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Jorge C G Blanco - One of the best experts on this subject based on the ideXlab platform.
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herpes simplex virus 1 induces brain inflammation and multifocal demyelination in the Cotton Rat sigmodon hispidus
Journal of Virology, 2019Co-Authors: Marina S Boukhvalova, Emma Mortensen, Aissatou Mbaye, Lorne F Kastrukoff, Diego Lopez, Jorge C G BlancoAbstract:Demyelinating central nervous system (CNS) disorders like multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) have been difficult to study and treat due to the lack of understanding of their etiology. Numerous cases point to the link between herpes simplex virus (HSV) infection and multifocal CNS demyelination in humans; however, convincing evidence from animal models has been missing. In this work, we found that HSV-1 infection of the Cotton Rat Sigmodon hispidus via a common route (lip abrasion) can cause multifocal CNS demyelination and inflammation. Remyelination occurred shortly after demyelination in HSV-1-infected Cotton Rats but could be incomplete, resulting in "scars," further supporting an association between HSV-1 infection and multifocal demyelinating disorders. Virus was detected sequentially in the lip, trigeminal ganglia, and brain of infected animals. Brain pathology developed primarily on the ipsilateral side of the brain stem, in the cerebellum, and contralateral side of the forebrain/midbrain, suggesting that the changes may ascend along the trigeminal lemniscus pathway. Neurologic defects occasionally detected in infected animals (e.g., defective whisker touch and blink responses and compromised balance) could be representative of the brain stem/cerebellum dysfunction. Immunization of Cotton Rats with a split HSV-1 vaccine protected animals against viral replication and brain pathology, suggesting that vaccination against HSV-1 may protect against demyelinating disorders.IMPORTANCE Our work demonstRates for the first time a direct association between infection with herpes simplex virus 1, a ubiquitous human pathogen generally associated with facial cold sores, and multifocal brain demyelination in an otherwise normal host, the Cotton Rat Sigmodon hispidus For a long time, demyelinating diseases were considered to be autoimmune in nature and were studied by indirect methods, such as immunizing animals with myelin components or feeding them toxic substances that induce demyelination. Treatment against demyelinating diseases has been elusive, partially because of their unknown etiology. This work provides the first experimental evidence for the role of HSV-1 as the etiologic agent of multifocal brain demyelination in a normal host and suggests that vaccination against HSV-1 can help to combat demyelinating disorders.
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Efficacy of a respiRatory syncytial virus vaccine candidate in a maternal immunization model
Nature Publishing Group, 2018Co-Authors: Jorge C G Blanco, Marina S Boukhvalova, Lioubov M Pletneva, Mira C Patel, Lori Mcginnes-cullen, Raymonde O. Otoa, Lurds R. Fernando, Trudy G. MorrisonAbstract:RSV infection is a major cause of bronchiolitis in infants and maternal vaccination is a potential preventive option. Here, Blanco et al. show efficacy of a Newcastle disease virus-based virus-like particle vaccine candidate in naive and pre-exposed Cotton Rat dams and their offspring
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Immunization with Live Human Rhinovirus (HRV) 16 Induces Protection in Cotton Rats against HRV14 Infection
Frontiers Media S.A., 2017Co-Authors: Mira C Patel, Marina S Boukhvalova, Lioubov M Pletneva, Stefanie N Vogel, Adriana E Kajon, Jorge C G BlancoAbstract:Human rhinoviruses (HRVs) are the main cause of cold-like illnesses, and currently no vaccine or antiviral therapies against HRVs are available to prevent or mitigate HRV infection. There are more than 150 antigenically heterogeneous HRV serotypes, with ∼90 HRVs belonging to major group species A and B. Development of small animal models that are susceptible to infection with major group HRVs would be beneficial for vaccine research. Previously, we showed that the Cotton Rat (Sigmodon hispidus) is semi-permissive to HRV16 (major group, species HRV-A virus) infection, replicating in the upper and lower respiRatory tracts with measurable pathology, mucus production, and expression of inflammatory mediators. Herein, we report that intranasal infection of Cotton Rats with HRV14 (major group, species HRV-B virus) results in isolation of infectious virus from the nose and lung. Similar to HRV16, intramuscular immunization with live HRV14 induces homologous protection that correlated with high levels of serum neutralizing antibodies. Vaccination and challenge experiments with HRV14 and HRV16 to evaluate the development of cross-protective immunity demonstRate that intramuscular immunization with live HRV16 significantly protects animals against HRV14 challenge. Determination of the immunological mechanisms involved in heterologous protection and further characterization of infection with other major HRV serotypes in the Cotton Rat could enhance the robustness of the model to define heterotypic relationships between this diverse group of viruses and thereby increase its potential for development of a multi-serotype HRV vaccine
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enterovirus d 68 infection prophylaxis and vaccination in a novel permissive animal model the Cotton Rat sigmodon hispidus
PLOS ONE, 2016Co-Authors: Mira C Patel, Marina S Boukhvalova, Lioubov M Pletneva, Stefanie N Vogel, Wei Wang, Seesandra V Rajagopala, Tina V Hartert, Jorge C G BlancoAbstract:In recent years, there has been a significant increase in detection of Enterovirus D-68 (EV-D68) among patients with severe respiRatory infections worldwide. EV-D68 is now recognized as a re-emerging pathogen; however, due to lack of a permissive animal model for EV-D68, a comprehensive understanding of the pathogenesis and immune response against EV-D68 has been hampered. Recently, it was shown that EV-D68 has a strong affinity for α2,6-linked sialic acids (SAs) and we have shown previously that α2,6-linked SAs are abundantly present in the respiRatory tract of Cotton Rats (Sigmodon hispidus). Thus, we hypothesized that Cotton Rats could be a potential model for EV-D68 infection. Here, we evaluated the ability of two recently isolated EV-D68 strains (VANBT/1 and MO/14/49), along with the historical prototype Fermon strain (ATCC), to infect Cotton Rats. We found that Cotton Rats are permissive to EV-D68 infection without virus adaptation. The different strains of EV-D68 showed variable infection profiles and the ability to produce neutralizing antibody (NA) upon intranasal infection or intramuscular immunization. Infection with the VANBT/1 resulted in significant induction of pulmonary cytokine gene expression and lung pathology. Intramuscular immunization with live VANBT/1 or MO/14/49 induced strong homologous antibody responses, but a modeRate heterologous NA response. We showed that passive prophylactic administRation of serum with high content of NA against VANBT/1 resulted in an efficient antiviral therapy. VANBT/1-immunized animals showed complete protection from VANBT/1 challenge, but induced strong pulmonary Th1 and Th2 cytokine responses and enhanced lung pathology, indicating the geneRation of exacerbated immune response by immunization. In conclusion, our data illustRate that the Cotton Rat is a powerful animal model that provides an experimental platform to investigate pathogenesis, immune response, anti-viral therapies and vaccines against EV-D68 infection.
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A Cotton Rat model of EV-D68 infection and replication.
2016Co-Authors: Mira C Patel, Marina S Boukhvalova, Lioubov M Pletneva, Stefanie N Vogel, Wei Wang, Seesandra V Rajagopala, Tina V Hartert, Yi Tan, Suman R. Das, Jorge C G BlancoAbstract:Cotton Rats were infected i.n. with 106 TCID50 per Rat with 3 different strains of EV-D68, ATCC (prototype Fermon strain), VANBT (2012 pre-outbreak strain from Nashville, TN) and MO/49 (2014 outbreak strain from Kansas, MO). (A) Evolutionary tree showing three major clades of EV-D68, A, B and C, distributed worldwide. Strains used in this study are shown in red. The tree is rooted by the oldest EV-D68 sequence in GenBank, the Fermon strain (referred to as ATCC), collected in 1962 in California, USA. (B, C) Quantification of infectious virus titers of each EV-D68 strain in nose and lung homogenates from infected animals at 10 h (B) and 24 h (C) p.i. Groups of 5 animals were euthanized at each time point. Each bar corresponds to an individual animal. UN = uninfected. (D, E, F) Time course of VANBT replication in Cotton Rats; groups of 4 animals were euthanized at the indicated time to measure infectious virus titers in nose (D) and lung (E) homogenates. Results are representative of 2 independent experiments. *p
Marina S Boukhvalova - One of the best experts on this subject based on the ideXlab platform.
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herpes simplex virus 1 induces brain inflammation and multifocal demyelination in the Cotton Rat sigmodon hispidus
Journal of Virology, 2019Co-Authors: Marina S Boukhvalova, Emma Mortensen, Aissatou Mbaye, Lorne F Kastrukoff, Diego Lopez, Jorge C G BlancoAbstract:Demyelinating central nervous system (CNS) disorders like multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) have been difficult to study and treat due to the lack of understanding of their etiology. Numerous cases point to the link between herpes simplex virus (HSV) infection and multifocal CNS demyelination in humans; however, convincing evidence from animal models has been missing. In this work, we found that HSV-1 infection of the Cotton Rat Sigmodon hispidus via a common route (lip abrasion) can cause multifocal CNS demyelination and inflammation. Remyelination occurred shortly after demyelination in HSV-1-infected Cotton Rats but could be incomplete, resulting in "scars," further supporting an association between HSV-1 infection and multifocal demyelinating disorders. Virus was detected sequentially in the lip, trigeminal ganglia, and brain of infected animals. Brain pathology developed primarily on the ipsilateral side of the brain stem, in the cerebellum, and contralateral side of the forebrain/midbrain, suggesting that the changes may ascend along the trigeminal lemniscus pathway. Neurologic defects occasionally detected in infected animals (e.g., defective whisker touch and blink responses and compromised balance) could be representative of the brain stem/cerebellum dysfunction. Immunization of Cotton Rats with a split HSV-1 vaccine protected animals against viral replication and brain pathology, suggesting that vaccination against HSV-1 may protect against demyelinating disorders.IMPORTANCE Our work demonstRates for the first time a direct association between infection with herpes simplex virus 1, a ubiquitous human pathogen generally associated with facial cold sores, and multifocal brain demyelination in an otherwise normal host, the Cotton Rat Sigmodon hispidus For a long time, demyelinating diseases were considered to be autoimmune in nature and were studied by indirect methods, such as immunizing animals with myelin components or feeding them toxic substances that induce demyelination. Treatment against demyelinating diseases has been elusive, partially because of their unknown etiology. This work provides the first experimental evidence for the role of HSV-1 as the etiologic agent of multifocal brain demyelination in a normal host and suggests that vaccination against HSV-1 can help to combat demyelinating disorders.
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Efficacy of a respiRatory syncytial virus vaccine candidate in a maternal immunization model
Nature Publishing Group, 2018Co-Authors: Jorge C G Blanco, Marina S Boukhvalova, Lioubov M Pletneva, Mira C Patel, Lori Mcginnes-cullen, Raymonde O. Otoa, Lurds R. Fernando, Trudy G. MorrisonAbstract:RSV infection is a major cause of bronchiolitis in infants and maternal vaccination is a potential preventive option. Here, Blanco et al. show efficacy of a Newcastle disease virus-based virus-like particle vaccine candidate in naive and pre-exposed Cotton Rat dams and their offspring
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Immunization with Live Human Rhinovirus (HRV) 16 Induces Protection in Cotton Rats against HRV14 Infection
Frontiers Media S.A., 2017Co-Authors: Mira C Patel, Marina S Boukhvalova, Lioubov M Pletneva, Stefanie N Vogel, Adriana E Kajon, Jorge C G BlancoAbstract:Human rhinoviruses (HRVs) are the main cause of cold-like illnesses, and currently no vaccine or antiviral therapies against HRVs are available to prevent or mitigate HRV infection. There are more than 150 antigenically heterogeneous HRV serotypes, with ∼90 HRVs belonging to major group species A and B. Development of small animal models that are susceptible to infection with major group HRVs would be beneficial for vaccine research. Previously, we showed that the Cotton Rat (Sigmodon hispidus) is semi-permissive to HRV16 (major group, species HRV-A virus) infection, replicating in the upper and lower respiRatory tracts with measurable pathology, mucus production, and expression of inflammatory mediators. Herein, we report that intranasal infection of Cotton Rats with HRV14 (major group, species HRV-B virus) results in isolation of infectious virus from the nose and lung. Similar to HRV16, intramuscular immunization with live HRV14 induces homologous protection that correlated with high levels of serum neutralizing antibodies. Vaccination and challenge experiments with HRV14 and HRV16 to evaluate the development of cross-protective immunity demonstRate that intramuscular immunization with live HRV16 significantly protects animals against HRV14 challenge. Determination of the immunological mechanisms involved in heterologous protection and further characterization of infection with other major HRV serotypes in the Cotton Rat could enhance the robustness of the model to define heterotypic relationships between this diverse group of viruses and thereby increase its potential for development of a multi-serotype HRV vaccine
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enterovirus d 68 infection prophylaxis and vaccination in a novel permissive animal model the Cotton Rat sigmodon hispidus
PLOS ONE, 2016Co-Authors: Mira C Patel, Marina S Boukhvalova, Lioubov M Pletneva, Stefanie N Vogel, Wei Wang, Seesandra V Rajagopala, Tina V Hartert, Jorge C G BlancoAbstract:In recent years, there has been a significant increase in detection of Enterovirus D-68 (EV-D68) among patients with severe respiRatory infections worldwide. EV-D68 is now recognized as a re-emerging pathogen; however, due to lack of a permissive animal model for EV-D68, a comprehensive understanding of the pathogenesis and immune response against EV-D68 has been hampered. Recently, it was shown that EV-D68 has a strong affinity for α2,6-linked sialic acids (SAs) and we have shown previously that α2,6-linked SAs are abundantly present in the respiRatory tract of Cotton Rats (Sigmodon hispidus). Thus, we hypothesized that Cotton Rats could be a potential model for EV-D68 infection. Here, we evaluated the ability of two recently isolated EV-D68 strains (VANBT/1 and MO/14/49), along with the historical prototype Fermon strain (ATCC), to infect Cotton Rats. We found that Cotton Rats are permissive to EV-D68 infection without virus adaptation. The different strains of EV-D68 showed variable infection profiles and the ability to produce neutralizing antibody (NA) upon intranasal infection or intramuscular immunization. Infection with the VANBT/1 resulted in significant induction of pulmonary cytokine gene expression and lung pathology. Intramuscular immunization with live VANBT/1 or MO/14/49 induced strong homologous antibody responses, but a modeRate heterologous NA response. We showed that passive prophylactic administRation of serum with high content of NA against VANBT/1 resulted in an efficient antiviral therapy. VANBT/1-immunized animals showed complete protection from VANBT/1 challenge, but induced strong pulmonary Th1 and Th2 cytokine responses and enhanced lung pathology, indicating the geneRation of exacerbated immune response by immunization. In conclusion, our data illustRate that the Cotton Rat is a powerful animal model that provides an experimental platform to investigate pathogenesis, immune response, anti-viral therapies and vaccines against EV-D68 infection.
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A Cotton Rat model of EV-D68 infection and replication.
2016Co-Authors: Mira C Patel, Marina S Boukhvalova, Lioubov M Pletneva, Stefanie N Vogel, Wei Wang, Seesandra V Rajagopala, Tina V Hartert, Yi Tan, Suman R. Das, Jorge C G BlancoAbstract:Cotton Rats were infected i.n. with 106 TCID50 per Rat with 3 different strains of EV-D68, ATCC (prototype Fermon strain), VANBT (2012 pre-outbreak strain from Nashville, TN) and MO/49 (2014 outbreak strain from Kansas, MO). (A) Evolutionary tree showing three major clades of EV-D68, A, B and C, distributed worldwide. Strains used in this study are shown in red. The tree is rooted by the oldest EV-D68 sequence in GenBank, the Fermon strain (referred to as ATCC), collected in 1962 in California, USA. (B, C) Quantification of infectious virus titers of each EV-D68 strain in nose and lung homogenates from infected animals at 10 h (B) and 24 h (C) p.i. Groups of 5 animals were euthanized at each time point. Each bar corresponds to an individual animal. UN = uninfected. (D, E, F) Time course of VANBT replication in Cotton Rats; groups of 4 animals were euthanized at the indicated time to measure infectious virus titers in nose (D) and lung (E) homogenates. Results are representative of 2 independent experiments. *p
Stefan Niewiesk - One of the best experts on this subject based on the ideXlab platform.
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immunogenicity and inflammatory properties of respiRatory syncytial virus attachment g protein in Cotton Rats
PLOS ONE, 2021Co-Authors: Margaret E Martinez, Cristina Capella Gonzalez, Devra Huey, Mark E Peeples, Douglas Mccarty, Stefan NiewieskAbstract:Human respiRatory syncytial virus (RSV) is a leading cause of lower respiRatory tract infection in infants and young children worldwide. The attachment (G) protein of RSV is synthesized by infected cells in both a membrane bound (mG) and secreted form (sG) and uses a CX3C motif for binding to its cellular receptor. Cell culture and mouse studies suggest that the G protein mimics the cytokine CX3CL1 by binding to CX3CR1 on immune cells, which is thought to cause increased pulmonary inflammation in vivo. However, because these studies have used RSV lacking its G protein gene or blockade of the G protein with a G protein specific monoclonal antibody, the observed reduction in inflammation may be due to reduced virus replication and spread, and not to a direct role for G protein as a viral chemokine. In order to more directly determine the influence of the soluble and the membrane-bound forms of G protein on the immune system independent of its attachment function for the virion, we expressed the G protein in Cotton Rat lungs using adeno-associated virus (AAV), a vector system which does not itself induce inflammation. We found no increase in pulmonary inflammation as determined by histology and bronchoalveolar lavage after inoculation of AAVs expressing the membrane bound G protein, the secreted G protein or the complete G protein gene which expresses both forms. The long-term low-level expression of AAV-G did, however, result in the induction of non-neutralizing antibodies, CD8 T cells and partial protection from challenge with RSV. Complete protection was accomplished through co-immunization with AAV-G and an AAV expressing Cotton Rat interferon α.
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Pulmonary function analysis in Cotton Rats after respiRatory syncytial virus infection.
'Public Library of Science (PLoS)', 2020Co-Authors: Margaret E Martinez, Olivia E Harder, Lucia E Rosas, Lisa Joseph, Ian C Davis, Stefan NiewieskAbstract:The Cotton Rat (Sigmodon hispidus) is an excellent small animal model for human respiRatory viral infections such as human respiRatory syncytial virus (RSV) and human metapneumovirus (HMPV). These respiRatory viral infections, as well as other pulmonary inflammatory diseases such as asthma, are associated with lung mechanic disturbances. So far, the pathophysiological effects of viral infection and allergy on Cotton Rat lungs have not been measured, although this information might be an important tool to determine the efficacy of vaccine and drug candidates. To characterize pulmonary function in the Cotton Rat, we established forced oscillation technique in uninfected, RSV infected and HDM sensitized Cotton Rats, and characterized pulmonary inflammation, mucus production, pulmonary edema, and oxygenation. There was a gender difference after RSV infection, with females demonstRating airway hyper-responsiveness while males did not. Female Cotton Rats 2dpi had a mild increase in pulmonary edema (wet: dry weight Ratios). At day 4 post infection, female Cotton Rats demonstRated mild pulmonary inflammation, no increase in mucus production or reduction in oxygenation. Pulmonary function was not significantly impaired after RSV infection. In contrast, Cotton Rats sensitized to HDM demonstRated airway hyper-responsiveness with a significant increase in pulmonary inflammation, increase in baseline tissue damping, and a decrease in baseline pulmonary compliance. In summary, we established baseline data for forced oscillation technique and other respiRatory measures in the Cotton Rat and used it to analyze respiRatory diseases in Cotton Rats
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characterization of Cotton Rat sigmodon hispidus eosinophils including their response to respiRatory syncytial virus infection
Comparative Medicine, 2018Co-Authors: Gia M Green, Natasha Petroff, Krista M D La Perle, Stefan NiewieskAbstract:Eosinophils have been postulated to play a protective role against infection with respiRatory syncytial virus (RSV), increase the severity of allergic asthma during respiRatory viral infection, and drive vaccine-enhanced disease. To address these questions in the Cotton Rat model of RSV infection, we characterized Cotton Rat eosinophils by electron microscopy as well as by bronchoalveolar lavage and histology of lung sections. Using these methods, we demonstRated that eosinophils comprise approximately half of all cells in the bronchoalveolar lavage fluids from Cotton Rats. The function of these cells was comparable to that of eosinophils of other species. Ex vivo, eosinophils stimulated with calcium ionophores secreted eosinophil peroxidase. In vivo, treatment with house dust mite antigen increased eosinophil numbers in lung. Infection with Staphylococcus aureus lead to a marked increase in neutrophils without an increase in eosinophils, and eosinophil numbers were not influenced by infection with influenza virus or measles virus. Similarly, infection with RSV did not result in an increase in eosinophils. Lastly, RSV infection did not increase eosinophil recruitment into the lung after challenge with house dust mite antigen, but it did increase eosinophil recruitment into the lungs of Cotton Rats previously immunized with formalin-inactivated RSV vaccine, thus contributing to vaccine-enhanced disease.
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function and expression of cd1d and invariant natural killer t cell receptor in the Cotton Rat sigmodon hispidus
Immunology, 2015Co-Authors: Alina Suzann Fichtner, Stefan Niewiesk, Daniel Paletta, Lisa Starick, Richard F Schumann, Thomas HerrmannAbstract:The Cotton Rat (Sigmodon hispidus) belongs to the rodent family of Cricetidae and provides a powerful model to study the pathogenesis of human respiRatory viruses and measles virus. Recent studies in other rodent models have suggested a role for invariant natural killer T (iNKT) cells in antiviral immunity and vaccination against respiRatory virus infections. Using new experimental tools, we provide the first evidence for a functional CD1d cell molecule (crCD1d) and iNKT T-cell receptor in Cotton Rats. The crCD1d cDNA sequence was identified and crCD1d transductants showed that monoclonal antibody WTH-2 stains crCD1d as efficiently as mouse or Rat CD1d. The expression of crCD1d was clearly weaker for thymocytes and B cells, and higher for T cells, which is different to what is found in murine species. The antigen-presenting capacity of crCD1d was demonstRated with crCD1d-immunoglobulin dimers loaded with the glycolipid PBS57, which bound iNKT T-cell receptors. Evidence for functional Cotton Rat iNKT cells was provided by detection of interferon-γ and interleukin-4 in cultures of splenocytes stimulated with PBS57 and α-galactosylceramide and by specific staining of about 0·2% of splenocytes with PBS57-loaded crCD1d dimers. Canonical AV14/AJ18 rearrangements were identified and found to contain multiple members of the AV14 (AV11) family. One of them was expressed and found to bind CD1d dimers. In summary, these data provide the first evidence for functional CD1d molecules and iNKT T-cell receptors in Cotton Rats and provide the tools to analyse them both in the Cotton Rat model of infectious diseases.
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Cotton Rat sigmodon hispidus signaling lymphocyte activation molecule cd150 is an entry receptor for measles virus
PLOS ONE, 2014Co-Authors: Thomas Carsillo, Devra Huey, Amy Levinsky, Karola Obojes, Jurgen Schneiderschaulies, Stefan NiewieskAbstract:Cotton Rats (Sigmodon hispidus) replicate measles virus (MV) after intranasal infection in the respiRatory tract and lymphoid tissue. We have cloned the Cotton Rat signaling lymphocytic activation molecule (CD150, SLAM) in order to investigate its role as a potential receptor for MV. Cotton Rat CD150 displays 58% and 78% amino acid homology with human and mouse CD150, respectively. By staining with a newly geneRated Cotton Rat CD150 specific monoclonal antibody expression of CD150 was confirmed in Cotton Rat lymphoid cells and in tissues with a pattern of expression similar to mouse and humans. Previously, binding of MV hemagglutinin has been shown to be dependent on amino acids 60, 61 and 63 in the V region of CD150. The human molecule contains isoleucine, histidine and valine at these positions and binds to MV-H whereas the mouse molecule contains valine, arginine and leucine and does not function as a receptor for MV. In the Cotton Rat molecule, amino acids 61 and 63 are identical with the mouse molecule and amino acid 60 with the human molecule. After transfection with Cotton Rat CD150 HEK 293 T cells became susceptible to infection with single cycle VSV pseudotype virus expressing wild type MV glycoproteins and with a MV wildtype virus. After infection, cells expressing Cotton Rat CD150 replicated virus to lower levels than cells expressing the human molecule and formed smaller plaques. These data might explain why the Cotton Rat is a semipermissive model for measles virus infection.
Gregory A Prince - One of the best experts on this subject based on the ideXlab platform.
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Cotton Rat Model
2016Co-Authors: Martin G. Ottolini, Val G. Hemming, Franco M. Piazza, Susan A. Johnson, Miriam E. R. Darnell, Gregory A PrinceAbstract:A Cotton Rat model was used to test the efficacy of topical immunotherapy against parainfluenza type 3 (PIV3) infection. On day 3 after experimental infection with 105.5 pfu of PIV3, animals were treated with 2-fold dilutions of convalescent Cotton Rat serum or with one of two purified human immunoglobulin prepaRations; all three had modeRate titers of anti-PIV3 neutralizing antibody (range, 1:200-1:1000). Therapy with high concentRations of all three prepaRations resulted in signifi-cant reductions of ~2 logs (~100-fold) of pulmonary virus titers compared with titers for control animals. Little or no reduction in virus titers were seen in nasal tissues. Parainfluenza type 3 (PIV3) is a major cause of bronchiolitis and pneumonia in children [I, 2]. In addition, PIV3 has been increasingly identified as a significant cause of morbidity and mortality in chronically ill patients, such as children with severe combined immunodeficiency [3], children with cardiopulmo-nary disease [4], and children and adults undergoing bone mar-row transplantation [5]. The patterns of clinical disease seen with PIV3 closely parallel those seen with respiRatory syncytia
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efficacy of trivalent inactivated influenza vaccines in the Cotton Rat sigmodon hispidus model
Vaccine, 2012Co-Authors: Brian Miles, Gregory A Prince, Rachel Zinsou, Marina S BoukhvalovaAbstract:Annually adjusted inactivated influenza vaccines can prevent infection and limit the spread of seasonal influenza when vaccine strain closely matches circulating strain. For the years when the match is difficult to achieve, a rapid screening of a larger repertoire of vaccines may be required but is difficult to accomplish due to the lack of a convenient small animal model of seasonal influenza vaccines. The goal of this work was to determine whether the Cotton Rat Sigmodon hispidus, a small laboRatory animal susceptible to infection with unadapted influenza viruses, may become such a model. Cotton Rats were immunized with a trivalent inactivated vaccine (TIV) FluLaval (2006/2007) and vaccine immunogenicity and antiviral efficacy was evaluated against the homologous H1N1 and a heterologous H3N2 challenge. FluLaval induced a strong virus-specific IgG and neutralizing antibody response against homologous virus, elicited sterilizing immunity in the lungs and significantly reduced viral replication in the nose of infected animals. FluLaval was efficacious in Cotton Rats as either a single-time or a double immunization, although higher level of protection of the upper respiRatory tract was achieved following two doses of vaccine. Antibodies against a heterologous influenza strain were induced in FluLaval-vaccinated animals, but vaccine lacked antiviral efficacy and did not reduce replication of a heterologous virus. Similarity of these findings to human TIV data suggests that the Cotton Rat may prove to be a reliable small animal model of human influenza vaccines.
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activation of interferon response through toll like receptor 3 impacts viral pathogenesis and pulmonary toll like receptor expression during respiRatory syncytial virus and influenza infections in the Cotton Rat sigmodon hispidus model
Journal of Interferon and Cytokine Research, 2010Co-Authors: Marina S Boukhvalova, Talia B Sotomayor, Ryan C Point, Lioubov M Pletneva, Gregory A Prince, Jorge C G BlancoAbstract:Interferon (IFN) therapy in humans often causes flu-like symptoms by an unknown mechanism. Poly ICLC is a synthetic dsRNA and a Toll-like receptor 3 (TLR3) agonist with a strong IFN-inducing ability. In this work, we analyzed the effect of poly ICLC on pulmonary responses to influenza and respiRatory syncytial virus (RSV) infections in the Cotton Rat (Sigmodon hispidus) model. Viral replication, pulmonary inflammation, and expression of IFN, TLR, and chemokines were monitored and compared. Antiviral effect of poly ICLC against influenza virus and RSV was best achieved at high poly ICLC concentRations that, in the absence of virus infection, induced a strong IFN response. The antiviral doses of poly ICLC, however, also increased lung inflammation, an unexpected finding because of the reported poly ICLC safety in BALB/c mice. Similarly, in contrast to murine model, pathology of RSV infection was increased in Cotton Rats treated with poly ICLC. Augmented lung inflammation was accompanied by an earlier induct...
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co infection of the Cotton Rat sigmodon hispidus with staphylococcus aureus and influenza a virus results in synergistic disease
Microbial Pathogenesis, 2007Co-Authors: Loranee E Braun, Jorge C G Blanco, Lioubov M Pletneva, Gregory A Prince, Deena E Sutter, Maryna Eichelberger, John F Kokaikun, Martin G. OttoliniAbstract:Bacterial super-infection of influenza patients is the primary cause of excess mortality during influenza pandemics, with Staphylococcus aureus (S. aureus) having the highest fatality Rate. The Cotton Rat (Sigmodon hispidus) is an excellent model for both influenza and S. aureus pathogenesis, and therefore a potential tool to model co-infection. We compared physiologic and pathologic changes in Cotton Rats infected with both S. aureus and influenza A/Wuhan/359/95 (H3N2), with animals infected with each pathogen alone. Co-infected Cotton Rats demonstRated significantly higher mortality, lower tempeRatures on 2 and 3 days post-inoculation (p.i.), higher levels of bacteremia and pulmonary bacterial load 4 days p.i., and worse pathology 7 days p.i. Early indicators of exacerbated disease coincided with higher pulmonary mRNA levels for IL-1β, IL-6, IL-10 and IFNy, supporting the idea that these may contribute to disease severity. Our results demonstRate that the Cotton Rat is a good model of influenza and S. aureus co-infection, with increased mortality and hypothermia as well as prolonged bacterial duRation indicative of synergistic disease that may be the result of increased induction of both pro- and anti-inflammatory cytokines.
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treatment of respiRatory syncytial virus bronchiolitis and pneumonia in a Cotton Rat model with systemically administered monoclonal antibody palivizumab and glucocorticosteroid
The Journal of Infectious Diseases, 2000Co-Authors: Gregory A Prince, Amy Mathews, Spencer J Curtis, David D PorterAbstract:Parenteral treatment of an experimental respiRatory syncytial virus (RSV) infection in a Cotton Rat model with a monoclonal antibody directed against the viral F protein resulted in the clearance of infectious virus within 24 h but had no effect on the pulmonary pathology at 24 h and only a small effect on the pulmonary pathology at 72 h. Treatment with parenteral triamcinolone acetonide dramatically reduced the pathologic lesions of viral bronchiolitis and pneumonia but resulted in the delayed clearance of the virus. The combination of the monoclonal antibody given in a single dose 72 h after infection, combined with 3 daily doses of the corticosteroid starting 72 h after infection, demonstRated both the loss of infectivity and the disappearance of lesions. No rebound of lesions or infectivity was noted. Combined antiviral and anti-inflammatory therapy for RSV disease appears promising.
Betsy C. Herold - One of the best experts on this subject based on the ideXlab platform.
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Efficacy of the Herpes Simplex Virus 2 (HSV-2) Glycoprotein D/AS04 Vaccine against Genital HSV-2 and HSV-1 Infection and Disease in the Cotton Rat Sigmodon hispidus Model
Journal of virology, 2015Co-Authors: Marina S Boukhvalova, Jorge C G Blanco, Aissatou Mbaye, Jamall Mckay, Hannah S. Sanford-crane, Ashley Huber, Betsy C. HeroldAbstract:ABSTRACT Subunit vaccines based on the herpes simplex virus 2 (HSV-2) glycoprotein D (gD-2) have been the major focus of HSV-2 vaccine development for the past 2 decades. Based on the promising data geneRated in the guinea pig model, a formulation containing truncated gD-2, aluminum salt, and MPL (gD/AS04) advanced to clinical trials. The results of these trials, however, were unexpected, as the vaccine protected against HSV-1 infection but not against HSV-2. To address this discrepancy, we developed a Depot medroxyprogesterone acetate (DMPA)-treated Cotton Rat Sigmodon hispidus model of HSV-2 and HSV-1 genital infection. The severity of HSV-1 genital herpes was less than that of HSV-2 genital herpes in Cotton Rats, and yet the model allowed for compaRative evaluation of gD/AS04 immunogenicity and efficacy. Cotton Rats were intramuscularly vaccinated using a prime boost stRategy with gD/AS04 (Simplirix vaccine) or control vaccine formulation (hepatitis B vaccine FENDrix) and subsequently challenged intravaginally with HSV-2 or HSV-1. The gD/AS04 vaccine was immunogenic in Cotton Rats and induced serum IgG directed against gD-2 and serum HSV-2 neutralizing antibodies but failed to efficiently protect against HSV-2 disease or to decrease the HSV-2 viral load. However, gD/AS04 significantly reduced vaginal titers of HSV-1 and better protected animals against HSV-1 compared to HSV-2 genital disease. The latter finding is generally consistent with the clinical outcome of the Herpevac trial of Simplirix. Passive transfer of serum from gD/AS04-immunized Cotton Rats conferred stronger protection against HSV-1 genital disease. These findings suggest the need for alternative vaccine stRategies and the identification of new correlates of protection. IMPORTANCE In spite of the high health burden of genital herpes, there is still no effective intervention against the disease. The significant gap in knowledge on genital herpes pathogenesis has been further highlighted by the recent failure of GSK HSV-2 vaccine Simplirix (gD/AS04) to protect humans against HSV-2 and the surprising finding that the vaccine protected against HSV-1 genital herpes instead. In this study, we report that gD/AS04 has higher efficacy against HSV-1 compared to HSV-2 genital herpes in the novel DMPA-synchronized Cotton Rat model of HSV-1 and HSV-2 infection. The findings help explain the results of the Simplirix trial.
