Lane, Whitney
(2018)
Temperature-dependent efficacy of the IFN-alpha/beta response against chikungunya and other arboviruses.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Chikungunya virus (CHIKV) is a mosquito-transmitted arbovirus in the genus Alphavirus that has reemerged in recent years to cause explosive epidemics of acute and chronic arthritic disease across the globe. Like other arboviruses, CHIKV has evolved to replicate efficiently in both its arthropod vector and its vertebrate hosts, which represent two very different thermal environments. Arthritogenic alphaviruses such as CHIKV preferentially replicate and cause disease in distal small joints that are lower in temperature than the body core. The type-I interferon (IFN-α/β) system is a critical innate immune response for controlling arbovirus infection. Recent evidence suggests that IFN-α/β is less effective in controlling virus infection at temperatures below the body core temperature. Therefore, we hypothesized that arboviruses such as CHIKV may exploit a weakened innate immune environment in low-temperature joint tissues to fuel exacerbated viral replication and disease at these sites.
To address this hypothesis, we examined the efficacy of IFN-α/β induction and antiviral efficacy against CHIKV and other arboviruses at different temperatures within the normal physiological range. In vitro, we found that mild hypothermia significantly compromised both the induction and effector arms of the IFN-α/β response compared to normal or febrile-range temperatures against diverse arboviruses. We narrowed this effect to delayed and reduced transcription of effector genes, as upstream signaling pathways were not attenuated by hypothermia, and demonstrated differential temperature-sensitivity profiles of interferon-stimulated gene (ISG) induction versus some lipopolysaccharide (LPS)-inducible genes. Finally, mice with reduced core temperatures suffered exacerbated CHIKV replication and disease compared with normal mice during the acute phase of infection, and this phenotype was dependent upon a functional IFN-α/β system. Reduced core temperature during the first few days of CHIKV infection also resulted in higher persistent viral signal at chronic time points, and temperature reduction >30 days post infection resulted in significantly increased viral protein production at persistently-infected sites. Together, these data indicate that reduced tissue temperature results in attenuated IFN-α/β and ISG gene transcription, leaving these tissues more vulnerable to arboviral infection than warmer sites. CHIKV can take advantage of this dynamic to infect and persist in low-temperature tissues in vivo.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
25 July 2018 |
| Date Type: |
Publication |
| Defense Date: |
10 July 2018 |
| Approval Date: |
25 July 2018 |
| Submission Date: |
23 July 2018 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
237 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Virology and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
alphavirus, arbovirus, chikungunya virus, interferons, temperature |
| Date Deposited: |
25 Jul 2018 18:20 |
| Last Modified: |
25 Jul 2018 18:20 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/34973 |
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