scholarly journals The Human Immune Response to Respiratory Syncytial Virus Infection

2017 ◽  
Vol 30 (2) ◽  
pp. 481-502 ◽  
Author(s):  
Clark D. Russell ◽  
Stefan A. Unger ◽  
Marc Walton ◽  
Jürgen Schwarze
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
T Cell ◽  
T Cell Response ◽  
Rsv Infection ◽  
Human Immune Response ◽  
Ifn Γ ◽  
Human Immune ◽  
Syncytial Virus

SUMMARY Respiratory syncytial virus (RSV) is an important etiological agent of respiratory infections, particularly in children. Much information regarding the immune response to RSV comes from animal models and in vitro studies. Here, we provide a comprehensive description of the human immune response to RSV infection, based on a systematic literature review of research on infected humans. There is an initial strong neutrophil response to RSV infection in humans, which is positively correlated with disease severity and mediated by interleukin-8 (IL-8). Dendritic cells migrate to the lungs as the primary antigen-presenting cell. An initial systemic T-cell lymphopenia is followed by a pulmonary CD8+ T-cell response, mediating viral clearance. Humoral immunity to reinfection is incomplete, but RSV IgG and IgA are protective. B-cell-stimulating factors derived from airway epithelium play a major role in protective antibody generation. Gamma interferon (IFN-γ) has a strongly protective role, and a Th2-biased response may be deleterious. Other cytokines (particularly IL-17A), chemokines (particularly CCL-5 and CCL-3), and local innate immune factors (including cathelicidins and IFN-λ) contribute to pathogenesis. In summary, neutrophilic inflammation is incriminated as a harmful response, whereas CD8+ T cells and IFN-γ have protective roles. These may represent important therapeutic targets to modulate the immunopathogenesis of RSV infection.

scholarly journals Gene signature of children with severe respiratory syncytial virus infection

2021 ◽  
Author(s):  
Clyde Dapat ◽  
Satoru Kumaki ◽  
Hiroki Sakurai ◽  
Hidekazu Nishimura ◽  
Hannah Karen Mina Labayo ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
T Cell ◽  
Blood Coagulation ◽  
Cell Response ◽  
T Cell Response ◽  
Severe Respiratory Syncytial Virus ◽  
Blood Samples ◽  
Cellular Processes ◽  
Rsv Infection ◽  
Syncytial Virus

Abstract Background The limited treatment options for children with severe respiratory syncytial virus (RSV) infection highlights the need for a comprehensive understanding of the host cellular response during infection. We aimed to identify host genes that are associated with severe RSV disease and to identify drugs that can be repurposed for the treatment of severe RSV infection. Methods We examined clinical data and blood samples from 37 hospitalized children (29 mild and 8 severe) with RSV infection. We tested RNA from blood samples using next-generation sequencing to profile global mRNA expression and identify cellular processes. Results Retractions, decreased breath sounds, and tachypnea were associated with disease severity. We observed upregulation of genes related to neutrophil, inflammatory response, blood coagulation, and downregulation of genes related to T cell response in children with severe RSV. Using network-based approach, 43 drugs were identified that are predicted to interact with the gene products of these differentially expressed genes. Conclusions These results suggest that the changes in the expression pattern in the innate and adaptive immune responses may be associated with RSV clinical severity. Compounds that target these cellular processes can be repositioned as candidate drugs in the treatment of severe RSV. Impact Neutrophil, inflammation, and blood coagulation genes are upregulated in children with severe RSV infection. Expression of T cell response genes are suppressed in cases of severe RSV. Genes identified in this study can contribute in understanding the pathogenesis of RSV disease severity. Drugs that target cellular processes associated with severe RSV can be repositioned as potential therapeutic options.

scholarly journals Chlorobenzoxime inhibits respiratory syncytial virus infection in neonatal rats via up-regulation of IFN-γ in dendritic cells

2020 ◽  
Vol 19 (2) ◽  
pp. 239-246
Author(s):  
Junzhao Li ◽  
Yonghai Zhang ◽  
Hongmei Qiao ◽  
Yingji Jin ◽  
Jianmin Wang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Respiratory Syncytial Virus ◽  
Neonatal Rat ◽  
Interleukin 4 ◽  
Neonatal Rats ◽  
Alveolar Cells ◽  
Rsv Infection ◽  
Ifn Γ ◽  
Syncytial Virus

Purpose: To investigate the effect of chlorobenzoxime on respiratory syncytial virus (RSV) infection in vitro in lung alveolar cells and in vivo in neonatal rats, as well as the mechanism of action involved. Methods: RSV infection in neonatal rats was induced via intranasal administration of 2 x 106PFU viral particles. Reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting were used for determination of changes in interleukin expression. Results: RSV infection in BEAS-2B cells caused significant reduction in viability and marked alteration in morphological appearance (p < 0.05). Exposure of RSV-infected BEAS-2B cells to chlorobenzoxime prevented viability reduction and changes in morphology, and led to reductions in RSV-mediated increases in levels of interleukin-6 and interleukin-8. Moreover, RSV infection significantly enhanced ROS levels in BEAS-2B cells, when compared to control cells (p < 0.05). Chlorobenzoxime at a concentration of 30 μM completely suppressed RSV-mediated generation of ROS in BEAS-2B cells. In neonatal rats, RSV-induced upregulation of interleukin-4, interleukin-13 and TNF-α, were suppressed in bronchoalveolar lavage fluid (BALF) and lung tissues by chlorobenzoxime. Moreover, the RSVmediated reduction in IFN-γ was maximally blocked by chlorobenzoxime at a dose of 10 mg/mL. Chlorobenzoxime enhanced the proportion of IFN-γ -producing cells in neonatal rat BALF. Conclusion: Chlorobenzoxime exhibits antiviral against RSV infection in neonatal rats via increase in dendritic cell population, leading to inhibition of cytokine production. Therefore, chlorobenzoxime is a potential therapeutic agent for RSV infection. Keywords: Respiratory syncytial virus, Cytokines, Dendritic cells, Lung aveolar cells, Morphology, Interleukins

scholarly journals Characterization of Respiratory Syncytial Virus M- and M2-Specific CD4 T Cells in a Murine Model

2009 ◽  
Vol 83 (10) ◽  
pp. 4934-4941 ◽  
Author(s):  
Jie Liu ◽  
Tracy J. Ruckwardt ◽  
Man Chen ◽  
Teresa R. Johnson ◽  
Barney S. Graham
Keyword(s):  
T Cells ◽  
Respiratory Syncytial Virus ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Rsv Infection ◽  
Ifn Γ ◽  
Syncytial Virus

ABSTRACT CD4 T cells have been shown to play an important role in the immunity and immunopathogenesis of respiratory syncytial virus (RSV) infection. We identified two novel CD4 T-cell epitopes in the RSV M and M2 proteins with core sequences M213-223 (FKYIKPQSQFI) and M227-37 (YFEWPPHALLV). Peptides containing the epitopes stimulated RSV-specific CD4 T cells to produce gamma interferon (IFN-γ), interleukin 2 (IL-2), and other Th1- and Th2-type cytokines in an I-Ab-restricted pattern. Construction of fluorochrome-conjugated peptide-I-Ab class II tetramers revealed RSV M- and M2-specific CD4 T-cell responses in RSV-infected mice in a hierarchical pattern. Peptide-activated CD4 T cells from lungs were more activated and differentiated, and had greater IFN-γ expression, than CD4 T cells from the spleen, which, in contrast, produced greater levels of IL-2. In addition, M209-223 peptide-activated CD4 T cells reduced IFN-γ and IL-2 production in M- and M2-specific CD8 T-cell responses to Db-M187-195 and Kd-M282-90 peptides more than M225-39 peptide-stimulated CD4 T cells. This correlated with the fact that I-Ab-M209-223 tetramer-positive cells responding to primary RSV infection had a much higher frequency of FoxP3 expression than I-Ab-M226-39 tetramer-positive CD4 T cells, suggesting that the M-specific CD4 T-cell response has greater regulatory function. Characterization of epitope-specific CD4 T cells by novel fluorochrome-conjugated peptide-I-Ab tetramers allows detailed analysis of their roles in RSV pathogenesis and immunity.

scholarly journals Respiratory Syncytial Virus Infection: Immune Response, Immunopathogenesis, and Treatment

1999 ◽  
Vol 12 (2) ◽  
pp. 298-309 ◽  
Author(s):  
Joseph B. Domachowske ◽  
Helene F. Rosenberg
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
Respiratory Tract ◽  
Neutralizing Antibodies ◽  
Lower Respiratory Tract ◽  
Immunoglobulin E ◽  
Neutralizing Antibody ◽  
Rsv Infection ◽  
Syncytial Virus

SUMMARY Respiratory syncytial virus (RSV) is the single most important cause of lower respiratory tract infection during infancy and early childhood. Once RSV infection is established, the host immune response includes the production of virus-neutralizing antibodies and T-cell-specific immunity. The humoral immune response normally results in the development of anti-RSV neutralizing-antibody titers, but these are often suboptimal during an infant’s initial infection. Even when the production of RSV neutralizing antibody following RSV infection is robust, humoral immunity wanes over time. Reinfection during subsequent seasons is common. The cellular immune response to RSV infection is also important for the clearance of virus. This immune response, vital for host defense against RSV, is also implicated in the immunopathogenesis of severe lower respiratory tract RSV bronchiolitis. Many details of the immunology and immunopathologic mechanisms of RSV disease known at present have been learned from rodent models of RSV disease and are discussed in some detail. In addition, the roles of immunoglobulin E, histamine, and eosinophils in the immunopathogenesis of RSV disease are considered. Although the treatment of RSV bronchiolitis is primarily supportive, the role of ribavirin is briefly discussed. Novel approaches to the development of new antiviral drugs with promising anti-RSV activity in vitro are also described.

scholarly journals Mathematical modelling identifies the role of adaptive immunity as a key controller of respiratory syncytial virus in cotton rats

2019 ◽  
Vol 16 (160) ◽  
pp. 20190389 ◽  
Author(s):  
Darren Wethington ◽  
Olivia Harder ◽  
Karthik Uppulury ◽  
William C. L. Stewart ◽  
Phylip Chen ◽  
...  
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
Mathematical Modelling ◽  
Adaptive Immune Response ◽  
Viral Titre ◽  
Adaptive Immune ◽  
Rsv Infection ◽  
Cotton Rats ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) is a common virus that can have varying effects ranging from mild cold-like symptoms to mortality depending on the age and immune status of the individual. We combined mathematical modelling using ordinary differential equations (ODEs) with measurement of RSV infection kinetics in primary well-differentiated human bronchial epithelial cultures in vitro and in immunocompetent and immunosuppressed cotton rats to glean mechanistic details that underlie RSV infection kinetics in the lung. Quantitative analysis of viral titre kinetics in our mathematical model showed that the elimination of infected cells by the adaptive immune response generates unique RSV titre kinetic features including a faster timescale of viral titre clearance than viral production, and a monotonic decrease in the peak RSV titre with decreasing inoculum dose. Parameter estimation in the ODE model using a nonlinear mixed effects approach revealed a very low rate (average single-cell lifetime > 10 days) of cell lysis by RSV before the adaptive immune response is initiated. Our model predicted negligible changes in the RSV titre kinetics at early times post-infection (less than 5 dpi) but a slower decay in RSV titre in immunosuppressed cotton rats compared to that in non-suppressed cotton rats at later times (greater than 5 dpi) in silico. These predictions were in excellent agreement with the experimental results. Our combined approach quantified the importance of the adaptive immune response in suppressing RSV infection in cotton rats, which could be useful in testing RSV vaccine candidates.

scholarly journals Evaluation of the Safety and Immune Efficacy of Recombinant Human Respiratory Syncytial Virus Strain Long Live Attenuated Vaccine Candidates

2021 ◽  
Author(s):  
Li-Nan Wang ◽  
Xiang-Lei Peng ◽  
Min Xu ◽  
Yuan-Bo Zheng ◽  
Yue-Ying Jiao ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Gene Deletion ◽  
Human Respiratory Syncytial Virus ◽  
Temperature Sensitive ◽  
T7 Promoter ◽  
Vaccine Candidates ◽  
Rsv Infection ◽  
Syncytial Virus

AbstractHuman respiratory syncytial virus (RSV) infection is the leading cause of lower respiratory tract illness (LRTI), and no vaccine against LRTI has proven to be safe and effective in infants. Our study assessed attenuated recombinant RSVs as vaccine candidates to prevent RSV infection in mice. The constructed recombinant plasmids harbored (5′ to 3′) a T7 promoter, hammerhead ribozyme, RSV Long strain antigenomic cDNA with cold-passaged (cp) mutations or cp combined with temperature-sensitive attenuated mutations from the A2 strain (A2cpts) or further combined with SH gene deletion (A2cptsΔSH), HDV ribozyme (δ), and a T7 terminator. These vectors were subsequently co-transfected with four helper plasmids encoding N, P, L, and M2-1 viral proteins into BHK/T7-9 cells, and the recovered viruses were then passaged in Vero cells. The rescued recombinant RSVs (rRSVs) were named rRSV-Long/A2cp, rRSV-Long/A2cpts, and rRSV-Long/A2cptsΔSH, respectively, and stably passaged in vitro, without reversion to wild type (wt) at sites containing introduced mutations or deletion. Although rRSV-Long/A2cpts and rRSV-Long/A2cptsΔSH displayed  temperature-sensitive (ts) phenotype in vitro and in vivo, all rRSVs were significantly attenuated in vivo. Furthermore, BALB/c mice immunized with rRSVs produced Th1-biased immune response, resisted wtRSV infection, and were free from enhanced respiratory disease. We showed that the combination of ΔSH with attenuation (att) mutations of cpts contributed to improving att phenotype, efficacy, and gene stability of rRSV. By successfully introducing att mutations and SH gene deletion into the RSV Long parent and producing three rRSV strains, we have laid an important foundation for the development of RSV live attenuated vaccines.

scholarly journals Inhibitory Effect of Sargassum fusiforme and Its Components on Replication of Respiratory Syncytial Virus In Vitro and In Vivo

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 548
Author(s):  
Kiramage Chathuranga ◽  
Asela Weerawardhana ◽  
Niranjan Dodantenna ◽  
Lakmal Ranathunga ◽  
Won-Kyung Cho ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Antiviral Agent ◽  
Active Components ◽  
Sargassum Fusiforme ◽  
Antiviral Effects ◽  
Improve Life Expectancy ◽  
Rsv Infection ◽  
Syncytial Virus

Sargassum fusiforme, a plant used as a medicine and food, is regarded as a marine vegetable and health supplement to improve life expectancy. Here, we demonstrate that S. fusiforme extract (SFE) has antiviral effects against respiratory syncytial virus (RSV) in vitro and in vivo mouse model. Treatment of HEp2 cells with a non-cytotoxic concentration of SFE significantly reduced RSV replication, RSV-induced cell death, RSV gene transcription, RSV protein synthesis, and syncytium formation. Moreover, oral inoculation of SFE significantly improved RSV clearance from the lungs of BALB/c mice. Interestingly, the phenolic compounds eicosane, docosane, and tetracosane were identified as active components of SFE. Treatment with a non-cytotoxic concentration of these three components elicited similar antiviral effects against RSV infection as SFE in vitro. Together, these results suggest that SFE and its potential components are a promising natural antiviral agent candidate against RSV infection.

scholarly journals Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment

2021 ◽  
Vol 9 (6) ◽  
pp. e002269
Author(s):  
Shota Aoyama ◽  
Ryosuke Nakagawa ◽  
Satoshi Nemoto ◽  
Patricio Perez-Villarroel ◽  
James J Mulé ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
T Cell Response ◽  
Effector Function ◽  
Checkpoint Blockade ◽  
Necrosis Factor Alpha ◽  
Ifn Γ

BackgroundThe temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth.MethodsC57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays.ResultsThe distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth.ConclusionsDespite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

scholarly journals The immune response against myelin basic protein in two strains of rat with different genetic capacity to develop experimental allergic encephalomyelitis.

1975 ◽  
Vol 141 (1) ◽  
pp. 72-81 ◽  
Author(s):  
D E McFarlin ◽  
S C Hsu ◽  
S B Slemenda ◽  
F C Chou ◽  
R F Kibler
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Experimental Allergic Encephalomyelitis ◽  
Cell Response ◽  
Basic Protein ◽  
T Cell Response ◽  
Skin Tests ◽  
Allergic Encephalomyelitis ◽  
Experimental Allergic

After challenge with guiena pig basic protein (GPBP) Lewis (Le) rats, which are homozygous for the immune response experimental allergic encephalomyelitis (Ir-EAE) gene, developed positive delayed skin tests against GPBP and the 43 residue encephalitogenic fragment (EF); in addition, Le rat lymph node cells (LNC) were stimulated and produced migration inhibitory factor (MIF) when incubated in vitro with these antigens. In contrast Brown Norway (BN) rats, which lack the Ir-EAE gene, did not develop delayed skin tests to EF and their LNC were not stimulated and did not produce MIF when incubated in vitro with EF. These observations indicate that the Ir-EAE gene controls a T-cell response against the EF. Le rats produced measurable anti-BP antibody by radioimmunoassay after primary challenge. Although no antibody was detectable in BN rats by radioimmunoassay, radioimmunoelectrophoresis indicated that a small amount of antibody was formed after primary immunization. After boosting intraperitoneally, both strains of rat exhibited a rise in anti-BP antibody; which was greater in Le rats. In both strains of rat the anti-BP antibody reacted with a portion of the molecule other than the EF. Since EF primarily evokes a T cell response, it is suggested that the EF portion of the BP molecule may contain a helper determinant in antibody production.

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