Our lungs are constantly under attack from the environment, including allergens, cigarette smoke, and viruses like influenza and SARS-CoV-2. These threats can cause serious illness and even death, highlighting the importance of lung health. Our research lab is dedicated to understanding how our bodies defend against these attacks.
We focus on three key areas:
- how lung cells repair themselves after injury
- how viral infections of the respiratory tract exacerbate cigarette smoke-induced lung inflammation, and
- how viruses hijack our cells to replicate and cause disease.
By understanding how viruses interact with our cells, we believe we can unlock new avenues for treatment and even vaccines. Our current NIH-funded research uses a patient-centered approach to investigate these critical questions. Viruses rely on our own cellular machinery to reproduce. Our current research focuses on pinpointing key host cell proteins in airway epithelial cells that play a crucial role in the replication of influenza A virus (IAV) and SARS-CoV-2. We are also delving deeper into the molecular mechanisms behind these interactions. By identifying the proteins involved, we can potentially disrupt this interaction and stop the virus in its tracks. This knowledge could lead to the development of new antiviral drugs or vaccines.
Our passion lies in improving lung health and preventing lung disease. We actively collaborate with researchers at leading institutions, such as The Ohio State University, Nationwide Children’s Hospital, Icahn School of Medicine at Mount Sinai, Brigham and Women’s Hospital, Harvard Medical School, and St. Jude Children’s Research Hospital, to build on existing knowledge and accelerate progress. This collaborative approach allows us to share expertise and ideas, ultimately leading to better treatments for lung diseases. In light of the COVID-19 pandemic, we've expanded our research to understand SARS-CoV-2 better. Our goal remains the same: to uncover new targets for treating both influenza and SARS-CoV-2 infections, while also identifying genetic factors that increase susceptibility to severe illness.
Our Team
Yohannes A. Mebratu, DVM, MS, PhD
Principal Investigator, Assistant Professor
My research journey began with the fundamental question of how the airways maintain a healthy balance of cells following injury from infections and other insults. My research program investigates the critical role of host gene polymorphisms and cellular proteins in influencing the replication of influenza A virus (IAV) and SARS-CoV-2, ultimately affecting disease severity in humans. I am driven to elucidate the host response and identify key cellular proteins critical for influenza A (IA) and SARS-CoV-2 replication and pathogenesis. In my free time, I enjoy activities like jogging, working out, and spending quality time with my family.
Sourabh Soni, PhD
Research Senior Associate
A molecular biologist by training, I earned my Ph.D. in Biological Sciences from CSIR-IHBT, India. Following my graduation in 2019, I pursued postdoctoral training at the Brigham & Women's Hospital, Harvard Medical School, Boston. While in Dr. Shule's Lab, I investigated the therapeutic potential of the AMPK-autophagy pathway in bronchopulmonary dysplasia. In June 2021, I joined Dr. Mebratu's lab at Brigham & Women's Hospital and transitioned to The Ohio State University's Division of Pulmonary, Critical Care & Sleep Medicine. My current research focuses on how influenza A viruses (IAVs) interact with host cells. By understanding how IAVs hijack cellular processes, we aim to identify potential therapeutic targets to treat influenza.
Vandana Anang, PhD
Postdoctoral Scholar
I hold a Ph.D. in Biomedical Science from the University of Delhi (February 2022) and recently completed a postdoctoral fellowship at the All India Institute of Medical Sciences (May-October 2023). Prior to that, I gained research experience at the International Centre for Genetic Engineering and Biotechnology's Parasite Cell Biology Lab. Currently, at Dr. Mebratu's lab in the Department of Medicine at The Ohio State University (Columbus, OH), I'm investigating how influenza A and SARS-CoV-2 viruses manipulate host cells for replication. With over 8 years of expertise in molecular biology and immunology, I possess a strong foundation in primary cell culture (including bone marrow-derived dendritic cells, T cells, PBMCs). My future research interests lie in immune regulation, host-pathogen interactions, and therapeutic development across various diseases. Outside of the lab, I enjoy socializing with friends, exploring new cuisines, and staying active through walks.
Laura Antonescu, BS
Laboratory Technician
Hailing from Cleveland, I recently graduated from The Ohio State University (December 2023) with a Bachelor of Science in Biology and a minor in Microbiology. Driven by an interest in medicine, I joined Dr. Mebratu's lab, where I gained valuable research experience studying the influenza A virus and honed my laboratory skills. Outside of research, I prioritize staying active, cherishing time with loved ones, and exploring new culinary adventures.
Research projects
- Investigate the molecular mechanisms by which host cell proteins regulate the replication of influenza A and SARS-CoV-2 viruses in airway epithelial cells.
- Elucidate the role of host gene polymorphisms in susceptibility to influenza A and SARS-CoV-2 infections.
- Investigate the mechanisms by which influenza A viruses exploit the host proteasome machinery to enhance their replication and disease severity.
- Explore how lung cells repair themselves after injury caused by viruses, allergens, and cigarette smoke.
- Uncover the molecular mechanisms of how viral infections of the respiratory tract exacerbate cigarette smoke-induced lung inflammation
Unveiling Our Research Journey: A Look at Our Lab's Workflow
Image description: The schematic workflow provides a glimpse into the models and methods we employ in our laboratory for the identification of novel mechanisms how influenza A virus (IAV) hijack and subvert host cellular processes to facilitate viral replication and disease progression in the lungs. Our research utilizes both basic and translational models of infectious/inflammatory lung diseases. We primarily use two models that mimic the human airway under more realistic conditions than cell cultures. The first model is the Air-Liquid Interface culture and the second is the Human Precision-Cut Lung Slices. We also use influenza-infected human cohorts from diverse ancestral backgrounds to identify genetic factors contributing to disease severity. By integrating diverse approaches like gene expression assays, protein analysis, and viral assays, we investigate the underlying mechanisms of lung function and disease. Ultimately, our research aims to uncover the enigma of host-virus interactions and to identify host cellular targets for the treatment of influenza infections.
The role of Bik in the replication and severity of influenza A virus
NIH/ NIAID
Role: PI ($1,319,500)
This study focuses on delineating the molecular mechanism by which a host cellular protein, Bik, promotes influenza A virus replication and influenza A disease severity in humans. The study will identify the Bik-binding domains of viral protein required for influenza A virus replication and investigates whether a SNP in the Bik gene associated with increased expression of Bik is a risk factor for influenza disease severity in humans.
Publications
Mebratu YA, Jones JT, Liu C, Negasi ZH, Rahman M, Rojas-Quintero J, O'Connor GT, Gao W, Dupuis J, Cho MH, Litonjua AA, Randell S, Tesfaigzi Y. Bik promotes proteasomal degradation to control low-grade inflammation. J Clin Invest. 2023 Dec 19;134(4). doi: 10.1172/JCI170594. PubMed PMID: 38113109; PubMed Central PMCID: PMC10866658.
Mebratu YA, Soni S, Rosas L, Rojas M, Horowitz JC, Nho R. The aged extracellular matrix and the profibrotic role of senescence-associated secretory phenotype. Am J Physiol Cell Physiol. 2023 Sep 1;325(3):C565-C579. doi: 10.1152/ajpcell.00124.2023. Epub 2023 Jul 24. Review. PubMed PMID: 37486065; PubMed Central PMCID: PMC10511170.
Soni S, Walton-Filipczak S, Nho RS, Tesfaigzi Y, Mebratu YA. Independent role of caspases and Bik in augmenting influenza A virus replication in airway epithelial cells and mice. Virol J. 2023 Apr 24;20(1):78. doi: 10.1186/s12985-023-02027-w. PubMed PMID: 37095508; PubMed Central PMCID: PMC10127399.
Soni S, Mebratu YA. B-cell lymphoma-2 family proteins-activated proteases as potential therapeutic targets for influenza A virus and severe acute respiratory syndrome coronavirus-2: Killing two birds with one stone? Rev Med Virol. 2023 Mar;33(2):e2411. doi: 10.1002/rmv.2411. Epub 2022 Nov 30. Review. PubMed PMID: 36451345; PubMed Central PMCID: PMC9877712.
Mebratu YA, Imani J, Jones JT, Tesfaigzi Y. Casein kinase II activates Bik to induce death of hyperplastic mucous cells in a cell cycle-dependent manner. J Cell Physiol. 2022 Feb;237(2):1561-1572. doi: 10.1002/jcp.30630. Epub 2021 Nov 6. PubMed PMID: 34741311; PubMed Central PMCID: PMC8866207.
Mebratu YA, Negasi ZH, Dutta S, Rojas-Quintero J, Tesfaigzi Y. Adaptation of Proteasomes and Lysosomes to Cellular Environments. Cells. 2020 Oct 1;9(10). doi: 10.3390/cells9102221. Review. PubMed PMID: 33019542; PubMed Central PMCID: PMC7600607.
Mebratu YA, Tesfaigzi Y. IL-17 Plays a Role in Respiratory Syncytial Virus-induced Lung Inflammation and Emphysema in Elastase and LPS-injured Mice. Am J Respir Cell Mol Biol. 2018 Jun;58(6):717-726. doi: 10.1165/rcmb.2017-0265OC. PubMed PMID: 29314865; PubMed Central PMCID: PMC6002655.
Zhang C, Jones JT, Chand HS, Wathelet MG, Evans CM, Dickey B, Xiang J, Mebratu YA, Tesfaigzi Y. Noxa/HSP27 complex delays degradation of ubiquitylated IkBα in airway epithelial cells to reduce pulmonary inflammation. Mucosal Immunol. 2018 May;11(3):741-751. doi: 10.1038/mi.2017.117. Epub 2018 Jan 24. PubMed PMID: 29363670; PubMed Central PMCID: PMC5976511.
Chand HS, Mebratu YA, Kuehl PJ, Tesfaigzi Y. Blocking Bcl-2 resolves IL-13-mediated mucous cell hyperplasia in a Bik-dependent manner. J Allergy Clin Immunol. 2017 Nov;140(5):1456-1459.e9. doi: 10.1016/j.jaci.2017.05.038. Epub 2017 Aug 4. PubMed PMID: 28784260; PubMed Central PMCID: PMC5675799.
Mebratu YA, Leyva-Baca I, Wathelet MG, Lacey N, Chand HS, Choi AMK, Tesfaigzi Y. Bik reduces hyperplastic cells by increasing Bak and activating DAPk1 to juxtapose ER and mitochondria. Nat Commun. 2017 Oct 6;8(1):803. doi: 10.1038/s41467-017-00975-w. PubMed PMID: 28986568; PubMed Central PMCID: PMC5630627.
Chand HS, Mebratu YA, Montera M, Tesfaigzi Y. T cells suppress memory-dependent rapid mucous cell metaplasia in mouse airways. Respir Res. 2016 Oct 20;17(1):132. doi: 10.1186/s12931-016-0446-0. PubMed PMID: 27765038; PubMed Central PMCID: PMC5073838.
Mebratu YA, Smith KR, Agga GE, Tesfaigzi Y. Inflammation and emphysema in cigarette smoke-exposed mice when instilled with poly (I:C) or infected with influenza A or respiratory syncytial viruses. Respir Res. 2016 Jul 1;17(1):75. doi: 10.1186/s12931-016-0392-x. PubMed PMID: 27363862; PubMed Central PMCID: PMC4929744.
Mebratu YA, Tipper J, Chand HS, Walton S, Harrod KS, Tesfaigzi Y. Bik Mediates Caspase-Dependent Cleavage of Viral Proteins to Promote Influenza A Virus Infection. Am J Respir Cell Mol Biol. 2016 May;54(5):664-73. doi: 10.1165/rcmb.2015-0133OC. PubMed PMID: 26437021; PubMed Central PMCID: PMC4942193.
Chand HS, Montano G, Huang X, Randell SH, Mebratu Y, Petersen H, Tesfaigzi Y. A genetic variant of p53 restricts the mucous secretory phenotype by regulating SPDEF and Bcl-2 expression. Nat Commun. 2014 Nov 27;5:5567. doi: 10.1038/ncomms6567. PubMed PMID: 25429397; PubMed Central PMCID: PMC4247165.
Nyunoya T, Mebratu Y, Contreras A, Delgado M, Chand HS, Tesfaigzi Y. Molecular processes that drive cigarette smoke-induced epithelial cell fate of the lung. Am J Respir Cell Mol Biol. 2014 Mar;50(3):471-82. doi: 10.1165/rcmb.2013-0348TR. Review. PubMed PMID: 24111585; PubMed Central PMCID: PMC4068939.
Chand HS, Harris JF, Mebratu Y, Chen Y, Wright PS, Randell SH, Tesfaigzi Y. Intracellular insulin-like growth factor-1 induces Bcl-2 expression in airway epithelial cells. J Immunol. 2012 May 1;188(9):4581-9. doi: 10.4049/jimmunol.1102673. Epub 2012 Mar 28. PubMed PMID: 22461702; PubMed Central PMCID: PMC3359962.
Mebratu YA, Schwalm K, Smith KR, Schuyler M, Tesfaigzi Y. Cigarette smoke suppresses Bik to cause epithelial cell hyperplasia and mucous cell metaplasia. Am J Respir Crit Care Med. 2011 Jun 1;183(11):1531-8. doi: 10.1164/rccm.201011-1930OC. Epub 2011 Feb 11. PubMed PMID: 21317312; PubMed Central PMCID: PMC3137142.
Mebratu YA, Dickey BF, Evans C, Tesfaigzi Y. The BH3-only protein Bik/Blk/Nbk inhibits nuclear translocation of activated ERK1/2 to mediate IFNgamma-induced cell death. J Cell Biol. 2008 Nov 3;183(3):429-39. doi: 10.1083/jcb.200801186. PubMed PMID: 18981230; PubMed Central PMCID: PMC2575785.
Collaborators
Internal
Jacob Yount
College of Arts and Sciences, Department of Microbiology, The Ohio State University, Columbus, OH
External
Yohannes Tesfaigzi, PhD
Brigham and Women’s Hospital, Harvard, Medical School, Boston, MA
Adolfo Garcia-Sastre, PhD
Icahn School of Medicine at Mount Sinai, NY
Paul Thomas, PhD
St. Jude Children’s Research Hospital
Mark Peeples, PhD
Nationwide Children’s Hospital, Columbus, OH