The Experts below are selected from a list of 30969 Experts worldwide ranked by ideXlab platform
Prasad Rallabhandi - One of the best experts on this subject based on the ideXlab platform.
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respiratory syncytial virus fusion Protein induced toll like receptor 4 tlr4 signaling is inhibited by the tlr4 antagonists rhodobacter sphaeroides lipopolysaccharide and eritoran e5564 and requires direct interaction with MD 2
Mbio, 2012Co-Authors: Kari Ann Shirey, Marina S Boukhvalova, Lioubov M Pletneva, Theresa L Gioannini, Jerrold Weiss, Prasad Rallabhandi, Rachel L Phillips, Jesse Chow, Lynn D HawkinsAbstract:ABSTRACT Respiratory syncytial virus (RSV) is a leading cause of infant mortality worldwide. Toll-like receptor 4 (TLR4), a signaling receptor for structurally diverse microbe-associated molecular patterns, is activated by the RSV fusion (F) Protein and by bacterial lipopolysaccharide (LPS) in a CD14-dependent manner. TLR4 signaling by LPS also requires the presence of an additional Protein, MD-2. Thus, it is possible that F Protein-mediated TLR4 activation relies on MD-2 as well, although this hypothesis has not been formally tested. LPS-free RSV F Protein was found to activate NF-κB in HEK293T transfectants that express wild-type (WT) TLR4 and CD14, but only when MD-2 was coexpressed. These findings were confirmed by measuring F-Protein-induced interleukin 1β (IL-1β) mRNA in WT versus MD-2 −/− macrophages, where MD-2 −/− macrophages failed to show IL-1β expression upon F-Protein treatment, in contrast to the WT. Both Rhodobacter sphaeroides LPS and synthetic E5564 (eritoran), LPS antagonists that inhibit TLR4 signaling by binding a hydrophobic pocket in MD-2, significantly reduced RSV F-Protein-mediated TLR4 activity in HEK293T-TLR4–CD14–MD-2 transfectants in a dose-dependent manner, while TLR4-independent NF-κB activation by tumor necrosis factor alpha (TNF-α) was unaffected. In vitro coimmunoprecipitation studies confirmed a physical interaction between native RSV F Protein and MD-2. Further, we demonstrated that the N-terminal domain of the F1 segment of RSV F Protein interacts with MD-2. These data provide new insights into the importance of MD-2 in RSV F-Protein-mediated TLR4 activation. Thus, targeting the interaction between MD-2 and RSV F Protein may potentially lead to novel therapeutic approaches to help control RSV-induced inflammation and pathology. IMPORTANCE This study shows for the first time that the fusion (F) Protein of respiratory syncytial virus (RSV), a major cause of bronchiolitis and death, particularly in infants and young children, physically interacts with the Toll-like receptor 4 (TLR4) coreceptor, MD-2, through its N-terminal domain. We show that F Protein-induced TLR4 activation can be blocked by lipid A analog antagonists. This observation provides a strong experimental rationale for testing such antagonists in animal models of RSV infection for potential use in people.
Lynn D Hawkins - One of the best experts on this subject based on the ideXlab platform.
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respiratory syncytial virus fusion Protein induced toll like receptor 4 tlr4 signaling is inhibited by the tlr4 antagonists rhodobacter sphaeroides lipopolysaccharide and eritoran e5564 and requires direct interaction with MD 2
Mbio, 2012Co-Authors: Kari Ann Shirey, Marina S Boukhvalova, Lioubov M Pletneva, Theresa L Gioannini, Jerrold Weiss, Prasad Rallabhandi, Rachel L Phillips, Jesse Chow, Lynn D HawkinsAbstract:ABSTRACT Respiratory syncytial virus (RSV) is a leading cause of infant mortality worldwide. Toll-like receptor 4 (TLR4), a signaling receptor for structurally diverse microbe-associated molecular patterns, is activated by the RSV fusion (F) Protein and by bacterial lipopolysaccharide (LPS) in a CD14-dependent manner. TLR4 signaling by LPS also requires the presence of an additional Protein, MD-2. Thus, it is possible that F Protein-mediated TLR4 activation relies on MD-2 as well, although this hypothesis has not been formally tested. LPS-free RSV F Protein was found to activate NF-κB in HEK293T transfectants that express wild-type (WT) TLR4 and CD14, but only when MD-2 was coexpressed. These findings were confirmed by measuring F-Protein-induced interleukin 1β (IL-1β) mRNA in WT versus MD-2 −/− macrophages, where MD-2 −/− macrophages failed to show IL-1β expression upon F-Protein treatment, in contrast to the WT. Both Rhodobacter sphaeroides LPS and synthetic E5564 (eritoran), LPS antagonists that inhibit TLR4 signaling by binding a hydrophobic pocket in MD-2, significantly reduced RSV F-Protein-mediated TLR4 activity in HEK293T-TLR4–CD14–MD-2 transfectants in a dose-dependent manner, while TLR4-independent NF-κB activation by tumor necrosis factor alpha (TNF-α) was unaffected. In vitro coimmunoprecipitation studies confirmed a physical interaction between native RSV F Protein and MD-2. Further, we demonstrated that the N-terminal domain of the F1 segment of RSV F Protein interacts with MD-2. These data provide new insights into the importance of MD-2 in RSV F-Protein-mediated TLR4 activation. Thus, targeting the interaction between MD-2 and RSV F Protein may potentially lead to novel therapeutic approaches to help control RSV-induced inflammation and pathology. IMPORTANCE This study shows for the first time that the fusion (F) Protein of respiratory syncytial virus (RSV), a major cause of bronchiolitis and death, particularly in infants and young children, physically interacts with the Toll-like receptor 4 (TLR4) coreceptor, MD-2, through its N-terminal domain. We show that F Protein-induced TLR4 activation can be blocked by lipid A analog antagonists. This observation provides a strong experimental rationale for testing such antagonists in animal models of RSV infection for potential use in people.
Marina S Boukhvalova - One of the best experts on this subject based on the ideXlab platform.
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respiratory syncytial virus fusion Protein induced toll like receptor 4 tlr4 signaling is inhibited by the tlr4 antagonists rhodobacter sphaeroides lipopolysaccharide and eritoran e5564 and requires direct interaction with MD 2
Mbio, 2012Co-Authors: Kari Ann Shirey, Marina S Boukhvalova, Lioubov M Pletneva, Theresa L Gioannini, Jerrold Weiss, Prasad Rallabhandi, Rachel L Phillips, Jesse Chow, Lynn D HawkinsAbstract:ABSTRACT Respiratory syncytial virus (RSV) is a leading cause of infant mortality worldwide. Toll-like receptor 4 (TLR4), a signaling receptor for structurally diverse microbe-associated molecular patterns, is activated by the RSV fusion (F) Protein and by bacterial lipopolysaccharide (LPS) in a CD14-dependent manner. TLR4 signaling by LPS also requires the presence of an additional Protein, MD-2. Thus, it is possible that F Protein-mediated TLR4 activation relies on MD-2 as well, although this hypothesis has not been formally tested. LPS-free RSV F Protein was found to activate NF-κB in HEK293T transfectants that express wild-type (WT) TLR4 and CD14, but only when MD-2 was coexpressed. These findings were confirmed by measuring F-Protein-induced interleukin 1β (IL-1β) mRNA in WT versus MD-2 −/− macrophages, where MD-2 −/− macrophages failed to show IL-1β expression upon F-Protein treatment, in contrast to the WT. Both Rhodobacter sphaeroides LPS and synthetic E5564 (eritoran), LPS antagonists that inhibit TLR4 signaling by binding a hydrophobic pocket in MD-2, significantly reduced RSV F-Protein-mediated TLR4 activity in HEK293T-TLR4–CD14–MD-2 transfectants in a dose-dependent manner, while TLR4-independent NF-κB activation by tumor necrosis factor alpha (TNF-α) was unaffected. In vitro coimmunoprecipitation studies confirmed a physical interaction between native RSV F Protein and MD-2. Further, we demonstrated that the N-terminal domain of the F1 segment of RSV F Protein interacts with MD-2. These data provide new insights into the importance of MD-2 in RSV F-Protein-mediated TLR4 activation. Thus, targeting the interaction between MD-2 and RSV F Protein may potentially lead to novel therapeutic approaches to help control RSV-induced inflammation and pathology. IMPORTANCE This study shows for the first time that the fusion (F) Protein of respiratory syncytial virus (RSV), a major cause of bronchiolitis and death, particularly in infants and young children, physically interacts with the Toll-like receptor 4 (TLR4) coreceptor, MD-2, through its N-terminal domain. We show that F Protein-induced TLR4 activation can be blocked by lipid A analog antagonists. This observation provides a strong experimental rationale for testing such antagonists in animal models of RSV infection for potential use in people.
Kari Ann Shirey - One of the best experts on this subject based on the ideXlab platform.
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respiratory syncytial virus fusion Protein induced toll like receptor 4 tlr4 signaling is inhibited by the tlr4 antagonists rhodobacter sphaeroides lipopolysaccharide and eritoran e5564 and requires direct interaction with MD 2
Mbio, 2012Co-Authors: Kari Ann Shirey, Marina S Boukhvalova, Lioubov M Pletneva, Theresa L Gioannini, Jerrold Weiss, Prasad Rallabhandi, Rachel L Phillips, Jesse Chow, Lynn D HawkinsAbstract:ABSTRACT Respiratory syncytial virus (RSV) is a leading cause of infant mortality worldwide. Toll-like receptor 4 (TLR4), a signaling receptor for structurally diverse microbe-associated molecular patterns, is activated by the RSV fusion (F) Protein and by bacterial lipopolysaccharide (LPS) in a CD14-dependent manner. TLR4 signaling by LPS also requires the presence of an additional Protein, MD-2. Thus, it is possible that F Protein-mediated TLR4 activation relies on MD-2 as well, although this hypothesis has not been formally tested. LPS-free RSV F Protein was found to activate NF-κB in HEK293T transfectants that express wild-type (WT) TLR4 and CD14, but only when MD-2 was coexpressed. These findings were confirmed by measuring F-Protein-induced interleukin 1β (IL-1β) mRNA in WT versus MD-2 −/− macrophages, where MD-2 −/− macrophages failed to show IL-1β expression upon F-Protein treatment, in contrast to the WT. Both Rhodobacter sphaeroides LPS and synthetic E5564 (eritoran), LPS antagonists that inhibit TLR4 signaling by binding a hydrophobic pocket in MD-2, significantly reduced RSV F-Protein-mediated TLR4 activity in HEK293T-TLR4–CD14–MD-2 transfectants in a dose-dependent manner, while TLR4-independent NF-κB activation by tumor necrosis factor alpha (TNF-α) was unaffected. In vitro coimmunoprecipitation studies confirmed a physical interaction between native RSV F Protein and MD-2. Further, we demonstrated that the N-terminal domain of the F1 segment of RSV F Protein interacts with MD-2. These data provide new insights into the importance of MD-2 in RSV F-Protein-mediated TLR4 activation. Thus, targeting the interaction between MD-2 and RSV F Protein may potentially lead to novel therapeutic approaches to help control RSV-induced inflammation and pathology. IMPORTANCE This study shows for the first time that the fusion (F) Protein of respiratory syncytial virus (RSV), a major cause of bronchiolitis and death, particularly in infants and young children, physically interacts with the Toll-like receptor 4 (TLR4) coreceptor, MD-2, through its N-terminal domain. We show that F Protein-induced TLR4 activation can be blocked by lipid A analog antagonists. This observation provides a strong experimental rationale for testing such antagonists in animal models of RSV infection for potential use in people.
Jesse Chow - One of the best experts on this subject based on the ideXlab platform.
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respiratory syncytial virus fusion Protein induced toll like receptor 4 tlr4 signaling is inhibited by the tlr4 antagonists rhodobacter sphaeroides lipopolysaccharide and eritoran e5564 and requires direct interaction with MD 2
Mbio, 2012Co-Authors: Kari Ann Shirey, Marina S Boukhvalova, Lioubov M Pletneva, Theresa L Gioannini, Jerrold Weiss, Prasad Rallabhandi, Rachel L Phillips, Jesse Chow, Lynn D HawkinsAbstract:ABSTRACT Respiratory syncytial virus (RSV) is a leading cause of infant mortality worldwide. Toll-like receptor 4 (TLR4), a signaling receptor for structurally diverse microbe-associated molecular patterns, is activated by the RSV fusion (F) Protein and by bacterial lipopolysaccharide (LPS) in a CD14-dependent manner. TLR4 signaling by LPS also requires the presence of an additional Protein, MD-2. Thus, it is possible that F Protein-mediated TLR4 activation relies on MD-2 as well, although this hypothesis has not been formally tested. LPS-free RSV F Protein was found to activate NF-κB in HEK293T transfectants that express wild-type (WT) TLR4 and CD14, but only when MD-2 was coexpressed. These findings were confirmed by measuring F-Protein-induced interleukin 1β (IL-1β) mRNA in WT versus MD-2 −/− macrophages, where MD-2 −/− macrophages failed to show IL-1β expression upon F-Protein treatment, in contrast to the WT. Both Rhodobacter sphaeroides LPS and synthetic E5564 (eritoran), LPS antagonists that inhibit TLR4 signaling by binding a hydrophobic pocket in MD-2, significantly reduced RSV F-Protein-mediated TLR4 activity in HEK293T-TLR4–CD14–MD-2 transfectants in a dose-dependent manner, while TLR4-independent NF-κB activation by tumor necrosis factor alpha (TNF-α) was unaffected. In vitro coimmunoprecipitation studies confirmed a physical interaction between native RSV F Protein and MD-2. Further, we demonstrated that the N-terminal domain of the F1 segment of RSV F Protein interacts with MD-2. These data provide new insights into the importance of MD-2 in RSV F-Protein-mediated TLR4 activation. Thus, targeting the interaction between MD-2 and RSV F Protein may potentially lead to novel therapeutic approaches to help control RSV-induced inflammation and pathology. IMPORTANCE This study shows for the first time that the fusion (F) Protein of respiratory syncytial virus (RSV), a major cause of bronchiolitis and death, particularly in infants and young children, physically interacts with the Toll-like receptor 4 (TLR4) coreceptor, MD-2, through its N-terminal domain. We show that F Protein-induced TLR4 activation can be blocked by lipid A analog antagonists. This observation provides a strong experimental rationale for testing such antagonists in animal models of RSV infection for potential use in people.
