The Experts below are selected from a list of 297 Experts worldwide ranked by ideXlab platform
Martin L Moore - One of the best experts on this subject based on the ideXlab platform.
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the respiratory syncytial virus fusion protein and neutrophils mediate the Airway Mucin response to pathogenic respiratory syncytial virus infection
Journal of Virology, 2013Co-Authors: Kate L Stokes, Michael G Currier, Kaori Sakamoto, Peter L Collins, Richard K Plemper, Martin L MooreAbstract:ABSTRACT Respiratory syncytial virus (RSV) is the leading cause of death due to a viral etiology in infants. RSV disease is characterized by epithelial desquamation, neutrophilic bronchiolitis and pneumonia, and obstructive pulmonary mucus. It has been shown that infection of BALB/cJ mice with RSV clinical isolate A2001/2-20 (2-20) results in a higher early viral load, greater Airway necrosis, and higher levels of interleukin-13 (IL-13) and Airway Mucin expression than infection with RSV laboratory strain A2. We hypothesized that the fusion (F) protein of RSV 2-20 is a mucus-inducing viral factor. In vitro , the fusion activity of 2-20 F but not that of A2 F was enhanced by expression of RSV G. We generated a recombinant F-chimeric RSV by replacing the F gene of A2 with the F gene of 2-20, generating A2–2-20F. Similar to the results obtained with the parent 2-20 strain, infection of BALB/cJ mice with A2–2-20F resulted in a higher early viral load and higher levels of subsequent pulmonary Mucin expression than infection with the A2 strain. A2–2-20F infection induced greater necrotic Airway damage and neutrophil infiltration than A2 infection. We hypothesized that the neutrophil response to A2–2-20F infection is involved in Mucin expression. Antibody-mediated depletion of neutrophils in RSV-infected mice resulted in lower tumor necrosis factor alpha levels, fewer IL-13-expressing CD4 T cells, and less Airway Mucin production in the lung. Our data are consistent with a model in which the F and attachment (G) glycoprotein functional interaction leads to enhanced fusion and F is a key factor in Airway epithelium infection, pathogenesis, and subsequent Airway Mucin expression.
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A Respiratory Syncytial Virus (RSV) Anti-G Protein F(ab′)2 Monoclonal Antibody Suppresses Mucous Production and Breathing Effort in RSV rA2-line19F-Infected BALB/c Mice
Journal of Virology, 2013Co-Authors: Seyhan Boyoglu-barnum, Sean O. Todd, Kelsey A. Gaston, Cemil Boyoglu, Tatiana Chirkova, Thomas R. Barnum, Patricia A. Jorquera, Lia M. Haynes, Ralph A. Tripp, Martin L MooreAbstract:ABSTRACT Respiratory syncytial virus (RSV) belongs to the family Paramyxoviridae and is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. Increased Airway resistance and increased Airway Mucin production are two manifestations of RSV infection in children. RSV rA2-line19F infection induces pulmonary mucous production and increased breathing effort in BALB/c mice and provides a way to assess these manifestations of RSV disease in an animal model. In the present study, we investigated the effect of prophylactic treatment with the F(ab′) 2 form of the anti-G protein monoclonal antibody (MAb) 131-2G on disease in RSV rA2-line19F-challenged mice. F(ab′) 2 131-2G does not affect virus replication. It and the intact form that does decrease virus replication prevented increased breathing effort and Airway Mucin production, as well as weight loss, pulmonary inflammatory-cell infiltration, and the pulmonary substance P and pulmonary Th2 cytokine levels that occur in mice challenged with this virus. These data suggest that the RSV G protein contributes to prominent manifestations of RSV disease and that MAb 131-2G can prevent these manifestations of RSV disease without inhibiting virus infection.
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Vaccine-elicited CD8+ T cells protect against respiratory syncytial virus strain A2-line19F-induced pathogenesis in BALB/c mice
Journal of Virology, 2012Co-Authors: Kate L Stokes, Michael G Currier, Kaori Sakamoto, Nicholas W. Lukacs, Esteban Celis, Martin L MooreAbstract:CD8+ T cells may contribute to vaccines for respiratory syncytial virus (RSV). Compared to CD8+ T cells responding to RSV infection, vaccine-elicited anti-RSV CD8+ T cells are less well defined. We used a peptide vaccine to test the hypothesis that vaccine-elicited RSV-specific CD8+ T cells are protective against RSV pathogenesis. BALB/c mice were treated with a mixture (previously termed TriVax) of an M282-90 peptide representing an immunodominant CD8 epitope, the Toll-like receptor (TLR) agonist poly(I·C), and a costimulatory anti-CD40 antibody. TriVax vaccination induced potent effector anti-RSV CD8+ cytotoxic T lymphocytes (CTL). Mice were challenged with RSV strain A2-line19F, a model of RSV pathogenesis leading to Airway Mucin expression. Mice were protected against RSV infection and against RSV-induced Airway Mucin expression and cellular lung inflammation when challenged 6 days after vaccination. Compared to A2-line19F infection alone, TriVax vaccination followed by challenge resulted in effector CD8+ T cells with greater cytokine expression and the more rapid appearance of RSV-specific CD8+ T cells in the lung. When challenged 42 days after TriVax vaccination, memory CD8+ T cells were elicited with RSV-specific tetramer responses equivalent to TriVax-induced effector CD8+ T cells. These memory CD8+ T cells had lower cytokine expression than effector CD8+ T cells, and protection against A2-line19F was partial during the memory phase. We found that vaccine-elicited effector anti-RSV CD8+ T cells protected mice against RSV infection and pathogenesis, and waning protection correlated with reduced CD8+ T cell cytokine expression.
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a chimeric a2 strain of respiratory syncytial virus rsv with the fusion protein of rsv strain line 19 exhibits enhanced viral load mucus and Airway dysfunction
Journal of Virology, 2009Co-Authors: Martin L Moore, Nicholas W. Lukacs, Cindy Luongo, Vasiliy V Polosukhin, M M Huckabee, Dawn C Newcomb, Ursula J Buchholz, James E Crowe, Kasia Goleniewska, John V WilliamsAbstract:Respiratory syncytial virus (RSV) is the leading cause of respiratory failure and viral death in infants. Abundant Airway mucus contributes to Airway obstruction in RSV disease. Interleukin-13 (IL-13) is a mediator of pulmonary mucus secretion. It has been shown that infection of BALB/c mice with the RSV line 19 strain but not with the RSV A2 laboratory strain results in lung IL-13 and mucus expression. Here, we sequenced the RSV line 19 genome and compared it to the commonly used A2 and Long strains. There were six amino acid differences between the line 19 strain and both the A2 and Long RSV strains, five of which are in the fusion (F) protein. The Long strain, like the A2 strain, did not induce lung IL-13 and mucus expression in BALB/c mice. We hypothesized that the F protein of RSV line 19 is more mucogenic than the F proteins of A2 and Long. We generated recombinant, F-chimeric RSVs by replacing the F gene of A2 with the F gene of either line 19 or Long. Infection of BALB/c mice with RSV rA2 line 19F resulted in lower alpha interferon lung levels 24 h postinfection, higher lung viral load, higher lung IL-13 levels, greater Airway Mucin expression levels, and greater Airway hyperresponsiveness than infection with rA2-A2F or rA2-LongF. We identified the F protein of RSV line 19 as a factor that plays a role in pulmonary Mucin expression in the setting of RSV infection.
Michael G Currier - One of the best experts on this subject based on the ideXlab platform.
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Syncytial Virus Infection Respiratory Mucin Response to Pathogenic Airway Protein and Neutrophils Mediate the The Respiratory Syncytial Virus Fusion
2020Co-Authors: Peter L Collins, Michael G Currier, Richard K Plemper, L. Stokes, Kaori SakamotoAbstract:Respiratory syncytial virus (RSV) is the leading cause of death due to a viral etiology in infants. RSV disease is characterized byepithelial desquamation, neutrophilic bronchiolitis and pneumonia, and obstructive pulmonary mucus. It has been shown thatinfection of BALB/cJ mice with RSV clinical isolate A2001/2-20 (2-20) results in a higher early viral load, greater Airway necrosis,and higher levels of interleukin-13 (IL-13) and Airway Mucin expression than infection with RSV laboratory strain A2. We hy-pothesized that the fusion (F) protein of RSV 2-20 is a mucus-inducing viral factor.
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EGFR Interacts with the Fusion Protein of Respiratory Syncytial Virus Strain 2-20 and Mediates Infection and Mucin Expression.
PLOS Pathogens, 2016Co-Authors: Michael G Currier, Christopher C. Stobart, Anne L. Hotard, Remi Villenave, Jia Meng, Carla Pretto, Michael D. Shields, Minh Trang Nguyen, Sean O. ToddAbstract:Respiratory syncytial virus (RSV) is the major cause of viral lower respiratory tract illness in children. In contrast to the RSV prototypic strain A2, clinical isolate RSV 2–20 induces Airway Mucin expression in mice, a clinically relevant phenotype dependent on the fusion (F) protein of the RSV strain. Epidermal growth factor receptor (EGFR) plays a role in Airway Mucin expression in other systems; therefore, we hypothesized that the RSV 2–20 F protein stimulates EGFR signaling. Infection of cells with chimeric strains RSV A2-2-20F and A2-2-20GF or over-expression of 2–20 F protein resulted in greater phosphorylation of EGFR than infection with RSV A2 or over-expression of A2 F, respectively. Chemical inhibition of EGFR signaling or knockdown of EGFR resulted in diminished infectivity of RSV A2-2-20F but not RSV A2. Over-expression of EGFR enhanced the fusion activity of 2–20 F protein in trans. EGFR co-immunoprecipitated most efficiently with RSV F proteins derived from “mucogenic” strains. RSV 2–20 F and EGFR co-localized in H292 cells, and A2-2-20GF-induced MUC5AC expression was ablated by EGFR inhibitors in these cells. Treatment of BALB/c mice with the EGFR inhibitor erlotinib significantly reduced the amount of RSV A2-2-20F-induced Airway Mucin expression. Our results demonstrate that RSV F interacts with EGFR in a strain-specific manner, EGFR is a co-factor for infection, and EGFR plays a role in RSV-induced Mucin expression, suggesting EGFR is a potential target for RSV disease.
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the respiratory syncytial virus fusion protein and neutrophils mediate the Airway Mucin response to pathogenic respiratory syncytial virus infection
Journal of Virology, 2013Co-Authors: Kate L Stokes, Michael G Currier, Kaori Sakamoto, Peter L Collins, Richard K Plemper, Martin L MooreAbstract:ABSTRACT Respiratory syncytial virus (RSV) is the leading cause of death due to a viral etiology in infants. RSV disease is characterized by epithelial desquamation, neutrophilic bronchiolitis and pneumonia, and obstructive pulmonary mucus. It has been shown that infection of BALB/cJ mice with RSV clinical isolate A2001/2-20 (2-20) results in a higher early viral load, greater Airway necrosis, and higher levels of interleukin-13 (IL-13) and Airway Mucin expression than infection with RSV laboratory strain A2. We hypothesized that the fusion (F) protein of RSV 2-20 is a mucus-inducing viral factor. In vitro , the fusion activity of 2-20 F but not that of A2 F was enhanced by expression of RSV G. We generated a recombinant F-chimeric RSV by replacing the F gene of A2 with the F gene of 2-20, generating A2–2-20F. Similar to the results obtained with the parent 2-20 strain, infection of BALB/cJ mice with A2–2-20F resulted in a higher early viral load and higher levels of subsequent pulmonary Mucin expression than infection with the A2 strain. A2–2-20F infection induced greater necrotic Airway damage and neutrophil infiltration than A2 infection. We hypothesized that the neutrophil response to A2–2-20F infection is involved in Mucin expression. Antibody-mediated depletion of neutrophils in RSV-infected mice resulted in lower tumor necrosis factor alpha levels, fewer IL-13-expressing CD4 T cells, and less Airway Mucin production in the lung. Our data are consistent with a model in which the F and attachment (G) glycoprotein functional interaction leads to enhanced fusion and F is a key factor in Airway epithelium infection, pathogenesis, and subsequent Airway Mucin expression.
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Vaccine-elicited CD8+ T cells protect against respiratory syncytial virus strain A2-line19F-induced pathogenesis in BALB/c mice
Journal of Virology, 2012Co-Authors: Kate L Stokes, Michael G Currier, Kaori Sakamoto, Nicholas W. Lukacs, Esteban Celis, Martin L MooreAbstract:CD8+ T cells may contribute to vaccines for respiratory syncytial virus (RSV). Compared to CD8+ T cells responding to RSV infection, vaccine-elicited anti-RSV CD8+ T cells are less well defined. We used a peptide vaccine to test the hypothesis that vaccine-elicited RSV-specific CD8+ T cells are protective against RSV pathogenesis. BALB/c mice were treated with a mixture (previously termed TriVax) of an M282-90 peptide representing an immunodominant CD8 epitope, the Toll-like receptor (TLR) agonist poly(I·C), and a costimulatory anti-CD40 antibody. TriVax vaccination induced potent effector anti-RSV CD8+ cytotoxic T lymphocytes (CTL). Mice were challenged with RSV strain A2-line19F, a model of RSV pathogenesis leading to Airway Mucin expression. Mice were protected against RSV infection and against RSV-induced Airway Mucin expression and cellular lung inflammation when challenged 6 days after vaccination. Compared to A2-line19F infection alone, TriVax vaccination followed by challenge resulted in effector CD8+ T cells with greater cytokine expression and the more rapid appearance of RSV-specific CD8+ T cells in the lung. When challenged 42 days after TriVax vaccination, memory CD8+ T cells were elicited with RSV-specific tetramer responses equivalent to TriVax-induced effector CD8+ T cells. These memory CD8+ T cells had lower cytokine expression than effector CD8+ T cells, and protection against A2-line19F was partial during the memory phase. We found that vaccine-elicited effector anti-RSV CD8+ T cells protected mice against RSV infection and pathogenesis, and waning protection correlated with reduced CD8+ T cell cytokine expression.
Yin Chen - One of the best experts on this subject based on the ideXlab platform.
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exposure to mold proteases stimulates Mucin production in Airway epithelial cells through ras raf1 erk signal pathway
PLOS ONE, 2020Co-Authors: Zhi Ding, Xianxian Wu, Yin ChenAbstract:Environmental mold (fungus) exposure poses a significant threat to public health by causing illnesses ranging from invasive fungal diseases in immune compromised individuals to allergic hypertensive diseases such as asthma and asthma exacerbation in otherwise healthy people. However, the molecular pathogenesis has not been completely understood, and treatment options are limited. Due to its thermo-tolerance to the normal human body temperature, Aspergillus. fumigatus (A.fumigatus) is one of the most important human pathogens to cause different lung fungal diseases including fungal asthma. Airway obstruction and hyperresponsiveness caused by mucus overproduction are the hallmarks of many A.fumigatus induced lung diseases. To understand the underlying molecular mechanism, we have utilized a well-established A.fumigatus extracts (AFE) model to elucidate downstream signal pathways that mediate A.fumigatus induced Mucin production in Airway epithelial cells. AFE was found to stimulate time- and dose-dependent increase of major Airway Mucin gene expression (MUC5AC and MUC5B) partly via the elevation of their promoter activities. We also demonstrated that EGFR was required but not sufficient for AFE-induced Mucin expression, filling the paradoxical gap from a previous study using the same model. Furthermore, we showed that fungal proteases in AFE were responsible for Mucin induction by activating a Ras/Raf1/ERK signaling pathway. Ca2+ signaling, but ROS, both of which were stimulated by fungal proteases, was an indispensable determinant for ERK activation and Mucin induction. The discovery of this novel pathway likely contributes to our understanding of the pathogenesis of fungal sensitization in allergic diseases such as fungal asthma.
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rhinovirus induced major Airway Mucin production involves a novel tlr3 egfr dependent pathway
American Journal of Respiratory Cell and Molecular Biology, 2009Co-Authors: Yuhua Zhao, Dongfang Yu, Yin ChenAbstract:Mucociliary clearance is a critical innate defense system responsible for clearing up invading pathogens including bacteria and virus. Although the right amount of mucus is good, excessive mucus causes Airway obstruction and tends to precipitate disease symptoms. Rhinovirus (RV) is a common cold virus that causes asthma and chronic obstructive pulmonary disease exacerbation. Mucus overproduction has been linked to the pathogenesis of RV-induced diseases and disease exacerbations. However, the molecular mechanism is not clear. In this study, using one of the major Airway Mucin-MUC5AC as marker, we found that both major and minor groups of RV induced Mucin production in primary human epithelial cells and cell line. RV1A (a minor group of RV) could induce mucous cell metaplasia in vivo. Viral replication was needed for RV-induced Mucin expression, and this induction was also dependent on TLR3, suggesting the involvement of double-stranded (ds) RNA signaling. Indeed, dsRNA alone could also induce Mucin expres...
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Rhinovirus-Induced Major Airway Mucin Production Involves a Novel TLR3-EGFR–Dependent Pathway
American Journal of Respiratory Cell and Molecular Biology, 2008Co-Authors: Yuhua Zhao, Dongfang Yu, Yin ChenAbstract:Mucociliary clearance is a critical innate defense system responsible for clearing up invading pathogens including bacteria and virus. Although the right amount of mucus is good, excessive mucus causes Airway obstruction and tends to precipitate disease symptoms. Rhinovirus (RV) is a common cold virus that causes asthma and chronic obstructive pulmonary disease exacerbation. Mucus overproduction has been linked to the pathogenesis of RV-induced diseases and disease exacerbations. However, the molecular mechanism is not clear. In this study, using one of the major Airway Mucin-MUC5AC as marker, we found that both major and minor groups of RV induced Mucin production in primary human epithelial cells and cell line. RV1A (a minor group of RV) could induce mucous cell metaplasia in vivo. Viral replication was needed for RV-induced Mucin expression, and this induction was also dependent on TLR3, suggesting the involvement of double-stranded (ds) RNA signaling. Indeed, dsRNA alone could also induce Mucin expres...
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stimulation of Airway Mucin gene expression by interleukin il 17 through il 6 paracrine autocrine loop
Journal of Biological Chemistry, 2003Co-Authors: Yin Chen, Philip Thai, Yuhua Zhao, Ye Shih Ho, Mary M Desouza, Reen WuAbstract:Abstract Mucus hypersecretion and persistent Airway inflammation are common features of various Airway diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. One key question is: does the associated Airway inflammation in these diseases affect mucus production? If so, what is the underlying mechanism? It appears that increased mucus secretion results from increased Mucin gene expression and is also frequently accompanied by an increased number of mucous cells (goblet cell hyperplasia/metaplasia) in the Airway epithelium. Many studies on Mucin gene expression have been directed toward Th2 cytokines such as interleukin (IL)-4, IL-9, and IL-13 because of their known pathophysiological role in allergic Airway diseases such as asthma. However, the effect of these cytokines has not been definitely linked to their direct interaction with Airway epithelial cells. In our study, we treated highly differentiated cultures of primary human tracheobronchial epithelial (TBE) cells with a panel of cytokines (interleukin-1α, 1β, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, and tumor necrosis factor α). We found that IL-6 and IL-17 could stimulate the Mucin genes, MUC5B andMUC5AC. The Th2 cytokines IL-4, IL-9, and IL-13 did not stimulate MUC5AC or MUC5B in our experiments. A similar stimulation of MUC5B/Muc5b expression by IL-6 and IL-17 was demonstrated in primary monkey and mouse TBE cells. Further investigation of MUC5B expression demonstrated that IL-17's effect is at least partly mediated through IL-6 by a JAK2-dependent autocrine/paracrine loop. Finally, evidence is presented to show that both IL-6 and IL-17 mediate MUC5Bexpression through the ERK signaling pathway.
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differential regulation of Airway Mucin gene expression and Mucin secretion by extracellular nucleotide triphosphates
American Journal of Respiratory Cell and Molecular Biology, 2001Co-Authors: Yin Chen, Yuhua Zhao, Reen WuAbstract:The effects of extracellular nucleotide triphosphates on the stimulation of Mucin production by Airway epithelial cells were examined. The order of potency in stimulating Mucin secretion in primary cultures of human tracheobronchial epithelial cells is: uridine 5 ′ -triphosphate (UTP) ≈ adenosine 5 ′ -triphosphate (ATP) ≈ ATP- γ -S > uridine 5 ′ -diphosphate ≈ adenosine 5 ′ -diphosphate > α , β -methylene ATP >> adenosine. However, only UTP can increase Mucin gene (MUC5AC, MUC5B) expression; ATP and other analogues have no stimulatory effect. The stimulation of MUC5AC and MUC5B expression by UTP is time- and dose-dependent. A similar effect on the elevation of mucous cell population in mouse Airway epithelium can be demonstrated in vivo by an intratracheal instillation of UTP–saline solution. The stimulatory effect of UTP or ATP on Mucin secretion was inhibited by pertussis toxin, U73122, and Calphostin C, but not by PD98059, suggesting a G-protein/ phospholipase (PL) C/protein kinase (PK) C–dependent and...
Kaori Sakamoto - One of the best experts on this subject based on the ideXlab platform.
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Syncytial Virus Infection Respiratory Mucin Response to Pathogenic Airway Protein and Neutrophils Mediate the The Respiratory Syncytial Virus Fusion
2020Co-Authors: Peter L Collins, Michael G Currier, Richard K Plemper, L. Stokes, Kaori SakamotoAbstract:Respiratory syncytial virus (RSV) is the leading cause of death due to a viral etiology in infants. RSV disease is characterized byepithelial desquamation, neutrophilic bronchiolitis and pneumonia, and obstructive pulmonary mucus. It has been shown thatinfection of BALB/cJ mice with RSV clinical isolate A2001/2-20 (2-20) results in a higher early viral load, greater Airway necrosis,and higher levels of interleukin-13 (IL-13) and Airway Mucin expression than infection with RSV laboratory strain A2. We hy-pothesized that the fusion (F) protein of RSV 2-20 is a mucus-inducing viral factor.
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the respiratory syncytial virus fusion protein and neutrophils mediate the Airway Mucin response to pathogenic respiratory syncytial virus infection
Journal of Virology, 2013Co-Authors: Kate L Stokes, Michael G Currier, Kaori Sakamoto, Peter L Collins, Richard K Plemper, Martin L MooreAbstract:ABSTRACT Respiratory syncytial virus (RSV) is the leading cause of death due to a viral etiology in infants. RSV disease is characterized by epithelial desquamation, neutrophilic bronchiolitis and pneumonia, and obstructive pulmonary mucus. It has been shown that infection of BALB/cJ mice with RSV clinical isolate A2001/2-20 (2-20) results in a higher early viral load, greater Airway necrosis, and higher levels of interleukin-13 (IL-13) and Airway Mucin expression than infection with RSV laboratory strain A2. We hypothesized that the fusion (F) protein of RSV 2-20 is a mucus-inducing viral factor. In vitro , the fusion activity of 2-20 F but not that of A2 F was enhanced by expression of RSV G. We generated a recombinant F-chimeric RSV by replacing the F gene of A2 with the F gene of 2-20, generating A2–2-20F. Similar to the results obtained with the parent 2-20 strain, infection of BALB/cJ mice with A2–2-20F resulted in a higher early viral load and higher levels of subsequent pulmonary Mucin expression than infection with the A2 strain. A2–2-20F infection induced greater necrotic Airway damage and neutrophil infiltration than A2 infection. We hypothesized that the neutrophil response to A2–2-20F infection is involved in Mucin expression. Antibody-mediated depletion of neutrophils in RSV-infected mice resulted in lower tumor necrosis factor alpha levels, fewer IL-13-expressing CD4 T cells, and less Airway Mucin production in the lung. Our data are consistent with a model in which the F and attachment (G) glycoprotein functional interaction leads to enhanced fusion and F is a key factor in Airway epithelium infection, pathogenesis, and subsequent Airway Mucin expression.
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Vaccine-elicited CD8+ T cells protect against respiratory syncytial virus strain A2-line19F-induced pathogenesis in BALB/c mice
Journal of Virology, 2012Co-Authors: Kate L Stokes, Michael G Currier, Kaori Sakamoto, Nicholas W. Lukacs, Esteban Celis, Martin L MooreAbstract:CD8+ T cells may contribute to vaccines for respiratory syncytial virus (RSV). Compared to CD8+ T cells responding to RSV infection, vaccine-elicited anti-RSV CD8+ T cells are less well defined. We used a peptide vaccine to test the hypothesis that vaccine-elicited RSV-specific CD8+ T cells are protective against RSV pathogenesis. BALB/c mice were treated with a mixture (previously termed TriVax) of an M282-90 peptide representing an immunodominant CD8 epitope, the Toll-like receptor (TLR) agonist poly(I·C), and a costimulatory anti-CD40 antibody. TriVax vaccination induced potent effector anti-RSV CD8+ cytotoxic T lymphocytes (CTL). Mice were challenged with RSV strain A2-line19F, a model of RSV pathogenesis leading to Airway Mucin expression. Mice were protected against RSV infection and against RSV-induced Airway Mucin expression and cellular lung inflammation when challenged 6 days after vaccination. Compared to A2-line19F infection alone, TriVax vaccination followed by challenge resulted in effector CD8+ T cells with greater cytokine expression and the more rapid appearance of RSV-specific CD8+ T cells in the lung. When challenged 42 days after TriVax vaccination, memory CD8+ T cells were elicited with RSV-specific tetramer responses equivalent to TriVax-induced effector CD8+ T cells. These memory CD8+ T cells had lower cytokine expression than effector CD8+ T cells, and protection against A2-line19F was partial during the memory phase. We found that vaccine-elicited effector anti-RSV CD8+ T cells protected mice against RSV infection and pathogenesis, and waning protection correlated with reduced CD8+ T cell cytokine expression.
Kate L Stokes - One of the best experts on this subject based on the ideXlab platform.
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the respiratory syncytial virus fusion protein and neutrophils mediate the Airway Mucin response to pathogenic respiratory syncytial virus infection
Journal of Virology, 2013Co-Authors: Kate L Stokes, Michael G Currier, Kaori Sakamoto, Peter L Collins, Richard K Plemper, Martin L MooreAbstract:ABSTRACT Respiratory syncytial virus (RSV) is the leading cause of death due to a viral etiology in infants. RSV disease is characterized by epithelial desquamation, neutrophilic bronchiolitis and pneumonia, and obstructive pulmonary mucus. It has been shown that infection of BALB/cJ mice with RSV clinical isolate A2001/2-20 (2-20) results in a higher early viral load, greater Airway necrosis, and higher levels of interleukin-13 (IL-13) and Airway Mucin expression than infection with RSV laboratory strain A2. We hypothesized that the fusion (F) protein of RSV 2-20 is a mucus-inducing viral factor. In vitro , the fusion activity of 2-20 F but not that of A2 F was enhanced by expression of RSV G. We generated a recombinant F-chimeric RSV by replacing the F gene of A2 with the F gene of 2-20, generating A2–2-20F. Similar to the results obtained with the parent 2-20 strain, infection of BALB/cJ mice with A2–2-20F resulted in a higher early viral load and higher levels of subsequent pulmonary Mucin expression than infection with the A2 strain. A2–2-20F infection induced greater necrotic Airway damage and neutrophil infiltration than A2 infection. We hypothesized that the neutrophil response to A2–2-20F infection is involved in Mucin expression. Antibody-mediated depletion of neutrophils in RSV-infected mice resulted in lower tumor necrosis factor alpha levels, fewer IL-13-expressing CD4 T cells, and less Airway Mucin production in the lung. Our data are consistent with a model in which the F and attachment (G) glycoprotein functional interaction leads to enhanced fusion and F is a key factor in Airway epithelium infection, pathogenesis, and subsequent Airway Mucin expression.
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Vaccine-elicited CD8+ T cells protect against respiratory syncytial virus strain A2-line19F-induced pathogenesis in BALB/c mice
Journal of Virology, 2012Co-Authors: Kate L Stokes, Michael G Currier, Kaori Sakamoto, Nicholas W. Lukacs, Esteban Celis, Martin L MooreAbstract:CD8+ T cells may contribute to vaccines for respiratory syncytial virus (RSV). Compared to CD8+ T cells responding to RSV infection, vaccine-elicited anti-RSV CD8+ T cells are less well defined. We used a peptide vaccine to test the hypothesis that vaccine-elicited RSV-specific CD8+ T cells are protective against RSV pathogenesis. BALB/c mice were treated with a mixture (previously termed TriVax) of an M282-90 peptide representing an immunodominant CD8 epitope, the Toll-like receptor (TLR) agonist poly(I·C), and a costimulatory anti-CD40 antibody. TriVax vaccination induced potent effector anti-RSV CD8+ cytotoxic T lymphocytes (CTL). Mice were challenged with RSV strain A2-line19F, a model of RSV pathogenesis leading to Airway Mucin expression. Mice were protected against RSV infection and against RSV-induced Airway Mucin expression and cellular lung inflammation when challenged 6 days after vaccination. Compared to A2-line19F infection alone, TriVax vaccination followed by challenge resulted in effector CD8+ T cells with greater cytokine expression and the more rapid appearance of RSV-specific CD8+ T cells in the lung. When challenged 42 days after TriVax vaccination, memory CD8+ T cells were elicited with RSV-specific tetramer responses equivalent to TriVax-induced effector CD8+ T cells. These memory CD8+ T cells had lower cytokine expression than effector CD8+ T cells, and protection against A2-line19F was partial during the memory phase. We found that vaccine-elicited effector anti-RSV CD8+ T cells protected mice against RSV infection and pathogenesis, and waning protection correlated with reduced CD8+ T cell cytokine expression.
