Interactions of highly pathogenic human coronaviruses with dsRNA-induced innate immune pathways / Courtney Elizabeth Comar.

Format:

Book

Thesis/Dissertation

Author/Creator:

Comar, Courtney Elizabeth, author.

Contributor:

Weiss, Susan R. (Susan Reich), degree supervisor.

University of Pennsylvania. Department of Cell and Molecular Biology, degree granting institution.

Language:

English

Subjects (All):

Virology.

Microbiology.

Cellular biology.

Molecular biology.

Genetics.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Local Subjects:

Virology.

Microbiology.

Cellular biology.

Molecular biology.

Genetics.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Genre:

Academic theses.

Physical Description:

1 online resource (164 pages)

Contained In:

Dissertations Abstracts International 82-11B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2021.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

In the last decade, two novel coronaviruses have emerged from zoonotic sources to humans. Middle East Respiratory Syndrome Coronavirus (MERS-CoV) emerged in 2012 causing several outbreaks of severe respiratory illness with a high case fatality ratio of 35%. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerged in late 2019 causing a devastating pandemic that has caused over 2.7 million deaths in over 124 million cases as of March 2021. Coronaviruses are positive sense single-stranded RNA viruses and are adept at delaying or suppressing activation of innate immune responses in their hosts, despite detectable double-stranded (ds)RNA production during infection. Our goal was to understand how the highly pathogenic human coronaviruses, MERS-CoV and SARS-CoV-2, interact with and evade the dsRNA-induced innate immune pathways: type I and III interferon (IFN) production and signaling, protein kinase R (PKR), and oligo adenylate synthetase ribonuclease L (OAS/RNase L). We found that MERS-CoV evades activation of IFN, PKR and OAS/RNase L due to the activities of three different proteins. We show during authentic MERS-CoV infection that dsRNA-binding accessory protein NS4a blocks PKR activation and IFN mRNA expression, and that accessory protein NS4b blocks IFN induction through its phosphodiesterase (PDE) activity and nuclear localization. Furthermore, we examined the role of conserved coronavirus protein nsp15 endoribonuclease (EndoU) catalytic activity during MERS-CoV infection. We found that inactivation of EndoU during MERS-CoV infection had mild effects on the dsRNA-induced innate immune pathways. However, inactivation of EndoU in combination with loss of expression of accessory protein NS4a or inactivation of PDE activity of NS4b caused defects in infectious virus production and robust activation of the innate immune pathways in MERS-CoV infected A549DPP4 cells. This highlighted redundant functions of EndoU, NS4a, and NS4b that together lead to strong suppression and evasion of dsRNA induced innate immunity during MERS-CoV infection. We also investigated the interactions of SARS-CoV-2 with the dsRNA-induced pathways. We found that SARS-CoV-2, unlike MERS-CoV, induced mild IFN expression and moderately activated PKR and OAS/RNase L in lung derived cell lines. Our findings fill some of the gaps in knowledge of how highly pathogenic human coronaviruses interact with the innate immune system.

Notes:

Source: Dissertations Abstracts International, Volume: 82-11, Section: B.

Advisors: Weiss, Susan R.; Committee members: Matthew Weitzman; Paul Bates; Stuart Isaacs; Kellie Ann Jurado.

Department: Cell and Molecular Biology.

Ph.D. University of Pennsylvania 2021.

Local Notes:

School code: 0175

ISBN:

9798738618321

Access Restriction:

Restricted for use by site license.

This item must not be sold to any third party vendors.