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1. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author

Shrine, Nick, Izquierdo, Abril G, Chen, Jing, Packer, Richard, Hall, Robert J, Guyatt, Anna L, Batini, Chiara, Thompson, Rebecca J, Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D, Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A, John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y, Chen, Zhengming, Li, Liming, China Kadoorie Biobank Collaborative Group, Wijnant, Sara RA, Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G, Manichaikul, Ani, Oelsner, Elizabeth C, Rich, Stephen S, Barr, R Graham, Kerr, Shona M, Vitart, Veronique, Brown, Michael R, Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M, Gharib, Sina A, Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E, Meyers, Deborah A, Bleecker, Eugene R, Gabriel, Stacey B, Gupta, Namrata, Smith, Albert Vernon, Luan, Jian'an, Zhao, Jing-Hua, Hansen, Ailin F, Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H, Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L, Yu, Bing, Lim, Elise, Xu, Hanfei, O'Connor, George T, Thareja, Gaurav, Albagha, Omar ME, Qatar Genome Program Research (QGPR) Consortium, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O, Hiemstra, Pieter S, Slats, Annelies M, Mullin, Benjamin H, Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T, Wyss, Annah B, Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A, Joshi, Peter K, Timmers, Paul RHJ, Williams, Alexander T, Free, Robert C, Wang, Xueyang, Morrison, John L, Gilliland, Frank D, Chen, Zhanghua, Wang, Carol A, Foong, Rachel E, Harris, Sarah E, Taylor, Adele, Redmond, Paul, Cook, James P, Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimäki, Terho, Raitakari, Olli T, Kaprio, Jaakko, Rantanen, Taina, Pietiläinen, Kirsi H, Cox, Simon R, Pennell, Craig E, Hall, Graham L, Gauderman, W James, Brightling, Chris, Wilson, James F, Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O, Timpson, Nicholas J, Zeggini, Eleftheria, Dupuis, Josée, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C, Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L, Dudbridge, Frank, Silverman, Edwin K, Strachan, David P, Walters, Robin G, Morris, Andrew P, London, Stephanie J, Cho, Michael H, Wain, Louise V, Hall, Ian P, Tobin, Martin D, Shrine, Nick [0000-0003-3641-4371], Chen, Jing [0000-0003-1287-1930], Guyatt, Anna L. [0000-0003-1860-6337], Hobbs, Brian D. [0000-0001-9564-0745], Kim, Wonji [0000-0002-1249-797X], Coley, Kayesha [0000-0003-4951-6799], Chen, Zhengming [0000-0001-6423-105X], Li, Liming [0000-0001-5873-7089], Lahousse, Lies [0000-0002-3494-4363], Uitterlinden, Andre G. [0000-0002-7276-3387], Oelsner, Elizabeth C. [0000-0002-7481-9671], Rich, Stephen S. [0000-0003-3872-7793], Kerr, Shona M. [0000-0002-4137-1495], Vitart, Veronique [0000-0002-4991-3797], Jeong, Ayoung [0000-0003-1542-0756], Gharib, Sina A. [0000-0002-2480-4367], Gieger, Christian [0000-0001-6986-9554], Peters, Annette [0000-0001-6645-0985], Hu, Xiaowei [0000-0001-7804-7392], Smith, Albert Vernon [0000-0003-1942-5845], Luan, Jian’an [0000-0003-3137-6337], Langhammer, Arnulf [0000-0001-5296-6673], Willer, Cristen [0000-0001-5645-4966], Porteous, David [0000-0003-1249-6106], Smith, Blair H. [0000-0002-5362-9430], Campbell, Archie [0000-0003-0198-5078], Sofer, Tamar [0000-0001-8520-8860], Lee, Jiwon [0000-0002-4079-7494], Lim, Elise [0000-0001-8967-8464], Thareja, Gaurav [0000-0003-2277-6400], Albagha, Omar M. E. [0000-0001-5916-5983], Suhre, Karsten [0000-0001-9638-3912], Granell, Raquel [0000-0002-4890-4012], Faquih, Tariq O. [0000-0001-8026-2251], Hiemstra, Pieter S. [0000-0002-0238-5982], Hysi, Pirro [0000-0001-5752-2510], Koskela, Jukka T. [0000-0002-0154-7222], Jin, Jianping [0000-0002-3774-1609], Sikdar, Sinjini [0000-0003-1230-5162], Lee, Mikyeong [0000-0002-3036-3684], May-Wilson, Sebastian [0000-0003-2668-5717], Joshi, Peter K. [0000-0002-6361-5059], Timmers, Paul R. H. J. [0000-0002-5197-1267], Gilliland, Frank D. [0000-0002-9033-7269], Wang, Carol A. [0000-0002-4301-3974], Harris, Sarah E. [0000-0002-4941-5106], Mahajan, Anubha [0000-0001-5585-3420], Palviainen, Teemu [0000-0002-7847-8384], Kaprio, Jaakko [0000-0002-3716-2455], Pietiläinen, Kirsi H. [0000-0002-8522-1288], Cox, Simon R. [0000-0003-4036-3642], Pennell, Craig E. [0000-0002-0937-6165], Wilson, James F. [0000-0001-5751-9178], Vasankari, Tuula [0000-0002-1413-8970], Salomaa, Veikko [0000-0001-7563-5324], Timpson, Nicholas J. [0000-0002-7141-9189], Dupuis, Josée [0000-0003-2871-3603], Brumpton, Ben [0000-0002-3058-1059], Langenberg, Claudia [0000-0002-5017-7344], Weiss, Stefan [0000-0002-3553-4315], Homuth, Georg [0000-0001-6839-0605], Jarvelin, Marjo-Riitta [0000-0002-2149-0630], Morrison, Alanna C. [0000-0001-6381-4296], Rudan, Igor [0000-0001-6993-6884], Lee, Joo-Hyeon [0000-0002-7364-6422], Sayers, Ian [0000-0001-5601-5410], Rawlins, Emma L. [0000-0001-7426-3792], Dudbridge, Frank [0000-0002-8817-8908], Strachan, David P. [0000-0001-7854-1366], Walters, Robin G. [0000-0002-9179-0321], Morris, Andrew P. [0000-0002-6805-6014], London, Stephanie J. [0000-0003-4911-5290], Cho, Michael H. [0000-0002-4907-1657], Wain, Louise V. [0000-0003-4951-1867], Hall, Ian P. [0000-0001-9933-3216], Tobin, Martin D. [0000-0002-3596-7874], Apollo - University of Cambridge Repository, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of General Administration, Guyatt, Anna L [0000-0003-1860-6337], Hobbs, Brian D [0000-0001-9564-0745], Uitterlinden, Andre G [0000-0002-7276-3387], Oelsner, Elizabeth C [0000-0002-7481-9671], Rich, Stephen S [0000-0003-3872-7793], Kerr, Shona M [0000-0002-4137-1495], Gharib, Sina A [0000-0002-2480-4367], Luan, Jian'an [0000-0003-3137-6337], Smith, Blair H [0000-0002-5362-9430], Albagha, Omar ME [0000-0001-5916-5983], Faquih, Tariq O [0000-0001-8026-2251], Hiemstra, Pieter S [0000-0002-0238-5982], Koskela, Jukka T [0000-0002-0154-7222], Joshi, Peter K [0000-0002-6361-5059], Timmers, Paul RHJ [0000-0002-5197-1267], Gilliland, Frank D [0000-0002-9033-7269], Wang, Carol A [0000-0002-4301-3974], Harris, Sarah E [0000-0002-4941-5106], Pietiläinen, Kirsi H [0000-0002-8522-1288], Cox, Simon R [0000-0003-4036-3642], Pennell, Craig E [0000-0002-0937-6165], Wilson, James F [0000-0001-5751-9178], Timpson, Nicholas J [0000-0002-7141-9189], Morrison, Alanna C [0000-0001-6381-4296], Rawlins, Emma L [0000-0001-7426-3792], Strachan, David P [0000-0001-7854-1366], Walters, Robin G [0000-0002-9179-0321], Morris, Andrew P [0000-0002-6805-6014], London, Stephanie J [0000-0003-4911-5290], Cho, Michael H [0000-0002-4907-1657], Wain, Louise V [0000-0003-4951-1867], Hall, Ian P [0000-0001-9933-3216], Tobin, Martin D [0000-0002-3596-7874], Epidemiology, and Internal Medicine

Subjects
Smoking, 631/208/205/2138, 45/43, article, 692/699/1785, Polymorphism, Single Nucleotide, 3142 Public health care science, environmental and occupational health, Pulmonary Disease, Chronic Obstructive, Genetics, Humans, 1182 Biochemistry, cell and molecular biology, Genetic Predisposition to Disease, Lung, Genome-Wide Association Study
Abstract

Funder: British Lung Foundation, Funder: National Institute for Health Research (NIHR), Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

Published
2023

2. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author

Shrine, Nick, Izquierdo, Abril G, Chen, Jing, Packer, Richard, Hall, Robert J, Guyatt, Anna L, Batini, Chiara, Thompson, Rebecca J, Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D, Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A, John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y, Chen, Zhengming, Li, Liming, Wijnant, Sara RA, Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G, Manichaikul, Ani, Oelsner, Elizabeth C, Rich, Stephen S, Barr, R Graham, Kerr, Shona M, Vitart, Veronique, Brown, Michael R, Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M, Gharib, Sina A, Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E, Meyers, Deborah A, Bleecker, Eugene R, Gabriel, Stacey B, Gupta, Namrata, Smith, Albert Vernon, Luan, Jian’an, Zhao, Jing-Hua, Hansen, Ailin F, Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H, Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L, Yu, Bing, Lim, Elise, Xu, Hanfei, O’Connor, George T, Thareja, Gaurav, Albagha, Omar ME, Ismail, Said I, Al-Muftah, Wadha, Badji, Radja, Mbarek, Hamdi, Darwish, Dima, Fadl, Tasnim, Yasin, Heba, Ennaifar, Maryem, Abdellatif, Rania, Alkuwari, Fatima, Alvi, Muhammad, Al-Sarraj, Yasser, Saad, Chadi, Althani, Asmaa, Fethnou, Eleni, Qafoud, Fatima, Alkhayat, Eiman, Afifi, Nahla, Tomei, Sara, Liu, Wei, Lorenz, Stephan, Syed, Najeeb, Almabrazi, Hakeem, Vempalli, Fazulur Rehaman, Temanni, Ramzi, Saqri, Tariq Abu, Khatib, Mohammedhusen, Hamza, Mehshad, Zaid, Tariq Abu, El Khouly, Ahmed, Pathare, Tushar, Poolat, Shafeeq, Al-Ali, Rashid, Al-Khodor, Souhaila, Alshafai, Mashael, Badii, Ramin, Chouchane, Lotfi, Estivill, Xavier, Fakhro, Khalid, Mokrab, Younes, Puthen, Jithesh V, Tatari, Zohreh, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O, Hiemstra, Pieter S, Slats, Annelies M, Mullin, Benjamin H, Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T, Wyss, Annah B, Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A, Joshi, Peter K, Timmers, Paul RHJ, Williams, Alexander T, Free, Robert C, Wang, Xueyang, Morrison, John L, Gilliland, Frank D, Chen, Zhanghua, Wang, Carol A, Foong, Rachel E, Harris, Sarah E, Taylor, Adele, Redmond, Paul, Cook, James P, Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimäki, Terho, Raitakari, Olli T, Kaprio, Jaakko, Rantanen, Taina, Pietiläinen, Kirsi H, Cox, Simon R, Pennell, Craig E, Hall, Graham L, Gauderman, W James, Brightling, Chris, Wilson, James F, Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O, Timpson, Nicholas J, Zeggini, Eleftheria, Dupuis, Josée, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C, Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L, Dudbridge, Frank, Silverman, Edwin K, Strachan, David P, Walters, Robin G, Morris, Andrew P, London, Stephanie J, Cho, Michael H, Wain, Louise V, Hall, Ian P, Tobin, Martin D, Shrine, Nick [0000-0003-3641-4371], Chen, Jing [0000-0003-1287-1930], Guyatt, Anna L [0000-0003-1860-6337], Hobbs, Brian D [0000-0001-9564-0745], Kim, Wonji [0000-0002-1249-797X], Coley, Kayesha [0000-0003-4951-6799], Chen, Zhengming [0000-0001-6423-105X], Li, Liming [0000-0001-5873-7089], Lahousse, Lies [0000-0002-3494-4363], Uitterlinden, Andre G [0000-0002-7276-3387], Oelsner, Elizabeth C [0000-0002-7481-9671], Rich, Stephen S [0000-0003-3872-7793], Kerr, Shona M [0000-0002-4137-1495], Vitart, Veronique [0000-0002-4991-3797], Jeong, Ayoung [0000-0003-1542-0756], Gharib, Sina A [0000-0002-2480-4367], Gieger, Christian [0000-0001-6986-9554], Peters, Annette [0000-0001-6645-0985], Hu, Xiaowei [0000-0001-7804-7392], Smith, Albert Vernon [0000-0003-1942-5845], Luan, Jian’an [0000-0003-3137-6337], Langhammer, Arnulf [0000-0001-5296-6673], Willer, Cristen [0000-0001-5645-4966], Porteous, David [0000-0003-1249-6106], Smith, Blair H [0000-0002-5362-9430], Campbell, Archie [0000-0003-0198-5078], Sofer, Tamar [0000-0001-8520-8860], Lee, Jiwon [0000-0002-4079-7494], Lim, Elise [0000-0001-8967-8464], Thareja, Gaurav [0000-0003-2277-6400], Albagha, Omar ME [0000-0001-5916-5983], Suhre, Karsten [0000-0001-9638-3912], Granell, Raquel [0000-0002-4890-4012], Faquih, Tariq O [0000-0001-8026-2251], Hiemstra, Pieter S [0000-0002-0238-5982], Hysi, Pirro [0000-0001-5752-2510], Koskela, Jukka T [0000-0002-0154-7222], Jin, Jianping [0000-0002-3774-1609], Sikdar, Sinjini [0000-0003-1230-5162], Lee, Mikyeong [0000-0002-3036-3684], May-Wilson, Sebastian [0000-0003-2668-5717], Joshi, Peter K [0000-0002-6361-5059], Timmers, Paul RHJ [0000-0002-5197-1267], Gilliland, Frank D [0000-0002-9033-7269], Wang, Carol A [0000-0002-4301-3974], Harris, Sarah E [0000-0002-4941-5106], Mahajan, Anubha [0000-0001-5585-3420], Palviainen, Teemu [0000-0002-7847-8384], Kaprio, Jaakko [0000-0002-3716-2455], Pietiläinen, Kirsi H [0000-0002-8522-1288], Cox, Simon R [0000-0003-4036-3642], Pennell, Craig E [0000-0002-0937-6165], Wilson, James F [0000-0001-5751-9178], Vasankari, Tuula [0000-0002-1413-8970], Salomaa, Veikko [0000-0001-7563-5324], Timpson, Nicholas J [0000-0002-7141-9189], Dupuis, Josée [0000-0003-2871-3603], Brumpton, Ben [0000-0002-3058-1059], Langenberg, Claudia [0000-0002-5017-7344], Weiss, Stefan [0000-0002-3553-4315], Homuth, Georg [0000-0001-6839-0605], Jarvelin, Marjo-Riitta [0000-0002-2149-0630], Morrison, Alanna C [0000-0001-6381-4296], Rudan, Igor [0000-0001-6993-6884], Lee, Joo-Hyeon [0000-0002-7364-6422], Sayers, Ian [0000-0001-5601-5410], Rawlins, Emma L [0000-0001-7426-3792], Dudbridge, Frank [0000-0002-8817-8908], Strachan, David P [0000-0001-7854-1366], Walters, Robin G [0000-0002-9179-0321], Morris, Andrew P [0000-0002-6805-6014], London, Stephanie J [0000-0003-4911-5290], Cho, Michael H [0000-0002-4907-1657], Wain, Louise V [0000-0003-4951-1867], Hall, Ian P [0000-0001-9933-3216], Tobin, Martin D [0000-0002-3596-7874], and Apollo - University of Cambridge Repository

Subjects
hengityselimet, genome-wide association studies, perimä, 631/208/205/2138, 45/43, article, keuhkosairaudet, hengityselinten taudit, riskitekijät, 692/699/1785, keuhkot, perinnöllisyys, respiratory tract diseases
Abstract

Funder: British Lung Foundation (BLF); doi: https://doi.org/10.13039/501100000351, Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272, Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

Published
2023

3. A spatially resolved atlas of the human lung characterizes a gland-associated immune niche

Author

Madissoon, Elo, Oliver, Amanda J, Kleshchevnikov, Vitalii, Wilbrey-Clark, Anna, Polanski, Krzysztof, Richoz, Nathan, Ribeiro Orsi, Ana, Mamanova, Lira, Bolt, Liam, Elmentaite, Rasa, Pett, J Patrick, Huang, Ni, Xu, Chuan, He, Peng, Dabrowska, Monika, Pritchard, Sophie, Tuck, Liz, Prigmore, Elena, Perera, Shani, Knights, Andrew, Oszlanczi, Agnes, Hunter, Adam, Vieira, Sara F, Patel, Minal, Lindeboom, Rik GH, Campos, Lia S, Matsuo, Kazuhiko, Nakayama, Takashi, Yoshida, Masahiro, Worlock, Kaylee B, Nikolić, Marko Z, Georgakopoulos, Nikitas, Mahbubani, Krishnaa T, Saeb-Parsy, Kourosh, Bayraktar, Omer Ali, Clatworthy, Menna R, Stegle, Oliver, Kumasaka, Natsuhiko, Teichmann, Sarah A, Meyer, Kerstin B, Oliver, Amanda J [0000-0003-1690-9027], Polanski, Krzysztof [0000-0002-2586-9576], Ribeiro Orsi, Ana [0000-0002-4939-1423], Mamanova, Lira [0000-0003-1463-8622], Elmentaite, Rasa [0000-0001-7366-5466], Pett, J Patrick [0000-0002-5249-444X], He, Peng [0000-0002-2457-3554], Tuck, Liz [0000-0002-1837-7549], Prigmore, Elena [0000-0001-8870-0316], Vieira, Sara F [0000-0002-1021-3021], Lindeboom, Rik GH [0000-0002-3660-504X], Nakayama, Takashi [0000-0002-8493-899X], Yoshida, Masahiro [0000-0002-3521-5322], Worlock, Kaylee B [0000-0002-5656-7634], Nikolić, Marko Z [0000-0001-6304-6848], Georgakopoulos, Nikitas [0000-0002-1879-6583], Mahbubani, Krishnaa T [0000-0002-1327-2334], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Bayraktar, Omer Ali [0000-0001-6055-277X], Kumasaka, Natsuhiko [0000-0002-3557-0375], Teichmann, Sarah A [0000-0002-6294-6366], Meyer, Kerstin B [0000-0001-5906-1498], and Apollo - University of Cambridge Repository

Subjects
B-Lymphocytes, 631/250, Genetics, article, Humans, Epithelial Cells, 631/443, Respiratory Mucosa, 631/80, 692/699/1785, Lung, Immunoglobulin A
Abstract

Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined. To (re)define tissue architecture of lung and airways, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and spatial transcriptomics (queryable atlungcellatlas.org). Using computational data integration and analysis, we extend beyond the suspension cell paradigm and discover macro and micro-anatomical tissue compartments including previously unannotated cell types in the epithelial, vascular, stromal and nerve bundle micro-environments. We identify and implicate peribronchial fibroblasts in lung disease. Importantly, we discover and validate a survival niche for IgA plasma cells in the airway submucosal glands (SMG). We show that gland epithelial cells recruit B cells and IgA plasma cells, and promote longevity and antibody secretion locally through expression of CCL28, APRIL and IL-6. This new ‘gland-associated immune niche’ has implications for respiratory health.

Published
2023

4. BA.2 and BA.5 omicron differ immunologically from both BA.1 omicron and pre-omicron variants

Author

Annika Rössler, Antonia Netzl, Ludwig Knabl, Helena Schäfer, Samuel H. Wilks, David Bante, Barbara Falkensammer, Wegene Borena, Dorothee von Laer, Derek J. Smith, Janine Kimpel, Netzl, Antonia [0000-0001-8034-2382], von Laer, Dorothee [0000-0001-5825-7237], Smith, Derek J [0000-0002-2393-1890], Kimpel, Janine [0000-0002-5210-7905], and Apollo - University of Cambridge Repository

Subjects
Multidisciplinary, SARS-CoV-2, Acclimatization, 631/250/255/2514, article, General Physics and Astronomy, COVID-19, General Chemistry, 692/699/1785, 13, Antibodies, Viral, Antibodies, Neutralizing, General Biochemistry, Genetics and Molecular Biology, 631/326/596/2558, 13/1, Humans, 692/308/174, 631/326/596/4130, Broadly Neutralizing Antibodies
Abstract

Several studies have shown that SARS-CoV-2 BA.1 omicron is an immune escape variant. Meanwhile, however, omicron BA.2 and BA.5 became dominant in many countries and replaced BA.1. As both have several mutations compared to BA.1, we analyzed whether BA.2 and BA.5 show further immune escape relative to BA.1. Here, we characterized neutralization profiles against the BA.2 and BA.5 omicron sub-variants in plasma samples from individuals with different history of exposures to infection/vaccination and found that unvaccinated individuals after a single exposure to BA.2 had limited cross-neutralizing antibodies to pre-omicron variants and to BA.1. Consequently, our antigenic map including all Variants of Concern and BA.1, BA.2 and BA.5 omicron sub-variants, showed that all omicron sub-variants are distinct to pre-omicron variants, but that the three omicron variants are also antigenically distinct from each other. The antibody landscapes illustrate that cross-neutralizing antibodies against the current antigenic space, as described in our maps, are generated only after three or more exposures to antigenically close variants but also after two exposures to antigenically distant variants. Here, we describe the antigenic space inhabited by the relevant SARS-CoV-2 variants, the understanding of which will have important implications for further vaccine strain adaptations.

Published
2022

5. Contrasting effects of linezolid on healthy and dysfunctional human neutrophils: reducing C5a-induced injury

Author

Rowena Jenkins, Stephen J. Evans, A. John Simpson, Dietrich Mack, Thomas S. Wilkinson, Llinos G. Harris, Aled E. L. Roberts, Andrew Conway Morris, Evans, Stephen J [0000-0002-5352-9800], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Neutrophils, Antibiotics, lcsh:Medicine, 692/699/1785, medicine.disease_cause, chemistry.chemical_compound, 0302 clinical medicine, 030212 general & internal medicine, Acute inflammation, lcsh:Science, 631/326, Respiratory Burst, Multidisciplinary, Pneumonia, Ventilator-Associated, Respiratory burst, Anti-Bacterial Agents, Staphylococcus aureus, Infectious diseases, Methicillin-Resistant Staphylococcus aureus, Cell biology, medicine.drug_class, 631/250/2504, Phagocytosis, 030106 microbiology, Complement C5a, Microbiology, Article, 03 medical and health sciences, medicine, Humans, 692/699/255, Mode of action, Inflammation, Respiratory tract diseases, business.industry, lcsh:R, Linezolid, biochemical phenomena, metabolism, and nutrition, medicine.disease, bacterial infections and mycoses, 631/250/255, Innate immune cells, Pneumonia, 631/250/256, 631/250/256/2516, chemistry, Concomitant, Immunology, lcsh:Q, 631/80, business
Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of ventilator-associated pneumonia (VAP). Patients with VAP have poorly functioning neutrophils, related to increased levels of the complement fragment C5a. The antibiotic linezolid has been useful in controlling MRSA-related VAP infections; however clinical benefit does not always correlate with antimicrobial effect, suggesting the possibility of immunomodulatory properties. Here the effects of linezolid on healthy and dysfunctional neutrophils (modelled by C5a-induced injury) was investigated. Functional assays (killing, phagocytosis, transmigration, and respiratory burst) were used to assess the effects of pre-, co- and post-incubating linezolid (0.4–40 mg/L) with healthy neutrophils relative to those with C5a-induced injury. C5a decreased neutrophil killing, and phagocytosis of MRSA. Furthermore, C5a significantly decreased neutrophil transmigration to IL-8, but did not affect respiratory burst. Co-incubation of linezolid significantly improved killing of MRSA by dysfunctional neutrophils, which was supported by concomitant increases in phagocytosis. Conversely linezolid impaired killing responses in healthy neutrophils. Pre- or post-incubation of linezolid prior or following C5a induced injury had no effect on neutrophil function. This study suggests that linezolid has immunomodulatory properties that protect human neutrophils from injury and provides insight into its mode of action beyond a basic antibiotic.

Published
2020

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