Jon Koff, MD
Associate Professor Term; Associate Director, Fellowship Research, Pulmonary, Critical Care & Sleep Medicine; Director, Adult Cystic Fibrosis Program
Research & Publications
Biography
News
Locations
Research Summary
The airways are continuously exposed to pathogens, allergens, toxins, and environmental contaminants. In addition to its role as a physical barrier, the airway epithelial surface represents a “battleground,” where the host intercepts signals from pathogens (e.g., viruses) and activates epithelial defenses to prevent infection. The defensive roles of the airway epithelium are crucial; the epithelium activates innate defense mechanisms and recruits inflammatory and immune cells to activate innate immune responses and to amplify adaptive immunity. Our research program focuses on elucidating airway epithelial inflammatory responses to viral infection. Utilizing both in vitro and ex vivo airway epithelial cell cultures and murine models, we have found novel signaling pathways which regulate viral infection. Currently, there are only limited therapies available to treat viral exacerbations of chronic airway diseases (e.g., asthma, COPD, and cystic fibrosis); therefore investigating novel viral mechanisms may provide targets for novel therapies. Recently, this work has progressed to investigate models of trained innate immunity in pulmonary disease.
In collaboration with Drs. Paul Turner and Ben Chan in Ecology and Evolutionary Biology at Yale, Dr. Koff's laboratory has investigated the potential therapeutic role of bacteriophages in lung disease. Bacteriophages (phages) are viruses that infect bacteria. This research has developed a strategy to use phages to target specific bacteria and manipulate surviving bacteria to decrease antibiotic resistance and virulence. These studies include clinical research trials, translational- and laboratory-based projects to investigate phage therapy.
Coauthors
Research Interests
Asthma; Bacteriophages; Bronchiectasis; Cystic Fibrosis; Immunity, Innate; Influenza, Human; Lung; Viruses; Immunity, Mucosal; Respiratory Mucosa
Selected Publications
- Pseudomonas lipopolysaccharide accelerates wound repair via activation of a novel epithelial cell signaling cascade.Koff JL, Shao MX, Kim S, Ueki IF, Nadel JA. Pseudomonas lipopolysaccharide accelerates wound repair via activation of a novel epithelial cell signaling cascade. Journal Of Immunology (Baltimore, Md. : 1950) 2006, 177:8693-700.
- Case report: a case of wood-smoke-related pulmonary disease.Diaz JV, Koff J, Gotway MB, Nishimura S, Balmes JR. Case report: a case of wood-smoke-related pulmonary disease. Environmental Health Perspectives 2006, 114:759-62.
- Regulation of interleukin-8 via an airway epithelial signaling cascade.Nakanaga T, Nadel JA, Ueki IF, Koff JL, Shao MX. Regulation of interleukin-8 via an airway epithelial signaling cascade. American Journal Of Physiology. Lung Cellular And Molecular Physiology 2007, 292:L1289-96.
- Multiple TLRs activate EGFR via a signaling cascade to produce innate immune responses in airway epithelium.Koff JL, Shao MX, Ueki IF, Nadel JA. Multiple TLRs activate EGFR via a signaling cascade to produce innate immune responses in airway epithelium. American Journal Of Physiology. Lung Cellular And Molecular Physiology 2008, 294:L1068-75.
- Neutrophil-derived IL-6 limits alveolar barrier disruption in experimental ventilator-induced lung injury.Wolters PJ, Wray C, Sutherland RE, Kim SS, Koff J, Mao Y, Frank JA. Neutrophil-derived IL-6 limits alveolar barrier disruption in experimental ventilator-induced lung injury. Journal Of Immunology (Baltimore, Md. : 1950) 2009, 182:8056-62.
- Airway microbiota and pathogen abundance in age-stratified cystic fibrosis patients.Cox MJ, Allgaier M, Taylor B, Baek MS, Huang YJ, Daly RA, Karaoz U, Andersen GL, Brown R, Fujimura KE, Wu B, Tran D, Koff J, Kleinhenz ME, Nielson D, Brodie EL, Lynch SV. Airway microbiota and pathogen abundance in age-stratified cystic fibrosis patients. PloS One 2010, 5:e11044.
- The impact of pretransplant mechanical ventilation on short- and long-term survival after lung transplantation.Singer JP, Blanc PD, Hoopes C, Golden JA, Koff JL, Leard LE, Cheng S, Chen H. The impact of pretransplant mechanical ventilation on short- and long-term survival after lung transplantation. American Journal Of Transplantation : Official Journal Of The American Society Of Transplantation And The American Society Of Transplant Surgeons 2011, 11:2197-204.
- Amphiregulin, an epidermal growth factor receptor ligand, plays an essential role in the pathogenesis of transforming growth factor-β-induced pulmonary fibrosis.Zhou Y, Lee JY, Lee CM, Cho WK, Kang MJ, Koff JL, Yoon PO, Chae J, Park HO, Elias JA, Lee CG. Amphiregulin, an epidermal growth factor receptor ligand, plays an essential role in the pathogenesis of transforming growth factor-β-induced pulmonary fibrosis. The Journal Of Biological Chemistry 2012, 287:41991-2000.
- Respiratory virus-induced EGFR activation suppresses IRF1-dependent interferon λ and antiviral defense in airway epithelium.Ueki IF, Min-Oo G, Kalinowski A, Ballon-Landa E, Lanier LL, Nadel JA, Koff JL. Respiratory virus-induced EGFR activation suppresses IRF1-dependent interferon λ and antiviral defense in airway epithelium. The Journal Of Experimental Medicine 2013, 210:1929-36.
- Rhinovirus and other respiratory viruses exert different effects on lung allograft function that are not mediated through acute rejection.Sayah DM, Koff JL, Leard LE, Hays SR, Golden JA, Singer JP. Rhinovirus and other respiratory viruses exert different effects on lung allograft function that are not mediated through acute rejection. Clinical Transplantation 2013, 27:E64-71.
- EGFR activation suppresses respiratory virus-induced IRF1-dependent CXCL10 production.Kalinowski A, Ueki I, Min-Oo G, Ballon-Landa E, Knoff D, Galen B, Lanier LL, Nadel JA, Koff JL. EGFR activation suppresses respiratory virus-induced IRF1-dependent CXCL10 production. American Journal Of Physiology. Lung Cellular And Molecular Physiology 2014, 307:L186-96.
- Pharmacological modulation of the AKT/microRNA-199a-5p/CAV1 pathway ameliorates cystic fibrosis lung hyper-inflammation.Zhang PX, Cheng J, Zou S, D'Souza AD, Koff JL, Lu J, Lee PJ, Krause DS, Egan ME, Bruscia EM. Pharmacological modulation of the AKT/microRNA-199a-5p/CAV1 pathway ameliorates cystic fibrosis lung hyper-inflammation. Nature Communications 2015, 6:6221.
- Ezrin links CFTR to TLR4 signaling to orchestrate anti-bacterial immune response in macrophages.Di Pietro C, Zhang PX, O'Rourke TK, Murray TS, Wang L, Britto CJ, Koff JL, Krause DS, Egan ME, Bruscia EM. Ezrin links CFTR to TLR4 signaling to orchestrate anti-bacterial immune response in macrophages. Scientific Reports 2017, 7:10882.
- Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice.Wong CK, Smith CA, Sakamoto K, Kaminski N, Koff JL, Goldstein DR. Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice. Journal Of Immunology (Baltimore, Md. : 1950) 2017, 199:1060-1068.
- DNA Repair Interacts with Autophagy To Regulate Inflammatory Responses to Pulmonary Hyperoxia.Ye Y, Lin P, Zhang W, Tan S, Zhou X, Li R, Pu Q, Koff JL, Dhasarathy A, Ma F, Deng X, Jiang J, Wu M. DNA Repair Interacts with Autophagy To Regulate Inflammatory Responses to Pulmonary Hyperoxia. Journal Of Immunology (Baltimore, Md. : 1950) 2017, 198:2844-2853.
- Cystic Fibrosis Transmembrane Regulator Modulators: Implications for the Management of Depression and Anxiety in Cystic Fibrosis.Talwalkar JS, Koff JL, Lee HB, Britto CJ, Mulenos AM, Georgiopoulos AM. Cystic Fibrosis Transmembrane Regulator Modulators: Implications for the Management of Depression and Anxiety in Cystic Fibrosis. Psychosomatics 2017, 58:343-354.
- Respiratory syncytial virus activates epidermal growth factor receptor to suppress interferon regulatory factor 1-dependent interferon-lambda and antiviral defense in airway epithelium.Kalinowski A, Galen BT, Ueki IF, Sun Y, Mulenos A, Osafo-Addo A, Clark B, Joerns J, Liu W, Nadel JA, Dela Cruz CS, Koff JL. Respiratory syncytial virus activates epidermal growth factor receptor to suppress interferon regulatory factor 1-dependent interferon-lambda and antiviral defense in airway epithelium. Mucosal Immunology 2018, 11:958-967.
- TGF-β: Master regulator of inflammation and fibrosis.Stewart AG, Thomas B, Koff J. TGF-β: Master regulator of inflammation and fibrosis. Respirology (Carlton, Vic.) 2018, 23:1096-1097.
- Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria.Kortright KE, Chan BK, Koff JL, Turner PE. Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria. Cell Host & Microbe 2019, 25:219-232.
- Metabolic Adaptation in Methicillin-Resistant Staphylococcus aureus Pneumonia.Gabryszewski SJ, Wong Fok Lung T, Annavajhala MK, Tomlinson KL, Riquelme SA, Khan IN, Noguera LP, Wickersham M, Zhao A, Mulenos AM, Peaper D, Koff JL, Uhlemann AC, Prince A. Metabolic Adaptation in Methicillin-Resistant Staphylococcus aureus Pneumonia. American Journal Of Respiratory Cell And Molecular Biology 2019, 61:185-197.
- Cystic Fibrosis.Koff JL. Cystic Fibrosis. Clinics In Chest Medicine 2016, 37:xv-xvi.
- Innate and Adaptive Immunity in the LungDela Cruz, C and Koff JL. Innate and Adaptive Immunity in the Lung. In: Fishman’s Pulmonary Diseases and Disorders, 5th Edition. Editors: Grippi M, Elias J, Fishman J, Kotloff R, Pack A, Senior R. McGraw-Hill, New York, 2015.
- Cystic FibrosisKoff, J.L.; Cystic Fibrosis; Clin Chest Med. Mar;37(1):xv-xvi., 2016
Clinical Trials
| Conditions | Study Title |
|---|---|
| Women's Health; COVID-19 Inpatient; COVID-19 Outpatient | I-SPY COVID TRIAL: An Adaptive Platform Trial to Reduce Mortality and Ventilator Requirements for Critically Ill Patients |
| Hepatitis; HIV/AIDS; Immune System; Infectious Diseases | Screening In Anticipation of Future Research |