The full text of this item is not available at this time because the student has placed this item under an embargo for a period of time. The Libraries are not authorized to provide a copy of this work during the embargo period, even for Texas A&M users with NetID.
Brucella and Coronavirdae Subversion of Novel Blos1-Directed Immune Defense
dc.contributor.advisor | de Figueiredo, Paul | |
dc.creator | Wells, Kelsey Michelle | |
dc.date.accessioned | 2023-09-18T16:34:44Z | |
dc.date.created | 2022-12 | |
dc.date.issued | 2022-11-07 | |
dc.date.submitted | December 2022 | |
dc.identifier.uri | https://hdl.handle.net/1969.1/198596 | |
dc.description.abstract | Blos1 is a novel immune defense factor that defends against bacterial and viral infections, and Brucella and coronaviruses subvert this innate immune defense to promote infection. Here we show Blos1 as a novel immune defense factor that defends against bacterial and viral infection and how Brucella and coronaviruses (CoVs) subvert this innate immune defense system to promote infection. Brucella, the causative agent of brucellosis, the most prevalent bacterial zoonosis globally, subverts this immune defense pathway by activating regulated IRE1α-dependent decay (RIDD) of Bloc1s1 mRNA encoding Blos1, a protein that promotes endosome-lysosome fusion. RIDD-deficient cells and mice harboring a RIDD-incompetent variant of IRE1α were resistant to infection. Inactivation of the Bloc1s1 gene impaired the ability to assemble BLOC-1-related complex (BORC), resulting in differential recruitment of BORC-related lysosome trafficking components, perinuclear trafficking of Brucella-containing vacuoles (BCVs), and enhanced susceptibility to infection. The RIDD-resistant Bloc1s1 variant maintains the integrity of BORC and a higher-level association of BORC-related components that promote centrifugal lysosome trafficking, resulting in enhanced BCV peripheral trafficking and lysosomal-destruction, and resistance to infection. These findings demonstrate that host RIDD activity on Blos1 regulates Brucella intracellular parasitism by disrupting BORC-directed lysosomal trafficking. Notably, coronavirus MHV (murine hepatitis virus) also subverted the RIDD-Blos1 axis to promote intracellular replication in the late stage of the virus infection. Interestingly, at the early stage of coronavirus MHV infection, we found that Blos1-directed Alyref acetylation controls the Alyref-directed selective export of 5-methylcytosine (m5C)-modified mRNAs in response to the virus infection. Host cells harboring the wild-type Blos1, or acetylation mimic Alyref promote nuclear export of m5C-modified mRNAs of interferons and/or interferon-stimulated genes, thereby impairing MHV replication; whereas cells with non-functional Blos1 or acetylation resistant Alyref block the selective m5C-modified mRNA export, and thus promotes the virus replication. Collectively, our findings demonstrate that MHV hijacks the host immune response pathway of Blos1-controlled Alyref-directed selectively m5C-modified mRNA export to support the virus early infection. | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en | |
dc.subject | Brucella | |
dc.subject | Blos1 | |
dc.subject | Coronavirus | |
dc.subject | Alyref | |
dc.subject | MHV | |
dc.title | Brucella and Coronavirdae Subversion of Novel Blos1-Directed Immune Defense | |
dc.type | Thesis | |
thesis.degree.department | College of Medicine | |
thesis.degree.discipline | Medical Sciences | |
thesis.degree.grantor | Texas A&M University | |
thesis.degree.name | Doctor of Philosophy | |
thesis.degree.level | Doctoral | |
dc.contributor.committeeMember | Ficht, Thomas A | |
dc.contributor.committeeMember | Patrick, Kristin | |
dc.contributor.committeeMember | McGregor, Alistair | |
dc.type.material | text | |
dc.date.updated | 2023-09-18T16:34:45Z | |
local.embargo.terms | 2024-12-01 | |
local.embargo.lift | 2024-12-01 | |
local.etdauthor.orcid | 0000-0002-1657-5189 |
Files in this item
This item appears in the following Collection(s)
-
Electronic Theses, Dissertations, and Records of Study (2002– )
Texas A&M University Theses, Dissertations, and Records of Study (2002– )