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Virulence of Emerging Arthrotropic Avian Reoviruses Correlates With Their Ability to Activate and Traffic Interferon-γ Producing Cytotoxic CD8(+) T Cells Into Gastrocnemius Tendon

Newly emerging arthrotropic avian reoviruses (ARVs) are genetically divergent, antigenically heterogeneous, and economically costly. Nevertheless, the mechanism of emerging ARV-induced disease pathogenesis and potential differences in virulence between virus genotypes have not been adequately addres...

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Autores principales: Ayalew, Lisanework E., Ahmed, Khawaja Ashfaque, Popowich, Shelly, Lockerbie, Betty-Chow, Gupta, Ashish, Tikoo, Suresh K., Ojkic, Davor, Gomis, Susantha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964311/
https://www.ncbi.nlm.nih.gov/pubmed/35369435
http://dx.doi.org/10.3389/fmicb.2022.869164
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author Ayalew, Lisanework E.
Ahmed, Khawaja Ashfaque
Popowich, Shelly
Lockerbie, Betty-Chow
Gupta, Ashish
Tikoo, Suresh K.
Ojkic, Davor
Gomis, Susantha
author_facet Ayalew, Lisanework E.
Ahmed, Khawaja Ashfaque
Popowich, Shelly
Lockerbie, Betty-Chow
Gupta, Ashish
Tikoo, Suresh K.
Ojkic, Davor
Gomis, Susantha
author_sort Ayalew, Lisanework E.
collection PubMed
description Newly emerging arthrotropic avian reoviruses (ARVs) are genetically divergent, antigenically heterogeneous, and economically costly. Nevertheless, the mechanism of emerging ARV-induced disease pathogenesis and potential differences in virulence between virus genotypes have not been adequately addressed. In this study, the life cycle of ARV, including the formation of cytoplasmic ARV neo-organelles, paracrystalline structures, and virus release mechanisms, were characterized in the infected host cell by transmission electron microscopy (TEM). In addition, progressive changes in the structure of infected cells were investigated by time-lapse and field emission scanning electron (FE-SE) microscopy. ARVs from the four genotypic cluster groups included in the study caused gross and microscopic lesions in the infected birds. Marked infiltration of γδT cells, CD4(+) and CD8(+) T lymphocytes were observed in ARV infected tendon tissues starting day 3 post-infection. The ARV variant from genotype cluster-2 triggered significantly high trafficking of IFN-γ producing CD8(+) T lymphocytes in tendon tissues and concomitantly showed high morbidity and severe disease manifestations. In contrast, the ARV variant from genotype cluster-4 was less virulent, caused milder disease, and accompanied less infiltration of IFN-γ producing CD8(+) T cells. Interestingly, when we blunted antiviral immune responses using clodronate liposomes (which depletes antigen-presenting cells) or cyclosporin (which inhibits cytokine production that regulates T-cell proliferation), significantly lower IFN-γ producing CD8(+) T cells infiltrated into tendon tissues, resulting in reduced tendon tissues apoptosis and milder disease manifestations. In summary, these data suggest that the degree of ARV virulence and tenosynovitis/arthritis are potentially directly associated with the ability of the virus to traffic massive infiltration of cytotoxic CD8(+) T cells into the infected tissues. Moreover, the ability to traffic cytotoxic CD8(+) T cells into infected tendon tissues and the severity of tenosynovitis differ between variants from different ARV genotype cluster groups. However, more than one virus isolate per genotype group needs to be tested to further confirm the association of pathogenicity with genotype. These findings can be used to further examine the interaction of viral and cellular pathways which are essential for the pathogenesis of the disease at the molecular level and to develop effective disease control strategies.
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spelling pubmed-89643112022-03-31 Virulence of Emerging Arthrotropic Avian Reoviruses Correlates With Their Ability to Activate and Traffic Interferon-γ Producing Cytotoxic CD8(+) T Cells Into Gastrocnemius Tendon Ayalew, Lisanework E. Ahmed, Khawaja Ashfaque Popowich, Shelly Lockerbie, Betty-Chow Gupta, Ashish Tikoo, Suresh K. Ojkic, Davor Gomis, Susantha Front Microbiol Microbiology Newly emerging arthrotropic avian reoviruses (ARVs) are genetically divergent, antigenically heterogeneous, and economically costly. Nevertheless, the mechanism of emerging ARV-induced disease pathogenesis and potential differences in virulence between virus genotypes have not been adequately addressed. In this study, the life cycle of ARV, including the formation of cytoplasmic ARV neo-organelles, paracrystalline structures, and virus release mechanisms, were characterized in the infected host cell by transmission electron microscopy (TEM). In addition, progressive changes in the structure of infected cells were investigated by time-lapse and field emission scanning electron (FE-SE) microscopy. ARVs from the four genotypic cluster groups included in the study caused gross and microscopic lesions in the infected birds. Marked infiltration of γδT cells, CD4(+) and CD8(+) T lymphocytes were observed in ARV infected tendon tissues starting day 3 post-infection. The ARV variant from genotype cluster-2 triggered significantly high trafficking of IFN-γ producing CD8(+) T lymphocytes in tendon tissues and concomitantly showed high morbidity and severe disease manifestations. In contrast, the ARV variant from genotype cluster-4 was less virulent, caused milder disease, and accompanied less infiltration of IFN-γ producing CD8(+) T cells. Interestingly, when we blunted antiviral immune responses using clodronate liposomes (which depletes antigen-presenting cells) or cyclosporin (which inhibits cytokine production that regulates T-cell proliferation), significantly lower IFN-γ producing CD8(+) T cells infiltrated into tendon tissues, resulting in reduced tendon tissues apoptosis and milder disease manifestations. In summary, these data suggest that the degree of ARV virulence and tenosynovitis/arthritis are potentially directly associated with the ability of the virus to traffic massive infiltration of cytotoxic CD8(+) T cells into the infected tissues. Moreover, the ability to traffic cytotoxic CD8(+) T cells into infected tendon tissues and the severity of tenosynovitis differ between variants from different ARV genotype cluster groups. However, more than one virus isolate per genotype group needs to be tested to further confirm the association of pathogenicity with genotype. These findings can be used to further examine the interaction of viral and cellular pathways which are essential for the pathogenesis of the disease at the molecular level and to develop effective disease control strategies. Frontiers Media S.A. 2022-03-14 /pmc/articles/PMC8964311/ /pubmed/35369435 http://dx.doi.org/10.3389/fmicb.2022.869164 Text en Copyright © 2022 Ayalew, Ahmed, Popowich, Lockerbie, Gupta, Tikoo, Ojkic and Gomis. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Ayalew, Lisanework E.
Ahmed, Khawaja Ashfaque
Popowich, Shelly
Lockerbie, Betty-Chow
Gupta, Ashish
Tikoo, Suresh K.
Ojkic, Davor
Gomis, Susantha
Virulence of Emerging Arthrotropic Avian Reoviruses Correlates With Their Ability to Activate and Traffic Interferon-γ Producing Cytotoxic CD8(+) T Cells Into Gastrocnemius Tendon
title Virulence of Emerging Arthrotropic Avian Reoviruses Correlates With Their Ability to Activate and Traffic Interferon-γ Producing Cytotoxic CD8(+) T Cells Into Gastrocnemius Tendon
title_full Virulence of Emerging Arthrotropic Avian Reoviruses Correlates With Their Ability to Activate and Traffic Interferon-γ Producing Cytotoxic CD8(+) T Cells Into Gastrocnemius Tendon
title_fullStr Virulence of Emerging Arthrotropic Avian Reoviruses Correlates With Their Ability to Activate and Traffic Interferon-γ Producing Cytotoxic CD8(+) T Cells Into Gastrocnemius Tendon
title_full_unstemmed Virulence of Emerging Arthrotropic Avian Reoviruses Correlates With Their Ability to Activate and Traffic Interferon-γ Producing Cytotoxic CD8(+) T Cells Into Gastrocnemius Tendon
title_short Virulence of Emerging Arthrotropic Avian Reoviruses Correlates With Their Ability to Activate and Traffic Interferon-γ Producing Cytotoxic CD8(+) T Cells Into Gastrocnemius Tendon
title_sort virulence of emerging arthrotropic avian reoviruses correlates with their ability to activate and traffic interferon-γ producing cytotoxic cd8(+) t cells into gastrocnemius tendon
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964311/
https://www.ncbi.nlm.nih.gov/pubmed/35369435
http://dx.doi.org/10.3389/fmicb.2022.869164
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