About

Yohannes Mebratu, PhD, is an Assistant Professor in the Department of Internal Medicine at Ohio State College of Medicine. His research program focuses on identifying novel mechanisms by which influenza A virus (IAV) hijacks and subverts host cellular processes to facilitate viral replication. His work aims to develop therapeutic host targets for treating influenza infections by studying how IAV exploits host cellular proteins to promote pathogenesis, identifying genetic factors that contribute to disease severity, and pinpointing host cellular targets for treatment. Dr. Mebratu's research utilizes both basic and translational models of infectious and inflammatory lung diseases, including studies involving influenza-infected human cohorts from diverse backgrounds to understand genetic susceptibility factors. His research has potential implications for targeted prevention, disease management, and treatment strategies for influenza and other respiratory viral infections.

Research topics

• Immunology
• Medicine
• Internal medicine
• Biology
• Pathology
• Genetics
• Cell biology
• Cancer research

Selected publications

• A new era in cancer therapy: targeting the Proteasome-Bcl-2 axis

  Journal of Experimental & Clinical Cancer Research · 2025-08-21 · 2 citations

  reviewOpen accessSenior author

  The B-cell lymphoma-2 (Bcl-2) family proteins, key regulators of apoptosis, are frequently dysregulated in cancer, tipping the balance of cell survival and apoptosis in favor of survival. The ubiquitin-proteasome system (UPS) is a critical cellular machinery that controls the Bcl-2 levels through regulation of protein stability. This review delves into the intricate interplay between the proteasome and Bcl-2 family members, exploring how proteasome-mediated degradation impacts cell survival and proliferation to influence cancer progression. We discuss the therapeutic potential of targeting the proteasome-Bcl-2 axis, including the use of proteasome inhibitors as anticancer agents. We examine their mechanisms of action, clinical efficacy, and limitations while exploring emerging strategies to overcome these challenges.

  PublisherOA PDFDOI

• Polymorphism of BIK as a Host Risk Factor for Severe Influenza

  DNA and Cell Biology · 2025-09-19 · 1 citations

  articleSenior author

  This essay focuses on a key host factor, the protein BIK (Bcl-2-interacting killer), that influences the severity of influenza A virus (IAV) infections. Our recent research published in Proceedings of the National Academy of Sciences describes a novel IAV-BIK-β5 axis that is critical for viral replication. The study demonstrates that BIK is essential for efficient IAV replication, and its overexpression leads to increased viral loads, lung inflammation, and heightened mortality in mouse models. We also identified a single nucleotide polymorphism (SNP), rs738276, in the BIK gene's promoter. This SNP influences the basal expression of BIK, and individuals with the high-expression AA genotype are at a higher risk for severe influenza. The molecular mechanism involves the viral nucleoprotein (NP) suppressing the proteasome's β5 subunit, which leads to BIK accumulation and promotes viral replication. These findings identify BIK as a potential therapeutic target and the rs738276 SNP as a biomarker for personalized medicine.

  PublisherDOI

• A New Role for Bcl-2 Interacting Killer (BIK) in COVID-19 Pathogenesis

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  articleSenior author

  Abstract Rationale: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a significant threat to global health, causing severe respiratory illnesses and substantial mortality worldwide. The ongoing challenge is compounded by limited therapeutic options, the frequent emergence of new viral strains, and the rapid development of drug and vaccine resistance. Our research identified Bcl-2 interacting killer (BIK) as a critical host cellular protein that enhances influenza A virus (IAV) replication in the airway epithelial cells (AECs) and exacerbates disease severity. Bik promotes IAV replication by mediating caspase 3-dependent cleavage of viral proteins. Caspases are implicated in both apoptotic and inflammatory pathways during SARS-CoV-2 infection. Therefore, we aimed to explore the role of BIK in modulating SARS-CoV-2-induced lung inflammation and disease severity. Methodology: For in vivo studies, bik+/+ and bik-/-mice in C57BL/6 background were infected with 1x10^5 tissue culture infectious dose (TCID50) of SARS-CoV-2 MA10 strain. On day 2 post infection, lung tissues were evaluated for histopathological and viral load analyses, using hematoxylin and eosin (H&E) staining and TCID50 assay, respectively. Mice were monitored for changes in body weight for 7 days. The levels of inflammatory cytokines and chemokines in lung tissues were analyzed using Luminex multiplex assays. Results: We found that bik-deficient mice exhibited heightened susceptibility to SARS-CoV-2 infection. This susceptibility was demonstrated by the significant weight loss in bik-/- mice compared to their bik+/+ counterparts. The viral load was significantly higher in the lungs of bik-/- mice compared with their bik+/+ counterparts. Histopathological analysis of murine lung tissues revealed more severe lung damage in bik-/- mice post-SARS-CoV-2 infection. Additionally, the levels of pro-inflammatory cytokines TNF-α, IL-1α, IL-1β, IL-6, IFN-γ, and chemokines CCL3, CXCL1, and CXCL2 were significantly elevated in the lung homogenates of bik-/- mice compared to their bik+/+ counterparts. We also found that infection with SARS-CoV-2 downregulated BIK mRNA and protein expression. Conclusions: Our data indicates that BIK is a key protein involved in SARS-CoV-2-induced lung pathogenesis. Future research will aim to uncover the specific regulatory mechanisms by which SARS-CoV-2 modulates BIK to promote viral replication and enhance disease severity. Understanding these pathways could lead to novel targeted interventions aimed at mitigating SARS-CoV-2 infection.

  PublisherDOI

• USP13 protects against influenza virus-induced lung injury by promoting IFN-β production

  Physiology · 2025-05-01

  article

  Influenza A virus (IAV) a negative-sense, single-stranded RNA virus, which belongs in the Orthomyxoviridae family. Influenza A is a common cause of acute respiratory illnesses worldwide and associated with considerable morbidity and mortality. Ubiquitin-specific protease 13 (USP13) belongs to the deubiquitinating enzyme (DUB) superfamily. The role of USP13 in the pathogenesis of IAV-induced lung injury has not been revealed. In this study, we investigated the role of USP13 in IAV-induced lung injury. Influenza A/Puerto Rico/8/34 (H1N1) virus was used to infect human lung epithelial cells and mice. IAV infection decreased USP13 protein levels in the mouse lung tissues at 7 days post-infection (dpi). Both USP13 mRNA and protein levels were significantly decreased in IAV-infected A549 cells in dose- and time-dependent manners. Next, we investigated the role of USP13 in IAV-triggered signaling in A549 cells by silencing and overexpressing USP13. Knockdown of USP13 impaired IAV-induced IFN-β mRNA and protein expression, whereas USP13 overexpression enhanced IAV-induced IFN-β mRNA and protein expression. Moreover, knockdown of USP13 significantly increased virus titers at 48 hours post-infection (hpi) in IAV-infected A549 cells. On the other hand, overexpression of USP13 resulted in a significantly decrease in virus titers at 48 hpi. To further investigate the role of USP13 in IAV infection, we infected wild type mice (USP13+/+) and USP13 knockout mice (USP13-/-) with intranasal administration of PR8 virus. USP13-/- mice showed significant more weight loss compared to USP13+/+ mice after PR8 infection. USP13 knockout mice were more susceptible to influenza virus pathology and USP13 deficiency decreases IAV-induced IFN-β production. Mechanistically, Knockdown of USP13 impaired IAV-triggered IRF3 nuclear translocation. Moreover, we found that IAV infection promoted association between USP13 and p-IRF3. Future studies will shed light on the role of USP13 in modulating the ubiquitin-proteasome system in antiviral innate immunity signaling. This work is supported by the National Institutes of Health; R01HL151513 and R01HL167846 to J.Z.; R01AI148180 to Y.A.M; R01AI130110 to J.S.Y. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

  PublisherDOI

• BIK polymorphism and proteasome regulation unveil host risk factor for severe influenza

  Proceedings of the National Academy of Sciences · 2025-07-08 · 3 citations

  articleOpen accessSenior authorCorresponding

  Influenza A viruses (IAVs) pose a significant public health threat, with host factors playing a crucial role in disease severity. We investigated the role of Bcl-2-interacting killer (BIK) in IAV infection using cellular and mouse models, and influenza-infected human cohort. In airway epithelial cells (AECs), BIK deficiency impaired viral replication, while BIK restoration enhanced it. Conversely, airway-specific BIK overexpression in mice increased viral load, inflammation, and mortality, whereas BIK suppression conferred protection. Critically, a genetic variation (rs738276) in the BIK gene, influencing BIK expression, correlates with altered viral replication in air–liquid interface differentiated primary normal human bronchial epithelial cells and influenza severity in humans. Mechanistically, we demonstrate that IAV nucleoprotein (NP) suppresses β5, a subunit of the proteasome, leading to increased BIK levels and enhanced viral replication. Conversely, β5 treatment dampened BIK levels and protected mice from IAV-induced morbidity and mortality. Furthermore, BIK interacts with NP, disrupting the Bcl-2/NP interaction and promoting viral replication. Our findings uncover an IAV–BIK–β5 axis that governs viral replication, suggesting that targeting BIK or β5 may offer therapeutic strategies against influenza.

  PublisherOA PDFDOI

• The Host Ubiquitin E3 Ligase ARIH2 Reduces Influenza A Virus Replication in the Airways and Mitigates Disease Progression in Mice

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  articleSenior author

  Abstract Rationale: Influenza A virus (IAV) poses a major public health threat, causing severe lung inflammation. Due to frequent mutations, IAVs often develop resistance to current antiviral treatments. Hence, to identify potential alternative therapies, it is crucial to understand how IAVs interact with host proteins. Our previous research showed that IAV induces the host cellular protein Bcl-2 interacting killer (BIK), promoting viral replication in airway epithelial cells (AECs). However, the precise mechanism remains unclear. Here, we further investigated how IAV hijacks the host cellular proteins to promote viral replication and exacerbate lung inflammation. Methods: Human precision-cut lung slices (hPCLS) were transduced with adeno-associated viral (AAV) vectors expressing EGFP or ARIH2, followed by IAV infection. To explore the translational potential, ARIH2 was delivered intranasally via AAV6.2 vector in C57BL/6 mice followed by IAV-infection, and the impact on lung inflammation and survival was evaluated. Lung histology was assessed using hematoxylin and eosin (H&E) staining. Western blot, co-immunoprecipitation, ubiquitination assays, mass spectrometry (MS), and immunofluorescence were performed to assess protein expression. Luminex multiplex assays quantified inflammatory cytokines/chemokines in lung homogenates and supernatants of IAV-infected mice and hPCLS. Results: MS analysis identified ARIH2 as the primary BIK-interacting E3 ligase suppressed by IAV to stabilize BIK. This finding was supported by the observation that decreasing ARIH2 levels increased BIK protein levels in IAV-infected AECs. IAV nucleoprotein, distinct from other viral ribonucleoprotein components, specifically inhibited ARIH2 and induced BIK. Overexpression of ARIH2 reduced BIK levels and diminished IAV yield. Conversely, ARIH2 depletion led to increased BIK protein levels. Furthermore, ARIH2 showed a robust interaction with BIK. IAV inhibited ARIH2-mediated K48-linked BIK ubiquitination. On the contrary, ARIH2 overexpression in IAV-infected cells restored BIK ubiquitination and dampened IAV-induced pro-inflammatory cytokines, affirming that IAV interferes with ARIH2-mediated BIK degradation. In hPCLS, IAV infection suppressed ARIH2, thereby increasing BIK protein levels, while AAV-ARIH2 treatment significantly reduced viral load, underscoring its significant translational implications. In vivo, intranasal delivery of AAV-ARIH2 reduced lung viral load and inflammation, thereby reducing IAV-induced morbidity and mortality. Conclusion: ARIH2 emerges as a novel host cellular protein exploited by IAV to inhibit BIK degradation, thereby promoting viral replication. Enhancing ARIH2-mediated BIK ubiquitination presents a promising novel therapeutic strategy to reduce IAV replication and lung inflammation.

  PublisherDOI

• SARS-CoV-2 innate immune recognition and implications for respiratory health

  Cytokine & Growth Factor Reviews · 2025-10-28 · 8 citations

  articleOpen accessSenior author

  The ongoing global health impact of SARS-CoV-2, particularly on lung and respiratory health, underscores the critical need to decipher the intricate interplay between the virus and the host innate immune system. This review provides an analysis of the key pattern recognition receptors (PRRs) involved in SARS-CoV-2 recognition within the lung, including toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs). We discuss how the engagement of these innate sentinels triggers crucial downstream consequences, ranging from protective antiviral interferon (IFN) responses to detrimental hyperinflammation characteristic of severe COVID-19. Numerous studies have identified sophisticated mechanisms employed by SARS-CoV-2 to evade or suppress early IFN induction, contributing to unchecked viral replication and subsequent immunopathology. We explore how this aberrant innate immune response drives the "cytokine storm", leading to acute respiratory distress syndrome (ARDS) and long-term sequelae. Furthermore, this review critically assesses current and emerging therapeutic strategies aimed at modulating innate immunity, including TLR agonists/antagonists, RIG-I/MDA5 modulators, NLRP3 inflammasome inhibitors, and IFN-based therapies, highlighting their potential and associated challenges. Finally, we identify key research gaps, emphasizing the need for cell-type-specific PRR studies, comprehensive mapping of viral evasion mechanisms, and the development of precision immunotherapies to enhance protective responses and mitigate pathogenic inflammation for future respiratory viral threats.

  PublisherDOI

• Influenza, SARS-CoV-2, and Their Impact on Chronic Lung Diseases and Fibrosis

  American Journal Of Pathology · 2024-07-18 · 12 citations

  reviewOpen access
  PublisherOA PDFDOI

• Targeting the Ubiquitin Proteasome System to Combat Influenza A Virus: Hijacking the Cleanup Crew

  Reviews in Medical Virology · 2024-11-01 · 5 citations

  reviewOpen accessSenior authorCorresponding

  Influenza A virus (IAV) remains a significant global public health threat, causing substantial illness and economic burden. Despite existing antiviral drugs, the emergence of resistant strains necessitates alternative therapeutic strategies. This review explores the complex interplay between the ubiquitin proteasome system (UPS) and IAV pathogenesis. We discuss how IAV manipulates the UPS to promote its lifecycle, while also highlighting how host cells utilise the UPS to counteract viral infection. Recent research on deubiquitinases as potential regulators of IAV infection is also addressed. By elucidating the multifaceted role of the UPS in IAV pathogenesis, this review aims to identify potential targets for novel therapeutic interventions.

  PublisherOA PDFDOI

• Toward a Radically Simple Multi‐Modal Nasal Spray for Preventing Respiratory Infections

  Advanced Materials · 2024-09-24 · 4 citations

  article

  Nasal sprays for pre-exposure prophylaxis against respiratory infections show limited protection (20-70%), largely due to their single mechanism of action-either neutralizing pathogens or blocking their entry at the nasal lining, and a failure to maximize the capture of respiratory droplets, allowing them to potentially rebound and reach deeper airways. This report introduces the Pathogen Capture and Neutralizing Spray (PCANS), which utilizes a multi-modal approach to enhance efficacy. PCANS coats the nasal cavity, capturing large respiratory droplets from the air, and serving as a physical barrier against a broad spectrum of viruses and bacteria, while rapidly neutralizing them with over 99.99% effectiveness. The formulation consists of excipients identified from the FDA's Inactive Ingredient Database and Generally Recognized as Safe list to maximize efficacy for each step in the multi-modal approach. PCANS demonstrates nasal retention for up to 8 hours in mice. In a severe Influenza A mouse model, a single pre-exposure dose of PCANS leads to a >99.99% reduction in lung viral titer and ensures 100% survival, compared to 0% in the control group. PCANS suppresses pathological manifestations and offers protection for at least 4 hours. This data suggest PCANS as a promising daily-use prophylactic against respiratory infections.

  PublisherDOI

Recent grants

• Bik Promotes Cleavage of Viral Proteins to Enhance Influenza A Virus Infection

  NIH · $600k · 2015–2018

Frequent coauthors

• Yohannes Tesfaigzi

  Brigham and Women's Hospital

  61 shared

• Hitendra S. Chand

  Florida International University

  16 shared

• Jeffrey M. Karp

  Brigham and Women's Hospital

  16 shared

• Joselyn Rojas

  Baylor College of Medicine

  15 shared

• Z.H. Negasi

  Brigham and Women's Hospital

  12 shared

• Sourabh Soni

  The Ohio State University Wexner Medical Center

  12 shared

• D. Tassew

  QPS (United States)

  9 shared

• John Joseph

  Brigham and Women's Hospital

  8 shared

Awards & honors

• German Catholic Academic Exchange Program Scholarship (1996)
• German Catholic Academic Exchange Program Scholarship (2002)
• American Thoracic Society Scholarship Award (2008)