Clemente Britto-Leon, MD
Research & Publications
Dr. Britto's research focuses on the role of the novel protein SPLUNC1 in the immunity of the respiratory tract. SPLUNC1 (Short Palate Lung and Nasal Epithelial Clone 1) is produced in the lining of the large airways, a location constantly exposed to infectious agents and irritants.
SPLUNC1 is one of the most abundantly secreted products of the respiratory tract and has antimicrobial and anti-inflammatory functions. It also participates in the maintenance of the airway surface liquid, the liquid layer that covers the airways, an important protective mechanism against infection.
The functions of SPLUNC1 suggest it is critical to maintain a healthy respiratory tract. Some of these functions are dramatically impaired in patients with cystic fibrosis (CF), where chronic airway inflammation, poor secretion clearance and recurrent infections are prominent features of their clinical course. Dr. Britto's interest is in understanding how high levels of SPLUNC1 in CF may contribute to the development of airway disease.
Specialized Terms: Airway epithelium; airway inflammation; innate immunity; SPLUNC1; BPIFA1
Extensive Research Description
Short Palate Lung and Nasal epithelium Clone 1 (SPLUNC1) is an abundant airway protein with host protective functions relevant to cystic fibrosis (CF), the most common fatal genetic disease in the United States. The antimicrobial defense, mucociliary clearance and ion tranport regulation properties of SPLUNC1 may be important in the development of CF lung disease, the main cause of mortality in these patients. Persistent pulmonary inflammation and neutrophilic infiltration are hallmarks of CF lung disease. Work in our laboratory suggests that SPLUNC1 may have a novel role in regulating neutrophilic airway inflammation, as SPLUNC1-deficient (splunc1-/-) mice have dramatically decreased airway neutrophils during acute inflammation induced by LPS compared to wild type (WT) littermates.
SPLUNC1 is decreased in the airways of patients during allergic inflammation and we have shown that SPLUNC1 is decreased by common respiratory pathogens in animal models of airway inflammation in vivo, and by interferon gamma in vitro. Interestingly, this suppression of SPLUNC1 appears to be impaired in lung explants of severe CF patients undergoing lung transplantation, where SPLUNC1 is increased despite chronic inflammation and infection. In preliminary work, we determined that the suppression of SPLUNC1 is also impaired in the bronchoalveolar lavage fluid (BALF) of unstimulated CFTR-deficient (cftr-/-) and F508del homozygous (F508del) mice, two animal models of CF indicating that these animal models may be useful to study the regulation of SPLUNC1 in CF.
Despite the apparent paradox between the pathological and protective role of SPLUNC1, little is known about the mechanisms that regulate its activity, the role that SPLUNC1 plays in neutrophilic inflammation and its sigificance in the development of CF lung disease. We believe that the suppression of SPLUNC1 is a protective mechanism to limit neutrophilic inflammation and subsequent airway injury and so, high SPLUNC1 in CF may be detrimental by promoting neutrophilic inflammation, a fundamental part of CF lung disease pathogenesis. The objective of our research program is to understand how SPLUNC1 influences neutrophilic airway inflammation and if the modulation of SPLUNC1 can limit airway inflammation in CF.
Regulation of SPLUNC1 expression by the airway epithelium: identification of mechanisms by which pathogens, PAMPs and cytokines modulate SPLUNC1 expression.
Mechanisms of neutrophilic inflammation control by SPLUNC1: characterization of the role of SPLUNC1 in neutrophil recruitment to the lungs during acute airway inflammation.
Role of SPLUNC1 in immune responses in CF: defining mechanisms by which SPLUNC1 is increased in CF and what effect this increase has in neutrophilic immune responses.
Bacterial Infections and Mycoses; Cystic Fibrosis; Epithelium; Immune System Diseases; Lung; Respiratory Tract Diseases; Pulmonary Medicine; Airway Management
- SPLUNC1: a novel marker of cystic fibrosis exacerbationsKhanal S, Webster M, Niu N, Zielonka J, Nunez M, Chupp G, Slade MD, Cohn L, Sauler M, Gomez JL, Tarran R, Sharma L, Dela Cruz CS, Egan M, Laguna T, Britto CJ. SPLUNC1: a novel marker of cystic fibrosis exacerbations European Respiratory Journal 2021, 58: 2000507. PMID: 33958427, PMCID: PMC8571118, DOI: 10.1183/13993003.00507-2020.
- Single-Cell Transcriptional Archetypes of Airway Inflammation in Cystic Fibrosis.Schupp JC, Khanal S, Gomez JL, Sauler M, Adams TS, Chupp GL, Yan X, Poli S, Zhao Y, Montgomery RR, Rosas IO, Dela Cruz CS, Bruscia EM, Egan ME, Kaminski N, Britto CJ. Single-Cell Transcriptional Archetypes of Airway Inflammation in Cystic Fibrosis. American Journal Of Respiratory And Critical Care Medicine 2020, 202: 1419-1429. PMID: 32603604, PMCID: PMC7667912, DOI: 10.1164/rccm.202004-0991oc.
- Charting a New Path: A Single-Cell Atlas of Porcine Cystic Fibrosis Airways at Birth.Britto CJ. Charting a New Path: A Single-Cell Atlas of Porcine Cystic Fibrosis Airways at Birth. American Journal Of Respiratory Cell And Molecular Biology 2022, 66: 585-586. PMID: 35294854, PMCID: PMC9163641, DOI: 10.1165/rcmb.2022-0065ED.
- Sexually Dimorphic Innate Immune Programs of Airway Monocytes in Cystic FibrosisYin H, Li N, Shiner N, Khanal S, Schupp J, Chupp G, Gomez J, Britto-Leon C. Sexually Dimorphic Innate Immune Programs of Airway Monocytes in Cystic Fibrosis 2022, a1984-a1984. DOI: 10.1164/ajrccm-conference.2022.205.1_meetingabstracts.a1984.
- Sex-Based Differences in Sputum Inflammation Markers of Acute Cystic Fibrosis ExacerbationAyala A, Yin H, Khanal S, Niu N, Nunez M, Chupp G, Laguna T, Britto-Leon C. Sex-Based Differences in Sputum Inflammation Markers of Acute Cystic Fibrosis Exacerbation 2022, a1988-a1988. DOI: 10.1164/ajrccm-conference.2022.205.1_meetingabstracts.a1988.
- Atrial Esophageal Fistula: A Rare and Lethal Complication Following Catheter Ablation of Atrial FibrillationHarrington L, Stanley G, Khosla A, Britto-Leon C. Atrial Esophageal Fistula: A Rare and Lethal Complication Following Catheter Ablation of Atrial Fibrillation 2022, a2853-a2853. DOI: 10.1164/ajrccm-conference.2022.205.1_meetingabstracts.a2853.
- Characterization of the COPD alveolar niche using single-cell RNA sequencingSauler M, McDonough JE, Adams TS, Kothapalli N, Barnthaler T, Werder RB, Schupp JC, Nouws J, Robertson MJ, Coarfa C, Yang T, Chioccioli M, Omote N, Cosme C, Poli S, Ayaub EA, Chu SG, Jensen KH, Gomez JL, Britto CJ, Raredon MSB, Niklason LE, Wilson AA, Timshel PN, Kaminski N, Rosas IO. Characterization of the COPD alveolar niche using single-cell RNA sequencing Nature Communications 2022, 13: 494. PMID: 35078977, PMCID: PMC8789871, DOI: 10.1038/s41467-022-28062-9.
- ResponsePrice CC, Altice FL, Azar MM, McManus D, Gleeson SE, Britto CJ, Azmy V, Kaman K, Davis M, Chupp G, Bucala R, Kaminski N, Topal JE, Dela Cruz C, Malinis M. Response CHEST Journal 2021, 159: 2116-2117. PMID: 33965143, PMCID: PMC8097398, DOI: 10.1016/j.chest.2020.12.032.
- Decreased NUPR1 in AT2 Cells Is Associated with Development of Emphysema in COPDMcDonough J, Adams T, Kothapalli N, Schupp J, Nouws J, Chioccioli M, Omote N, Cosme Jr. C, Poli De Frias S, Ayaub E, Chu S, Jensen K, Gomez J, Britto-Leon C, Raredon M, Niklason L, Timshel P, Kaminski N, Rosas I, Sauler M. Decreased NUPR1 in AT2 Cells Is Associated with Development of Emphysema in COPD 2021, a4281-a4281. DOI: 10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a4281.
- Host-Defense Protein SPLUNC1 Regulates Influenza-Induced Acute Lung InjuryMora Carpio A, Khanal S, Zielonka J, Niu N, Shiner N, Sharma L, Dela Cruz C, Britto-Leon C. Host-Defense Protein SPLUNC1 Regulates Influenza-Induced Acute Lung Injury 2021, a3883-a3883. DOI: 10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a3883.
- Sputum Inflammation Markers as Predictors of Acute Exacerbations in Cystic FibrosisZielonka J, Khanal S, Niu N, Slade M, Chupp G, Britto-Leon C. Sputum Inflammation Markers as Predictors of Acute Exacerbations in Cystic Fibrosis 2021, a4252-a4252. DOI: 10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a4252.
- Single-cell characterization of a model of poly I:C-stimulated peripheral blood mononuclear cells in severe asthmaChen A, Diaz-Soto MP, Sanmamed MF, Adams T, Schupp JC, Gupta A, Britto C, Sauler M, Yan X, Liu Q, Nino G, Cruz CSD, Chupp GL, Gomez JL. Single-cell characterization of a model of poly I:C-stimulated peripheral blood mononuclear cells in severe asthma Respiratory Research 2021, 22: 122. PMID: 33902571, PMCID: PMC8074196, DOI: 10.1186/s12931-021-01709-9.
- Cytokine profiles in severe SARS-CoV-2 infection requiring extracorporeal membrane oxygenation supportKaman K, Azmy V, Chichra A, Britto-Leon C, Price C. Cytokine profiles in severe SARS-CoV-2 infection requiring extracorporeal membrane oxygenation support Respiratory Medicine Case Reports 2021, 33: 101376. PMID: 33680800, PMCID: PMC7925237, DOI: 10.1016/j.rmcr.2021.101376.
- Staphylococcus aureus induces an itaconate-dominated immunometabolic response that drives biofilm formation.Tomlinson KL, Lung TWF, Dach F, Annavajhala MK, Gabryszewski SJ, Groves RA, Drikic M, Francoeur NJ, Sridhar SH, Smith ML, Khanal S, Britto CJ, Sebra R, Lewis I, Uhlemann AC, Kahl BC, Prince AS, Riquelme SA. Staphylococcus aureus induces an itaconate-dominated immunometabolic response that drives biofilm formation. Nature Communications 2021, 12: 1399. PMID: 33658521, PMCID: PMC7930111, DOI: 10.1038/s41467-021-21718-y.
- MicroRNA miR-24-3p reduces DNA damage responses, apoptosis, and susceptibility to chronic obstructive pulmonary diseaseNouws J, Wan F, Finnemore E, Roque W, Kim SJ, Bazan IS, Li CX, Sköld C, Dai Q, Yan X, Chioccioli M, Neumeister V, Britto CJ, Sweasy J, Bindra RS, Wheelock ÅM, Gomez JL, Kaminski N, Lee PJ, Sauler M. MicroRNA miR-24-3p reduces DNA damage responses, apoptosis, and susceptibility to chronic obstructive pulmonary disease JCI Insight 2021, 6: e134218. PMID: 33290275, PMCID: PMC7934877, DOI: 10.1172/jci.insight.134218.
- A Network of Sputum MicroRNAs is Associated with Neutrophilic Airway Inflammation in AsthmaGomez JL, Chen A, Diaz MP, Zirn N, Gupta A, Britto C, Sauler M, Yan X, Stewart E, Santerian K, Grant N, Liu Q, Fry R, Rager J, Cohn L, Alexis N, Chupp GL. A Network of Sputum MicroRNAs is Associated with Neutrophilic Airway Inflammation in Asthma American Journal Of Respiratory And Critical Care Medicine 2020, 0: 51-64. PMID: 32255668, PMCID: PMC7328332, DOI: 10.1164/rccm.201912-2360oc.
- Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019 Survival and Clinical OutcomesPrice CC, Altice FL, Shyr Y, Koff A, Pischel L, Goshua G, Azar MM, Mcmanus D, Chen SC, Gleeson SE, Britto CJ, Azmy V, Kaman K, Gaston DC, Davis M, Burrello T, Harris Z, Villanueva MS, Aoun-Barakat L, Kang I, Seropian S, Chupp G, Bucala R, Kaminski N, Lee AI, LoRusso PM, Topal JE, Dela Cruz C, Malinis M. Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019 Survival and Clinical Outcomes CHEST Journal 2020, 158: 1397-1408. PMID: 32553536, PMCID: PMC7831876, DOI: 10.1016/j.chest.2020.06.006.
- Repurposing antimicrobial stewardship tools in the electronic medical record for the management of COVID-19 patientsDavis MW, McManus D, Koff A, Jaszczur GR, Malinis M, Dela Cruz C, Britto CJ, Price C, Azmy V, Kaman K, Gaston D, Early K, DeWitt M, Song JS, Ortiz C, Juthani-Mehta M, Topal JE. Repurposing antimicrobial stewardship tools in the electronic medical record for the management of COVID-19 patients Infection Control And Hospital Epidemiology 2020, 41: 1335-1337. PMID: 32507113, PMCID: PMC7308631, DOI: 10.1017/ice.2020.281.
- Pseudomonas aeruginosa Utilizes Host-Derived Itaconate to Redirect Its Metabolism to Promote Biofilm Formation.Riquelme SA, Liimatta K, Wong Fok Lung T, Fields B, Ahn D, Chen D, Lozano C, Sáenz Y, Uhlemann AC, Kahl BC, Britto CJ, DiMango E, Prince A. Pseudomonas aeruginosa Utilizes Host-Derived Itaconate to Redirect Its Metabolism to Promote Biofilm Formation. Cell Metabolism 2020, 31: 1091-1106.e6. PMID: 32428444, PMCID: PMC7272298, DOI: 10.1016/j.cmet.2020.04.017.
- SPLUNC1 Interacts with Pathogen Recognition Receptors to Regulate Influenza-Induced Lung InflammationKhanal S, Sharma L, Dela Cruz C, Britto-Leon C. SPLUNC1 Interacts with Pathogen Recognition Receptors to Regulate Influenza-Induced Lung Inflammation 2020, a7426-a7426. DOI: 10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a7426.
- Mechanisms of Epithelial Immunity Evasion by Respiratory Bacterial PathogensSharma L, Feng J, Britto CJ, Dela Cruz CS. Mechanisms of Epithelial Immunity Evasion by Respiratory Bacterial Pathogens Frontiers In Immunology 2020, 11: 91. PMID: 32117248, PMCID: PMC7027138, DOI: 10.3389/fimmu.2020.00091.
- Escalating Mucus Inhibition to the Top of Our PrioritiesBritto CJ, Cohn L. Escalating Mucus Inhibition to the Top of Our Priorities American Journal Of Respiratory Cell And Molecular Biology 2019, 61: 275-276. PMID: 31063695, PMCID: PMC6839933, DOI: 10.1165/rcmb.2019-0143ed.
- CFTR-PTEN-dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection.Riquelme SA, Lozano C, Moustafa AM, Liimatta K, Tomlinson KL, Britto C, Khanal S, Gill SK, Narechania A, Azcona-Gutiérrez JM, DiMango E, Saénz Y, Planet P, Prince A. CFTR-PTEN-dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection. Science Translational Medicine 2019, 11 PMID: 31270271, PMCID: PMC6784538, DOI: 10.1126/scitranslmed.aav4634.
- BPIFA1 Regulates Neutrophilic Response of Influenza A Virus InfectionKhanal S, Niu N, Sharma L, Bermejo S, Liu W, Delacruz C, Cohn L, Britto-Leon C. BPIFA1 Regulates Neutrophilic Response of Influenza A Virus Infection 2019, a5745-a5745. DOI: 10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a5745.
- Circulating Mitochondrial DNA Is Associated with Acute Exacerbations of Cystic FibrosisOrtiz V, Ryu C, Herzog E, Britto-Leon C, Koff J. Circulating Mitochondrial DNA Is Associated with Acute Exacerbations of Cystic Fibrosis 2019, a7332-a7332. DOI: 10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a7332.
- BPIFA1 regulates lung neutrophil recruitment and interferon signaling during acute inflammationBritto CJ, Niu N, Khanal S, Huleihel L, Herazo-Maya J, Thompson A, Sauler M, Slade MD, Sharma L, Dela Cruz CS, Kaminski N, Cohn LE. BPIFA1 regulates lung neutrophil recruitment and interferon signaling during acute inflammation American Journal Of Physiology - Lung Cellular And Molecular Physiology 2018, 316: l321-l333. PMID: 30461288, PMCID: PMC6397348, DOI: 10.1152/ajplung.00056.2018.
- Regulation and Role of Chitotriosidase during Lung Infection with Klebsiella pneumoniaeSharma L, Amick AK, Vasudevan S, Lee SW, Marion CR, Liu W, Brady V, Losier A, Bermejo SD, Britto CJ, Lee CG, Elias JA, Dela Cruz CS. Regulation and Role of Chitotriosidase during Lung Infection with Klebsiella pneumoniae The Journal Of Immunology 2018, 201: 615-626. PMID: 29891554, PMCID: PMC6291403, DOI: 10.4049/jimmunol.1701782.
- Impaired type I interferon regulation in the blood transcriptome of recurrent asthma exacerbations.Gomez JL, Diaz MP, Nino G, Britto CJ. Impaired type I interferon regulation in the blood transcriptome of recurrent asthma exacerbations. BMC Medical Genomics 2018, 11: 21. PMID: 29486764, PMCID: PMC5830339, DOI: 10.1186/s12920-018-0340-3.
- A Woman in Her 60s With Lung Adenocarcinoma Presents With Copious Watery Sputum and Respiratory Failure.Roeder NL, Marshall JD, Britto CJ. A Woman in Her 60s With Lung Adenocarcinoma Presents With Copious Watery Sputum and Respiratory Failure. Chest 2017, 152: e143-e146. PMID: 29223274, DOI: 10.1016/j.chest.2017.07.011.
- Ezrin links CFTR to TLR4 signaling to orchestrate anti-bacterial immune response in macrophagesDi Pietro C, Zhang PX, O’Rourke T, 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. PMID: 28883468, PMCID: PMC5589856, DOI: 10.1038/s41598-017-11012-7.
- Cystic Fibrosis Transmembrane Regulator Modulators: Implications for the Management of Depression and Anxiety in Cystic FibrosisTalwalkar 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 Journal Of The Academy Of Consultation-Liaison Psychiatry 2017, 58: 343-354. PMID: 28576305, DOI: 10.1016/j.psym.2017.04.001.
- Multiparameter Single Cell Profiling of Airway Inflammatory CellsYao Y, Welp T, Liu Q, Niu N, Wang X, Britto CJ, Krishnaswamy S, Chupp G, Montgomery RR. Multiparameter Single Cell Profiling of Airway Inflammatory Cells Cytometry Part B Clinical Cytometry 2017, 92: 12-20. PMID: 27807928, PMCID: PMC5250532, DOI: 10.1002/cyto.b.21491.
- Respiratory Viral Infections in Chronic Lung DiseasesBritto CJ, Brady V, Lee S, Dela Cruz CS. Respiratory Viral Infections in Chronic Lung Diseases Clinics In Chest Medicine 2016, 38: 87-96. PMID: 28159164, PMCID: PMC5679206, DOI: 10.1016/j.ccm.2016.11.014.
- Bactericidal/Permeability-Increasing Protein Fold–Containing Family Member A1 in Airway Host Protection and Respiratory DiseaseBritto CJ, Cohn L. Bactericidal/Permeability-Increasing Protein Fold–Containing Family Member A1 in Airway Host Protection and Respiratory Disease American Journal Of Respiratory Cell And Molecular Biology 2015, 52: 525-534. PMID: 25265466, PMCID: PMC4491141, DOI: 10.1165/rcmb.2014-0297rt.
- Short Palate, Lung, and Nasal Epithelial Clone–1 Is a Tightly Regulated Airway Sensor in Innate and Adaptive ImmunityBritto CJ, Liu Q, Curran DR, Patham B, Dela Cruz CS, Cohn L. Short Palate, Lung, and Nasal Epithelial Clone–1 Is a Tightly Regulated Airway Sensor in Innate and Adaptive Immunity American Journal Of Respiratory Cell And Molecular Biology 2013, 48: 717-724. PMID: 23470624, PMCID: PMC3727874, DOI: 10.1165/rcmb.2012-0072oc.
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