Dissertation Defense: Characterization of pro- and anti-inflammatory immune responses to SARS-CoV-2
Dissertation Defense: Characterization of pro- and anti-inflammatory immune responses to SARS-CoV-2
Hannah Ivester
Graduate Student, Translational Biology, Medicine, and Health
Graduate Research Assistant, Allen Lab
April 24, 2024, at 12 p.m.
Room 102, VetMed Phase II
About this Dissertation
Following infection with a viral pathogen, the host immediately begins mounting an immune response characterized by the increase in production of pro-inflammatory cytokines and chemokines that work to begin changing the environment surrounding the viral invader. A crucial step in mounting these immune responses is recognition of pathogen associated molecular patterns (PAMPs) from the virus, or from other signatures characteristic of tissue damage, damage associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs) that in turn stimulate pro-inflammatory signaling cascades. The results of these signaling pathways include the release of cytokines responsible for continuing to upregulate these signaling pathways and chemokines that work to attract immune cells to the site of infection. In the case of SARS-CoV-2 infection, these responses can become problematic if they go unmitigated and unresolved, resulting in the severe COVID-19 disease manifestation of the ‘cytokine storm,’ or multisystem inflammatory syndrome in children (MIS-C) in pediatric patients. On classically increased protein in cytokine storm presenting-COVID-19 patients is C-X-C motif chemokine 10 (CXCL10), which has been explored as a prognostic marker as it has been shown to be predictive of disease outcome in hospitalized patients. To combat severe outcomes like cytokine storm, the result of unregulated pro-inflammatory signaling, a delicate balance must be struck, to ensure that this inflammation does not result in high levels of diffuse tissue damage when trying to clear the viral infection. To achieve this, anti-inflammatory pathways exist within the immune system that help dampen the signals being induced. One unique anti-inflammatory protein shown to do just that is a protein known as NLRX1 (Nucleotide binding oligomerization domain, leucine rich repeat containing X1); a PRR that can interact with two main pathways involved with anti-viral immunity, the NF-kB and Interferon pathways, downregulating them to keep off-target tissue damage at bay. NLRX1 is also involved in a number of other cellular processes, including modulating cell death processes and cellular metabolism which can also impact viral replication and clearance indirectly.
In this work, both the pro- and anti-inflammatory arms of the anti-SARS-CoV-2 response focusing on two key proteins – pro-inflammatory chemokine CXCL10 and immunoregulatory PRR NLRX1. The roles of these two proteins were explored utilizing transcriptomic analysis of both human and mouse RNA samples, immortalized cell culture work, primary cell culture work, humanized mouse models of SARS-CoV-2 infection, and mouse-adapted virus models to be able to utilize mouse models with gene deletions, making them deficient in these proteins. In this work we better characterize the immune response to SARS-CoV-2 and its related immune-driven pathobiology of disease. The data presented in this work criticizes the utility of CXCL10 as a prognostic marker for disease while supporting its role as an important driver of viral clearance of SARS-CoV-2. Additionally, the work shown here furthers the understanding of NLRX1and its role in antiviral immunity with specific context related to SARS-CoV-2. The culmination of work here emphasizes the importance for both the pro- and anti-inflammatory responses in SARS-CoV-2 infection and offers insight into two possible related targets for future drug development.
More About the Candidate and Project
Education
Virginia Tech, Translational Biology, Medicine, and Health, Ph.D. Candidate
North Carolina Wesleyan College, B.S., Mathematics, B.S. Biomedical Sciences
Training
Graduate Research Assistant, Allen Lab
Mentor
Irving Coy Allen, Ph.D., Professor, Assistant Head for Research Support, Department of Biomedical Sciences and Pathobiology, VA-MD College of Veterinary Medicine
Committee Members
- Andrea Bertke, Ph.D., Associate Professor, Department of Population Health Sciences, VA-MD College of Veterinary Medicine
- Nisha Duggal, Ph.D., Associate Professor, Department of Biomedical Sciences and Pathobiology, VA-MD College of Veterinary Medicine
- James Smyth, Ph.D., Associate Professor, Fralin Biomedical Research Institute at VTC
- James Weger, Ph.D., Assistant Professor, Department of Biomedical Sciences and Pathobiology, VA-MD College of Veterinary Medicine
- Yanjin Zhang, Ph.D., Associate Professor, Veterinary Medicine, University of Maryland
Publications
Callahan V, Hawks S, Crawford MA, Lehman CW, Morrison HA, Ivester HM, Akhrymuk I, Boghdeh N, Flor R, Finkielstein CV, Allen IC, Weger-Lucarelli J, Duggal N, Hughes MA, Kehn-Hall K. The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner. Viruses. 2021;13(6). Epub 2021/07/03. doi: 10.3390/v13061062. PubMed PMID: 34205098; PMCID: PMC8226769.
Behzadinasab S, Hosseini M, Williams MD, Ivester HM, Allen IC, Falkinham JO, 3rd, Ducker WA. Antimicrobial activity of cuprous oxide-coated and cupric oxide-coated surfaces. J Hosp Infect. 2022;129:58-64. Epub 2022/08/09. doi: 10.1016/j.jhin.2022.07.022. PubMed PMID: 35940287.
Ivester HM, Tupik JD, Nagai-Singer MA, Coutermarsh-Ott SL, Allen IC. Methods to evaluate virus-mediated acute lung inflammation. Methods Cell Biol. 2022;168:329-41. Epub 2022/04/04. doi: 10.1016/bs.mcb.2021.12.021. PubMed PMID: 35366990.
Tupik JD, Markov Madanick JW, Ivester HM, Allen IC. Detecting DNA: An Overview of DNA Recognition by Inflammasomes and Protection against Bacterial Respiratory Infections. Cells. 2022;11(10). Epub 2022/05/29. doi: 10.3390/cells11101681. PubMed PMID: 35626718; PMCID: PMC9139316.
Hassebroek AM, Sooryanarain H, Heffron CL, Hawks SA, LeRoith T, Cecere TE, Stone WB, Walter D, Mahsoub HM, Wang B, Tian D, Ivester HM, Allen IC, Auguste AJ, Duggal NK, Zhang C, Meng XJ. A hepatitis B virus core antigen-based virus-like particle vaccine expressing SARS-CoV-2 B and T cell epitopes induces epitope-specific humoral and cell-mediated immune responses but confers limited protection against SARS-CoV-2 infection. J Med Virol. 2023;95(2):e28503. Epub 2023/01/20. doi: 10.1002/jmv.28503. PubMed PMID: 36655751; PMCID: PMC9974889.
Imran KM, Gannon J, Morrison HA, Tupik JD, Tintera B, Nagai-Singer MA, Ivester H, Madanick JM, Hendricks-Wenger A, Uh K, Luyimbazi DT, Edwards M, Coutermarsh-Ott S, Eden K, Byron C, Clark-Deener S, Lee K, Vlaisavljevich E, Allen IC. Successful In Situ Targeting of Pancreatic Tumors in a Novel Orthotopic Porcine Model Using Histotripsy. Ultrasound Med Biol. 2023;49(11):2361-70. Epub 2023/08/19. doi: 10.1016/j.ultrasmedbio.2023.07.013. PubMed PMID: 37596154; PMCID: PMC10529075.
Imran KM, Tintera B, Morrison HA, Tupik JD, Nagai-Singer MA, Ivester H, Council-Troche M, Edwards M, Coutermarsh-Ott S, Byron C, Clark-Deener S, Uh K, Lee K, Boulos P, Rowe C, Coviello C, Allen IC. Improved Therapeutic Delivery Targeting Clinically Relevant Orthotopic Human Pancreatic Tumors Engrafted in Immunocompromised Pigs Using Ultrasound-Induced Cavitation: A Pilot Study. Pharmaceutics. 2023;15(6). Epub 2023/06/28. doi: 10.3390/pharmaceutics15061585. PubMed PMID: 37376034; PMCID: PMC10302458.
Morrison HA, Hoyt KJ, Mounzer C, Ivester HM, Barnes BH, Sauer B, McGowan EC, Allen IC. Expression profiling identifies key genes and biological functions associated with eosinophilic esophagitis in human patients. Front Allergy. 2023;4:1239273. Epub 2023/09/11. doi: 10.3389/falgy.2023.1239273. PubMed PMID: 37692891; PMCID: PMC10484407.
Khan M*, Irvin P*, Park SB, Ivester H, Ricardo-Lax I, Leek M, Grieshaber A, Maio N, Jiang J-K, Huang W, Wang AQ, Xu X, Hu Z, Rouault T, Rice CM, Allen IC, Liang TJ. Repurposing of lonafarnib as an effective inhibitor of SARS-CoV-2 infection for COVID-19 treatment. Under review.
Ivester HM, Morrison HA, Tupik JD, Chuong C, Coutermarsh-Ott SC, Eden K, Grider DJ, Finkielstein CV, Auguste AJ, Duggal NK, Smyth JW, Weger-Lucarelli J, Allen IC. CXCR3 ligand CXCL10 regulates inflammation following SARS-CoV-2 infection in mice and humans. In prep.
Ivester HM, Gregory JA, Allen IC. Breathing easy; NLRX1 impacts immune responses in pulmonary pathogens In prep.
Ivester, HM, Irvin, P, Liang, J, Allen, IC. Antiviral compound Remdesivir as a potential treatment for COVID19. (2021) Abstract – Virginia Tech Graduate Student Assembly Research Symposium.
Allen, IC*, Ivester, HM, Morrison, H, Finkielstein, C, Auguste, J, Duggal, N, Smyth, J, Meng, XJ, Kehn-Hall, K, Weger, J. Novel Mechanisms of Innate Immune System Regulation Following SARS-CoV-2 Exposure. (2021) Abstract – American Association of Immunologists. *Presenting author
Ivester, HM, Morrison, HA, Finkielstein, C, Duggal, Weger-Lucarelli, J, Allen, IC. Chemokine CXCL10’s role in the immune response to SARS-CoV-2. (2022) Abstract – American Association of Immunologists.
Ivester, HM, Morrison, HA, Finkielstein, C, Duggal, Weger-Lucarelli, J, Allen, IC. The Essential Role of CXCL10 in the Immune Response to SARS-CoV-2 (2022) Poster – Southeastern Immunology Symposium
Ivester, HM, Morrison, HA, Tupik, JD, Chuong, C, Finkielstein, C, Duggal, Weger-Lucarelli, J, Allen, IC. Calming the storm: The role of the anti-inflammatory protein NLRX1 in the immune response to SARS-CoV-2 (2023) Poster – VCOM Research Day 2023; Second place award – Biomedical Science
Ivester, HM, Woolls, M, Morrison, HA, Tupik, JD, Chuong, C, Finkielstein, CV, Duggal, NK, Weger-Lucarelli, J, Allen, IC. Calming the storm: Immunoregulatory receptor NLRX1 and its role in the immune response to SARS-CoV-2 (2023) Poster – American Association of Immunologists.
Ivester, HM, Woolls, M, Mott, M, Morrison, HA, Tupik, JD, Chuong, C, Finkielstein, CV, Duggal, NK, Weger-Lucarelli, J, Allen, IC. Anti-inflammatory protein and pattern recognition receptor NLRX1 might calm the storm of SARS-CoV-2 infection (2023) Poster – Southeastern Immunology Symposium.
Ivester, HM, Woolls, M, Mott, M, Morrison, HA, Tupik, JD, Chuong, C, Finkielstein, CV, Duggal, NK, Weger-Lucarelli, J, Allen, IC. Anti-inflammatory pattern recognition receptor NLRX1 may calm the storm of SARS-CoV-2 infection (2023) Poster – American Society for Virologists – Trainee travel award winner
- Virginia Tech GRDP Spring 2021 Awardee
- CeZAP Mini-Grant Awardee
- CeZAP Fellow – Summer I 202