild-type mice as well as mice with various combined genetic deficiencies in the alpha/beta interferon receptor or gamma interferon receptor and in the ability to produce mature B and T lymphocytes (RAG-2 deletion) were infected with BHV-1 and BHV-5 and monitored clinically, serologically, histopathologically, and virologically. A functional immune system protected the mice from disease and death due to BHV infection, and the immune response was Th1 like. BHV-5 was transported to the central nervous system by the axonal pathway, whereas viremia was required for this outcome with BHV-1. The alpha/beta interferon system was able to obstruct quantitative spread of the viruses in the infected organism. The gamma interferon system had a protective effect against BHV-1, even in mice with the RAG-2 deletion. In contrast, the same mice succumbed to neurological disease and death upon infection with BHV-5. Productively infected neurons were detected only in BHV-5-infected mice with an intact gamma interferon system. We conclude that the alpha/beta interferon system had a protective effect, while an intact gamma interferon system was required for efficient replication of BHV-5 in mouse neurons and for the development of neurological disease.

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