See the published version of this article at Journal of Neuroinflammation.
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Research
Yuejin Liang
University of Texas Medical Branch at Galveston
Corresponding Author
ORCiD: https://orcid.org/0000-0002-9557-1847
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Journal of Neuroinflammation.
Background
The Zika virus (ZIKV) outbreak that occurred in multiple countries was linked to increased risk of neurological disorders and congenital defects. However, host immunity and immune-mediated pathogenesis in ZIKV infection are not well understood. Interleukin-22 (IL-22) is a crucial cytokine for regulating host immunity in infectious diseases. Whether IL-22 plays a role in ZIKV infection is unknown.
Methods
The cellular source of IL-22 was identified in IFNAR−/− mice and WT neonatal mice during ZIKV infection. To determine the role of IL-22, we challenged 1-day-old wild-type (WT) and IL-22−/− mice with ZIKV and monitored clinical manifestations. Glial cell activation in the brain was assessed by confocal imaging. ZIKV-specific CD8+ T cell responses in both the spleen and brain were analyzed by flow cytometry. In addition, we infected mouse primary astrocytes in vitro, and characterized the reactive astrocyte phenotype. Human glial cell line was also infected with ZIKV in the presence of IL-22, followed by the evaluation of cell proliferation, cytokine expression and viral loads.
Results
We found that γδ T cells were the main source of IL-22 during ZIKV infection in both the spleen and brain. WT mice began to develop weight loss, staggered steps, bilateral hind limb paralysis, weakness at 10 days post-infection (dpi), and ultimately succumbed to infection at 16–19 dpi. Surprisingly, IL-22 deficiency lessened weight loss, moderated the systemic inflammatory response, and greatly reduced the incidence of neurological disorders and mortality. ZIKV infection facilitated a neurotoxic polarization of A1-prone astrocytes in vitro. Additional analysis demonstrated that the absence of IL-22 resulted in reduced activation of microglia and astrocytes in the cortex. Although IL-22 displayed a marginal effect on glial cells in vitro, IL-22−/− mice mounted more vigorous ZIKV-specific CD8+ T cell responses, which led to a more effective control of ZIKV in the brain.
Conclusions
Our data revealed a pathogenic role of IL-22 in ZIKV encephalitis.
Keywords
ZIKV, IL-22, Astrocytes, Brain, Microglia, Encephalitis, Neonatal mice, CD8
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CURRENT STATUS: Published
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On 25 Aug, 2020
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Editorial decision: Major Revision
On 26 Jun, 2020
Review #2 received
Received 24 Jun, 2020
Review #3 received
Received 22 Jun, 2020
Reviewer #3 agreed
On 14 Jun, 2020
Reviewer #2 agreed
On 10 Jun, 2020
Review #1 received
Received 10 Jun, 2020
Reviewer #1 agreed
On 04 Jun, 2020
Reviewers invited
Invitations sent on 02 Jun, 2020
Editor assigned
On 29 May, 2020
Submission checks complete
On 28 May, 2020
Editor invited
On 28 May, 2020
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On 27 May, 2020
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Subject Areas
Neurobiology of Disease
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This preprint is under consideration at Journal of Neuroinflammation. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Yuejin Liang
University of Texas Medical Branch at Galveston
Corresponding Author
ORCiD: https://orcid.org/0000-0002-9557-1847
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 1
Posted 02 Jun, 2020
Published
On 25 Aug, 2020
No community comments so far
Editorial decision: Major Revision
On 26 Jun, 2020
Review #2 received
Received 24 Jun, 2020
Review #3 received
Received 22 Jun, 2020
Reviewer #3 agreed
On 14 Jun, 2020
Reviewer #2 agreed
On 10 Jun, 2020
Review #1 received
Received 10 Jun, 2020
Reviewer #1 agreed
On 04 Jun, 2020
Reviewers invited
Invitations sent on 02 Jun, 2020
Editor assigned
On 29 May, 2020
Submission checks complete
On 28 May, 2020
Editor invited
On 28 May, 2020
First submitted
On 27 May, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Neurobiology of Disease
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Journal of Neuroinflammation.
Background
The Zika virus (ZIKV) outbreak that occurred in multiple countries was linked to increased risk of neurological disorders and congenital defects. However, host immunity and immune-mediated pathogenesis in ZIKV infection are not well understood. Interleukin-22 (IL-22) is a crucial cytokine for regulating host immunity in infectious diseases. Whether IL-22 plays a role in ZIKV infection is unknown.
Methods
The cellular source of IL-22 was identified in IFNAR−/− mice and WT neonatal mice during ZIKV infection. To determine the role of IL-22, we challenged 1-day-old wild-type (WT) and IL-22−/− mice with ZIKV and monitored clinical manifestations. Glial cell activation in the brain was assessed by confocal imaging. ZIKV-specific CD8+ T cell responses in both the spleen and brain were analyzed by flow cytometry. In addition, we infected mouse primary astrocytes in vitro, and characterized the reactive astrocyte phenotype. Human glial cell line was also infected with ZIKV in the presence of IL-22, followed by the evaluation of cell proliferation, cytokine expression and viral loads.
Results
We found that γδ T cells were the main source of IL-22 during ZIKV infection in both the spleen and brain. WT mice began to develop weight loss, staggered steps, bilateral hind limb paralysis, weakness at 10 days post-infection (dpi), and ultimately succumbed to infection at 16–19 dpi. Surprisingly, IL-22 deficiency lessened weight loss, moderated the systemic inflammatory response, and greatly reduced the incidence of neurological disorders and mortality. ZIKV infection facilitated a neurotoxic polarization of A1-prone astrocytes in vitro. Additional analysis demonstrated that the absence of IL-22 resulted in reduced activation of microglia and astrocytes in the cortex. Although IL-22 displayed a marginal effect on glial cells in vitro, IL-22−/− mice mounted more vigorous ZIKV-specific CD8+ T cell responses, which led to a more effective control of ZIKV in the brain.
Conclusions
Our data revealed a pathogenic role of IL-22 in ZIKV encephalitis.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
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