IL-27R–Mediated Regulation of IL-17 Controls the Development of Respiratory Syncytial Virus–Associated Pathogenesis

Nagata, Denise E. de Almeida; Demoor, Tine; Ptaschinski, Catherine; Ting, Hung An; Jang, Sihyug; Reed, Michelle; Mukherjee, Sumanta; Lukacs, Nicholas W.

doi:10.1016/j.ajpath.2014.02.004

Cited by 44 publications

(49 citation statements)

References 59 publications

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“…Thus, reevaluating the gene functions for clinical isolates of RSV may contribute to our understanding of the pathogenesis of RSV. The strain used in this study, 2-20, has been shown to induce disease that is more severe than that seen with RSV A2 in the BALB/c mouse model (21,38,39). The contribution of the 2-20 G protein may be linked to its pathogenesis, and it would be interesting to explore whether the relatively greater contribution of G can be extended to other RSV clinical isolates.…”

Section: Discussionmentioning

confidence: 99%

Respiratory Syncytial Virus Attachment Glycoprotein Contribution to Infection Depends on the Specific Fusion Protein

Meng

Hotard

Currier

et al. 2016

J Virol

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Human respiratory syncytial virus (RSV) is an important pathogen causing acute lower respiratory tract disease in children. The RSV attachment glycoprotein (G) is not required for infection, as G-null RSV replicates efficiently in several cell lines. Our laboratory previously reported that the viral fusion (F) protein is a determinant of strain-dependent pathogenesis. Here, we hypothesized that virus dependence on G is determined by the strain specificity of F. We generated recombinant viruses expressing G and F, or null for G, from the laboratory A2 strain (Katushka RSV-A2GA2F [kRSV-A2GA2F] and kRSV-GstopA2F) or the clinical isolate A2001/2-20 (kRSV-2-20G2-20F and kRSV-Gstop2-20F). We quantified the virus cell binding, entry kinetics, infectivity, and growth kinetics of these four recombinant viruses in vitro. RSV expressing the 2-20 G protein exhibited the greatest binding activity. Compared to the parental viruses expressing G and F, removal of 2-20 G had more deleterious effects on binding, entry, infectivity, and growth than removal of A2 G. Overall, RSV expressing 2-20 F had a high dependence on G for binding, entry, and infection. IMPORTANCERSV is the leading cause of childhood acute respiratory disease requiring hospitalization. As with other paramyxoviruses, two major RSV surface viral glycoproteins, the G attachment protein and the F fusion protein, mediate virus binding and subsequent membrane fusion, respectively. Previous work on the RSV A2 prototypical strain demonstrated that the G protein is functionally dispensable for in vitro replication. This is in contrast to other paramyxoviruses that require attachment protein function as a prerequisite for fusion. We reevaluated this requirement for RSV using G and F proteins from clinical isolate 2-20. Compared to the laboratory A2 strain, the G protein from 2-20 had greater contributions to virus binding, entry, infectivity, and in vitro growth kinetics. Thus, the clinical isolate 2-20 F protein function depended more on its G protein, suggesting that RSV has a higher dependence on G than previously thought. H uman respiratory syncytial virus (hRSV or RSV) causes an annual global 3.4 million estimated severe acute lower respiratory tract infections (ALRI) in children younger than 5 years of age (1). In the United States, about 132,000 to 172,000 children younger than 5 years of age are hospitalized due to RSV every year (2). Thus far, there are no licensed vaccines, although there are multiple vaccine candidates undergoing clinical trials (3). Development of antivirals against RSV is also an active field of research and clinical development (4-6).RSV is a member of the Paramyxoviridae family, Pneumovirus genus. Members of the paramyxovirus family encode two major glycoproteins important early during infection for attachment to the host cell and the subsequent entry process. Paramyxovirus fusion mediated by the viral fusion (F) protein is generally initiated by interaction with the homologous attachment protein upon receptor engagement (reviewed ...

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Section: Discussionmentioning

confidence: 99%

Respiratory Syncytial Virus Attachment Glycoprotein Contribution to Infection Depends on the Specific Fusion Protein

Meng

Hotard

Currier

et al. 2016

J Virol

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“…Neutralizing IL-17 in RSV-infected mice led to the reduction of mucus production, inflammation and viral load, an increased number of CD8 + cells and a reduction of Th2 cytokines (50). Moreover, induction of IL-17 by RSV appears to attenuate suppression of Th17 development by IL-27 (51).…”

Section: Th17 Cells and Rsvmentioning

confidence: 99%

“…Negative control over Th17 differentiation is regulated through four distinct mechanisms: IL-27 and IFN-γ through STAT1 activation (9,46,51,70,71); IL-2 and IL-4 through STAT5 activation (72,73); IL-13 through stimulation of IL-10 production by Th17 cells, leading to IL-6 downregulation and thus diminished IL-17 production (74); loss of the inhibition of RORγt by Foxp3 when IL-6 is present (75,76). The balance between Foxp3 and RORγt is therefore a very important factor in the Th17/iTreg equilibrium.…”

Section: Th17 Subsetmentioning

confidence: 99%

The role of Th17 and Treg responses in the pathogenesis of RSV infection

et al. 2015

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“…For example, genetically constructed vaccinia virus (VV) expressing IL-17A (VV IL-17A ) caused more severe disease in mice (42), but VV IL-17A was also reported to be less virulent, and IL-17-deficient (Il17a Ϫ/Ϫ ) mice were more susceptible to VV infection (43). In addition, IL-17A was implicated in priming T cell responses during lymphocytic choriomeningitis virus (LCMV) hepatitis (44) and mediating the immunopathogenicity of viral infections, such as influenza virus (45), respiratory syncytial virus (46,47), murine encephalomyelitis virus (48), and hepatitis B virus (49) infections.…”

mentioning

confidence: 99%

Interleukin-17A Promotes CD8⁺T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

Acharya

Wang

Paul

et al. 2017

J Virol

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CD8 ϩ T cells are crucial components of immunity and play a vital role in recovery from West Nile virus (WNV) infection. Here, we identify a previously unrecognized function of interleukin-17A (IL-17A) in inducing cytotoxic-mediator gene expression and promoting CD8 ϩ T cell cytotoxicity against WNV infection in mice. We find that IL-17A-deficient (Il17a Ϫ/Ϫ ) mice are more susceptible to WNV infection and develop a higher viral burden than wild-type (WT) mice. Interestingly, the CD8 ϩ T cells isolated from Il17a Ϫ/Ϫ mice are less cytotoxic and express lower levels of cytotoxic-mediator genes, which can be restored by supplying recombinant IL-17A in vitro and in vivo. Importantly, treatment of WNV-infected mice with recombinant IL-17A, as late as day 6 postinfection, significantly reduces the viral burden and increases survival, suggesting a therapeutic potential for IL-17A. In conclusion, we report a novel function of IL-17A in promoting CD8 ϩ T cell cytotoxicity, which may have broad implications in other microbial infections and cancers.IMPORTANCE Interleukin-17A (IL-17A) and CD8 ϩ T cells regulate diverse immune functions in microbial infections, malignancies, and autoimmune diseases. IL-17A is a proinflammatory cytokine produced by diverse cell types, while CD8 ϩ T cells (known as cytotoxic T cells) are major cells that provide immunity against intracellular pathogens. Previous studies have demonstrated a crucial role of CD8 ϩ T cells in recovery from West Nile virus (WNV) infection. However, the role of IL-17A during WNV infection remains unclear. Here, we demonstrate that IL-17A protects mice from lethal WNV infection by promoting CD8 ϩ T cell-mediated clearance of WNV. In addition, treatment of WNV-infected mice with recombinant IL-17A reduces the viral burden and increases survival of mice, suggesting a potential therapeutic. This novel IL-17A-CD8 ϩ T cell axis may also have broad implications for immunity to other microbial infections and cancers, where CD8 ϩ T cell functions are crucial.

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IL-27R–Mediated Regulation of IL-17 Controls the Development of Respiratory Syncytial Virus–Associated Pathogenesis

Cited by 44 publications

References 59 publications

Respiratory Syncytial Virus Attachment Glycoprotein Contribution to Infection Depends on the Specific Fusion Protein

Respiratory Syncytial Virus Attachment Glycoprotein Contribution to Infection Depends on the Specific Fusion Protein

The role of Th17 and Treg responses in the pathogenesis of RSV infection

Interleukin-17A Promotes CD8⁺T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

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IL-27R–Mediated Regulation of IL-17 Controls the Development of Respiratory Syncytial Virus–Associated Pathogenesis

Cited by 44 publications

References 59 publications

Respiratory Syncytial Virus Attachment Glycoprotein Contribution to Infection Depends on the Specific Fusion Protein

Respiratory Syncytial Virus Attachment Glycoprotein Contribution to Infection Depends on the Specific Fusion Protein

The role of Th17 and Treg responses in the pathogenesis of RSV infection

Interleukin-17A Promotes CD8+T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

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Interleukin-17A Promotes CD8⁺T Cell Cytotoxicity To Facilitate West Nile Virus Clearance