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Type I IFN Signaling Limits Hemorrhage-Like Disease After Infection With Japanese Encephalitis Virus Through Modulating A Prerequisite Infection of CD11b+Ly-6C+ Monocytes
Seong Kug Eo
Chonbuk National University College of Veterinary Medicine
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9243-4268
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: The crucial role of type I interferon (IFN-I, IFN-a/b) is well known to control central nervous system (CNS)-neuroinflammation caused by neurotrophic flaviviruses such as Japanese encephalitis virus (JEV) and West Nile virus. However, an in-depth analysis of IFN-I signal-dependent cellular factors that govern CNS-restricted tropism in JEV infection in vivo remains to elucidate.
Methods: Viral dissemination, tissue tropism, and cytokine production were examined in IFN-I signal-competent and incompetent mice after JEV inoculation in tissues distal from the CNS such as the footpad. Bone marrow (BM) chimeric models were used for defining hematopoietic and tissue-resident cells in viral dissemination and tissue tropism.
Results: The paradoxical and interesting finding was that IFN-I signaling was essentially required for CNS neuroinflammation following JEV inoculation in distal footpad tissue. IFN-I signal-competent mice died after a prolonged neurological illness, but IFN-I signal-incompetent mice all succumbed without neurological signs. Rather, IFN-I signal-incompetent mice developed hemorrhage-like disease as evidenced by thrombocytopenia, functional injury of liver and kidney, increased vascular leakage, and excessive cytokine production. This hemorrhage-like disease was closely associated with quick viral dissemination and impaired IFN-I innate responses before invasion of JEV into the CNS. Using bone marrow (BM) chimeric models, we found that intrinsic IFN-I signaling in tissue-resident cells in peripheral organs played a major role in inducing the hemorrhage-like disease because IFN-I signal-incompetent recipients of BM cells from IFN-I signal-competent mice showed enhanced viral dissemination, uncontrolled cytokine production, and increased vascular leakage. IFN-I signal-deficient hepatocytes and enterocytes were permissive to JEV replication with impaired induction of antiviral IFN-stimulated genes, and neuron cells derived from both IFN-I signal-competent and incompetent mice were vulnerable to JEV replication. Finally, circulating CD11b+Ly-6C+ monocytes infiltrated into the distal tissues inoculated by JEV participated in quick viral dissemination to peripheral organs of IFN-I signal-incompetent mice at an early stage.
Conclusion: An IFN-I signal-dependent model is proposed to demonstrate how CD11b+Ly-6C+ monocytes are involved in restricting the tissue tropism of JEV to the CNS.
Keywords
Type I IFN, Japanese encephalitis, Monocytes, Hemorrhagic disease, Cytokine storm
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Received 03 Jan, 2021
Editorial decision: Major Revision
On 03 Jan, 2021
Review #1 received
Received 28 Dec, 2020
Reviewer #2 agreed
On 12 Dec, 2020
Reviewer #1 agreed
On 09 Dec, 2020
Editor assigned
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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
Type I IFN Signaling Limits Hemorrhage-Like Disease After Infection With Japanese Encephalitis Virus Through Modulating A Prerequisite Infection of CD11b+Ly-6C+ Monocytes
Seong Kug Eo
Chonbuk National University College of Veterinary Medicine
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9243-4268
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: Under Revision
Version 1
Posted 16 Dec, 2020
No community comments so far
Review #2 received
Received 03 Jan, 2021
Editorial decision: Major Revision
On 03 Jan, 2021
Review #1 received
Received 28 Dec, 2020
Reviewer #2 agreed
On 12 Dec, 2020
Reviewer #1 agreed
On 09 Dec, 2020
Editor assigned
On 08 Dec, 2020
Reviewers invited
Invitations sent on 08 Dec, 2020
Submission checks complete
On 08 Dec, 2020
Editor invited
On 08 Dec, 2020
First submitted
On 03 Dec, 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
Background: The crucial role of type I interferon (IFN-I, IFN-a/b) is well known to control central nervous system (CNS)-neuroinflammation caused by neurotrophic flaviviruses such as Japanese encephalitis virus (JEV) and West Nile virus. However, an in-depth analysis of IFN-I signal-dependent cellular factors that govern CNS-restricted tropism in JEV infection in vivo remains to elucidate.
Methods: Viral dissemination, tissue tropism, and cytokine production were examined in IFN-I signal-competent and incompetent mice after JEV inoculation in tissues distal from the CNS such as the footpad. Bone marrow (BM) chimeric models were used for defining hematopoietic and tissue-resident cells in viral dissemination and tissue tropism.
Results: The paradoxical and interesting finding was that IFN-I signaling was essentially required for CNS neuroinflammation following JEV inoculation in distal footpad tissue. IFN-I signal-competent mice died after a prolonged neurological illness, but IFN-I signal-incompetent mice all succumbed without neurological signs. Rather, IFN-I signal-incompetent mice developed hemorrhage-like disease as evidenced by thrombocytopenia, functional injury of liver and kidney, increased vascular leakage, and excessive cytokine production. This hemorrhage-like disease was closely associated with quick viral dissemination and impaired IFN-I innate responses before invasion of JEV into the CNS. Using bone marrow (BM) chimeric models, we found that intrinsic IFN-I signaling in tissue-resident cells in peripheral organs played a major role in inducing the hemorrhage-like disease because IFN-I signal-incompetent recipients of BM cells from IFN-I signal-competent mice showed enhanced viral dissemination, uncontrolled cytokine production, and increased vascular leakage. IFN-I signal-deficient hepatocytes and enterocytes were permissive to JEV replication with impaired induction of antiviral IFN-stimulated genes, and neuron cells derived from both IFN-I signal-competent and incompetent mice were vulnerable to JEV replication. Finally, circulating CD11b+Ly-6C+ monocytes infiltrated into the distal tissues inoculated by JEV participated in quick viral dissemination to peripheral organs of IFN-I signal-incompetent mice at an early stage.
Conclusion: An IFN-I signal-dependent model is proposed to demonstrate how CD11b+Ly-6C+ monocytes are involved in restricting the tissue tropism of JEV to the CNS.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11
Due to technical limitations, table 2 is only available as a download in the Supplemental Files section.