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1. Unbiased discovery of cancer pathways and therapeutics using Pathway Ensemble Tool and Benchmark

Author

Wang, Luopin, Pattnaik, Aryamav, Sahoo, Subhransu Sekhar, Stone, Ella G., Zhuang, Yuxin, Benton, Annaleigh, Tajmul, Md, Chakravorty, Srishti, Dhawan, Deepika, Nguyen, My An, Sirit, Isabella, Mundy, Kyle, Ricketts, Christopher J., Hadisurya, Marco, Baral, Garima, Tinsley, Samantha L., Anderson, Nicole L., Hoda, Smriti, Briggs, Scott D., Kaimakliotis, Hristos Z., Allen-Petersen, Brittany L., Tao, W. Andy, Linehan, W. Marston, Knapp, Deborah W., Hanna, Jason A., Olson, Matthew R., Afzali, Behdad, and Kazemian, Majid

Published
2024
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2. Loss of CD4+ T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection

Author

West, Erin E., Merle, Nicolas S., Kamiński, Marcin M., Palacios, Gustavo, Kumar, Dhaneshwar, Wang, Luopin, Bibby, Jack A., Overdahl, Kirsten, Jarmusch, Alan K., Freeley, Simon, Lee, Duck-Yeon, Thompson, J. Will, Yu, Zu-Xi, Taylor, Naomi, Sitbon, Marc, Green, Douglas R., Bohrer, Andrea, Mayer-Barber, Katrin D., Afzali, Behdad, Kazemian, Majid, Scholl-Buergi, Sabine, Karall, Daniela, Huemer, Martina, and Kemper, Claudia

Published
2023
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3. C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection

Author

Desai, Jigar V., Kumar, Dhaneshwar, Freiwald, Tilo, Chauss, Daniel, Johnson, Melissa D., Abers, Michael S., Steinbrink, Julie M., Perfect, John R., Alexander, Barbara, Matzaraki, Vasiliki, Snarr, Brendan D., Zarakas, Marissa A., Oikonomou, Vasileios, Silva, Lakmali M., Shivarathri, Raju, Beltran, Emily, Demontel, Luciana Negro, Wang, Luopin, Lim, Jean K., Launder, Dylan, Conti, Heather R., Swamydas, Muthulekha, McClain, Micah T., Moutsopoulos, Niki M., Kazemian, Majid, Netea, Mihai G., Kumar, Vinod, Köhl, Jörg, Kemper, Claudia, Afzali, Behdad, and Lionakis, Michail S.

Published
2023
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4. Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells

Author

Chauss, Daniel, Freiwald, Tilo, McGregor, Reuben, Yan, Bingyu, Wang, Luopin, Nova-Lamperti, Estefania, Kumar, Dhaneshwar, Zhang, Zonghao, Teague, Heather, West, Erin E., Vannella, Kevin M., Ramos-Benitez, Marcos J., Bibby, Jack, Kelly, Audrey, Malik, Amna, Freeman, Alexandra F., Schwartz, Daniella M., Portilla, Didier, Chertow, Daniel S., John, Susan, Lavender, Paul, Kemper, Claudia, Lombardi, Giovanna, Mehta, Nehal N., Cooper, Nichola, Lionakis, Michail S., Laurence, Arian, Kazemian, Majid, and Afzali, Behdad

Published
2022
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6. CD4 T cell intrinsic arginase 1 controls the kinetics of Th1 induction and contraction

Author

West, Erin E, primary, Merle, Nicolas S, additional, Kamiński, Marcin M, additional, Palacios, Gustavo, additional, Kumar, Dhaneshwar, additional, Wang, Luopin, additional, Overdahl, Kristen, additional, Jarmusch, Alan K, additional, Freeley, Simon, additional, Taylor, Naomi, additional, Sitbon, Marc, additional, Green, Douglas R, additional, Bohrer, Andrea, additional, Mayer-Barber, Katrin, additional, Afzali, Behdad, additional, Kazemian, Majid, additional, Scholl-Buergi, Sabine, additional, Karall, Daniela, additional, Huemer, Martina, additional, and Kemper, Claudia, additional

Published
2023
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7. Data from Integrated Pan-Cancer Map of EBV-Associated Neoplasms Reveals Functional Host–Virus Interactions

Author

Chakravorty, Srishti, primary, Yan, Bingyu, primary, Wang, Chong, primary, Wang, Luopin, primary, Quaid, Joseph Taylor, primary, Lin, Chin Fang, primary, Briggs, Scott D., primary, Majumder, Joydeb, primary, Canaria, D. Alejandro, primary, Chauss, Daniel, primary, Chopra, Gaurav, primary, Olson, Matthew R., primary, Zhao, Bo, primary, Afzali, Behdad, primary, and Kazemian, Majid, primary

Published
2023
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8. Table S3-4 from Integrated Pan-Cancer Map of EBV-Associated Neoplasms Reveals Functional Host–Virus Interactions

Author

Chakravorty, Srishti, primary, Yan, Bingyu, primary, Wang, Chong, primary, Wang, Luopin, primary, Quaid, Joseph Taylor, primary, Lin, Chin Fang, primary, Briggs, Scott D., primary, Majumder, Joydeb, primary, Canaria, D. Alejandro, primary, Chauss, Daniel, primary, Chopra, Gaurav, primary, Olson, Matthew R., primary, Zhao, Bo, primary, Afzali, Behdad, primary, and Kazemian, Majid, primary

Published
2023
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9. Table S5J-part2 from Integrated Pan-Cancer Map of EBV-Associated Neoplasms Reveals Functional Host–Virus Interactions

Author

Chakravorty, Srishti, primary, Yan, Bingyu, primary, Wang, Chong, primary, Wang, Luopin, primary, Quaid, Joseph Taylor, primary, Lin, Chin Fang, primary, Briggs, Scott D., primary, Majumder, Joydeb, primary, Canaria, D. Alejandro, primary, Chauss, Daniel, primary, Chopra, Gaurav, primary, Olson, Matthew R., primary, Zhao, Bo, primary, Afzali, Behdad, primary, and Kazemian, Majid, primary

Published
2023
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10. Table S5 from Integrated Pan-Cancer Map of EBV-Associated Neoplasms Reveals Functional Host–Virus Interactions

Author

Chakravorty, Srishti, primary, Yan, Bingyu, primary, Wang, Chong, primary, Wang, Luopin, primary, Quaid, Joseph Taylor, primary, Lin, Chin Fang, primary, Briggs, Scott D., primary, Majumder, Joydeb, primary, Canaria, D. Alejandro, primary, Chauss, Daniel, primary, Chopra, Gaurav, primary, Olson, Matthew R., primary, Zhao, Bo, primary, Afzali, Behdad, primary, and Kazemian, Majid, primary

Published
2023
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11. Supplementary methods from Integrated Pan-Cancer Map of EBV-Associated Neoplasms Reveals Functional Host–Virus Interactions

Author

Chakravorty, Srishti, primary, Yan, Bingyu, primary, Wang, Chong, primary, Wang, Luopin, primary, Quaid, Joseph Taylor, primary, Lin, Chin Fang, primary, Briggs, Scott D., primary, Majumder, Joydeb, primary, Canaria, D. Alejandro, primary, Chauss, Daniel, primary, Chopra, Gaurav, primary, Olson, Matthew R., primary, Zhao, Bo, primary, Afzali, Behdad, primary, and Kazemian, Majid, primary

Published
2023
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12. Figure S1-4 from Integrated Pan-Cancer Map of EBV-Associated Neoplasms Reveals Functional Host–Virus Interactions

Author

Chakravorty, Srishti, primary, Yan, Bingyu, primary, Wang, Chong, primary, Wang, Luopin, primary, Quaid, Joseph Taylor, primary, Lin, Chin Fang, primary, Briggs, Scott D., primary, Majumder, Joydeb, primary, Canaria, D. Alejandro, primary, Chauss, Daniel, primary, Chopra, Gaurav, primary, Olson, Matthew R., primary, Zhao, Bo, primary, Afzali, Behdad, primary, and Kazemian, Majid, primary

Published
2023
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13. Figure S5-6 from Integrated Pan-Cancer Map of EBV-Associated Neoplasms Reveals Functional Host–Virus Interactions

Author

Chakravorty, Srishti, primary, Yan, Bingyu, primary, Wang, Chong, primary, Wang, Luopin, primary, Quaid, Joseph Taylor, primary, Lin, Chin Fang, primary, Briggs, Scott D., primary, Majumder, Joydeb, primary, Canaria, D. Alejandro, primary, Chauss, Daniel, primary, Chopra, Gaurav, primary, Olson, Matthew R., primary, Zhao, Bo, primary, Afzali, Behdad, primary, and Kazemian, Majid, primary

Published
2023
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14. Loss of CD4+ T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection

Author

West, Erin E; https://orcid.org/0000-0002-7103-8394, Merle, Nicolas S, Kamiński, Marcin M, Palacios, Gustavo, Kumar, Dhaneshwar, Wang, Luopin, Bibby, Jack A, Overdahl, Kirsten, Jarmusch, Alan K, Freeley, Simon, Lee, Duck-Yeon, Thompson, J Will, Yu, Zu-Xi, Taylor, Naomi, Sitbon, Marc, Green, Douglas R, Bohrer, Andrea, Mayer-Barber, Katrin D, Afzali, Behdad, Kazemian, Majid, Scholl-Buergi, Sabine, Karall, Daniela, Huemer, Martina; https://orcid.org/0000-0002-0590-678X, Kemper, Claudia, West, Erin E; https://orcid.org/0000-0002-7103-8394, Merle, Nicolas S, Kamiński, Marcin M, Palacios, Gustavo, Kumar, Dhaneshwar, Wang, Luopin, Bibby, Jack A, Overdahl, Kirsten, Jarmusch, Alan K, Freeley, Simon, Lee, Duck-Yeon, Thompson, J Will, Yu, Zu-Xi, Taylor, Naomi, Sitbon, Marc, Green, Douglas R, Bohrer, Andrea, Mayer-Barber, Katrin D, Afzali, Behdad, Kazemian, Majid, Scholl-Buergi, Sabine, Karall, Daniela, Huemer, Martina; https://orcid.org/0000-0002-0590-678X, and Kemper, Claudia

Abstract

Arginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its expression in T cells is disputed. Here, we demonstrate that induction of Arg1 expression is a key feature of lung CD4+ T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4+ T cells accelerated both virus-specific T helper 1 (Th1) effector responses and its resolution, resulting in efficient viral clearance and reduced lung pathology. Using unbiased transcriptomics and metabolomics, we found that Arg1-deficiency was distinct from Arg2-deficiency and caused altered glutamine metabolism. Rebalancing this perturbed glutamine flux normalized the cellular Th1 response. CD4+ T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4+ T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies.

Published
2023

15. A comprehensive single cell data analysis of lymphoblastoid cells reveals the role of super‐enhancers in maintaining EBV latency

Author

Yan, Bingyu, primary, Wang, Chong, additional, Chakravorty, Srishti, additional, Zhang, Zonghao, additional, Kadadi, Simran D., additional, Zhuang, Yuxin, additional, Sirit, Isabella, additional, Hu, Yonghua, additional, Jung, Minwoo, additional, Sahoo, Subhransu S., additional, Wang, Luopin, additional, Shao, Kunming, additional, Anderson, Nicole L., additional, Trujillo‐Ochoa, Jorge L., additional, Briggs, Scott D., additional, Liu, Xing, additional, Olson, Matthew R., additional, Afzali, Behdad, additional, Zhao, Bo, additional, and Kazemian, Majid, additional

Published
2022
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16. A comprehensive single cell data analysis of in lymphoblastoid cells reveals the role of Super-enhancers in maintaining EBV latency

Author

Yan, Bingyu, primary, Wang, Chong, additional, Chakravorty, Srishti, additional, Zhang, Zonghao, additional, Kadadi, Simran D., additional, Zhuang, Yuxin, additional, Sirit, Isabella, additional, Hu, Yonghua, additional, Jung, Minwoo, additional, Sahoo, Subhransu, additional, Wang, Luopin, additional, Shao, Kunming, additional, Anderson, Nicole L., additional, Trujillo-Ochoa, Jorge L., additional, Liu, Xing, additional, Olson, Matthew R., additional, Afzali, Behdad, additional, Zhao, Bo, additional, and Kazemian, Majid, additional

Published
2022
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18. SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation

Author

Yan, Bingyu, primary, Freiwald, Tilo, additional, Chauss, Daniel, additional, Wang, Luopin, additional, West, Erin, additional, Mirabelli, Carmen, additional, Zhang, Charles J., additional, Nichols, Eva-Maria, additional, Malik, Nazish, additional, Gregory, Richard, additional, Bantscheff, Marcus, additional, Ghidelli-Disse, Sonja, additional, Kolev, Martin, additional, Frum, Tristan, additional, Spence, Jason R., additional, Sexton, Jonathan Z., additional, Alysandratos, Konstantinos D., additional, Kotton, Darrell N., additional, Pittaluga, Stefania, additional, Bibby, Jack, additional, Niyonzima, Nathalie, additional, Olson, Matthew R., additional, Kordasti, Shahram, additional, Portilla, Didier, additional, Wobus, Christiane E., additional, Laurence, Arian, additional, Lionakis, Michail S., additional, Kemper, Claudia, additional, Afzali, Behdad, additional, and Kazemian, Majid, additional

Published
2022
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19. Complement activates an autocrine Vitamin D system that recruits a defined transcription factor network to shut down pro-inflammatory programs of Th1 cells

Author

Chauss, Daniel C, primary, Freiwald, Tilo, additional, McGregor, Reuben, additional, Yan, Bingyu, additional, Wang, Luopin, additional, Nova-Lamperti, Estafania, additional, Kumar, Dhaneshwar, additional, Zhang, Zonghao, additional, Teague, Heather, additional, West, Erin, additional, Vannella, Kevin M, additional, Ramos-Benitez, Marcos J, additional, Bibby, Jack, additional, Kelly, Audrey, additional, Malik, Amna, additional, Freeman, Alexandra F, additional, Schwartz, Daniella M, additional, Portilla, Didier, additional, Chertow, Daniel S, additional, John, Susan, additional, Lavender, Paul, additional, Kemper, Claudia, additional, Lombardi, Giovanna, additional, Mehta, Nehal N, additional, Cooper, Nichola, additional, Lionakis, Michail S, additional, Laurence, Arian, additional, Kazemian, Majid, additional, and Afzali, Behdad, additional

Published
2022
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21. Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells

Author

Chauss, Daniel, primary, Freiwald, Tilo, additional, McGregor, Reuben, additional, Yan, Bingyu, additional, Wang, Luopin, additional, Nova-Lamperti, Estefania, additional, Kumar, Dhaneshwar, additional, Zhang, Zonghao, additional, Teague, Heather, additional, West, Erin E., additional, Vannella, Kevin M., additional, Ramos-Benitez, Marcos J., additional, Bibby, Jack, additional, Kelly, Audrey, additional, Malik, Amna, additional, Freeman, Alexandra F., additional, Schwartz, Daniella M., additional, Portilla, Didier, additional, Chertow, Daniel S., additional, John, Susan, additional, Lavender, Paul, additional, Kemper, Claudia, additional, Lombardi, Giovanna, additional, Mehta, Nehal N., additional, Cooper, Nichola, additional, Lionakis, Michail S., additional, Laurence, Arian, additional, Kazemian, Majid, additional, and Afzali, Behdad, additional

Published
2021
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22. A comprehensive single cell data analysis of lymphoblastoid cells reveals the role of super‐enhancers in maintaining EBV latency.

Author

Yan, Bingyu, Wang, Chong, Chakravorty, Srishti, Zhang, Zonghao, Kadadi, Simran D., Zhuang, Yuxin, Sirit, Isabella, Hu, Yonghua, Jung, Minwoo, Sahoo, Subhransu S., Wang, Luopin, Shao, Kunming, Anderson, Nicole L., Trujillo‐Ochoa, Jorge L., Briggs, Scott D., Liu, Xing, Olson, Matthew R., Afzali, Behdad, Zhao, Bo, and Kazemian, Majid

Subjects
LYMPHOBLASTOID cell lines, GENE expression, CELL analysis, MYC oncogenes, VIROLOGY
Abstract

We probed the lifecycle of Epstein‐Barr virus (EBV) on a cell‐by‐cell basis using single cell RNA sequencing (scRNA‐seq) data from nine publicly available lymphoblastoid cell lines (LCLs). While the majority of LCLs comprised cells containing EBV in the latent phase, two other clusters of cells were clearly evident and were distinguished by distinct expression of host and viral genes. Notably, both were high expressors of EBV LMP1/BNLF2 and BZLF1 compared to another cluster that expressed neither gene. The two novel clusters differed from each other in their expression of EBV lytic genes, including glycoprotein gene GP350. The first cluster, comprising GP350–LMP1hi cells, expressed high levels of HIF1A and was transcriptionally regulated by HIF1‐α. Treatment of LCLs with Pevonedistat, a drug that enhances HIF1‐α signaling, markedly induced this cluster. The second cluster, containing GP350+LMP1hi cells, expressed EBV lytic genes. Host genes that are controlled by super‐enhancers (SEs), such as transcription factors MYC and IRF4, had the lowest expression in this cluster. Functionally, the expression of genes regulated by MYC and IRF4 in GP350+LMP1hi cells were lower compared to other cells. Indeed, induction of EBV lytic reactivation in EBV+ AKATA reduced the expression of these SE‐regulated genes. Furthermore, CRISPR‐mediated perturbation of the MYC or IRF4 SEs in LCLs induced the lytic EBV gene expression, suggesting that host SEs and/or SE target genes are required for maintenance of EBV latency. Collectively, our study revealed EBV‐associated heterogeneity among LCLs that may have functional consequence on host and viral biology. [ABSTRACT FROM AUTHOR]

Published
2023
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23. Reply to Grigoriev et al., “Sequences of SARS-CoV-2 “Hybrids” with the Human Genome: Signs 1 of Non-coding RNA?”

Author

Yan, Bingyu, primary, Chakravorty, Srishti, additional, Mirabelli, Carmen, additional, Wang, Luopin, additional, Trujillo-Ochoa, Jorge L., additional, Chauss, Daniel, additional, Kumar, Dhaneshwar, additional, Lionakis, Michail S., additional, Olson, Matthew R., additional, Wobus, Christiane E., additional, Afzali, Behdad, additional, and Kazemian, Majid, additional

Published
2021
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24. Host-Virus Chimeric Events in SARS-CoV-2-Infected Cells Are Infrequent and Artifactual

Author

Yan, Bingyu, primary, Chakravorty, Srishti, additional, Mirabelli, Carmen, additional, Wang, Luopin, additional, Trujillo-Ochoa, Jorge L., additional, Chauss, Daniel, additional, Kumar, Dhaneshwar, additional, Lionakis, Michail S., additional, Olson, Matthew R., additional, Wobus, Christiane E., additional, Afzali, Behdad, additional, and Kazemian, Majid, additional

Published
2021
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25. SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation

Author

Yan, Bingyu, primary, Freiwald, Tilo, additional, Chauss, Daniel, additional, Wang, Luopin, additional, West, Erin, additional, Mirabelli, Carmen, additional, Zhang, Charles J., additional, Nichols, Eva-Maria, additional, Malik, Nazish, additional, Gregory, Richard, additional, Bantscheff, Marcus, additional, Ghidelli-Disse, Sonja, additional, Kolev, Martin, additional, Frum, Tristan, additional, Spence, Jason R., additional, Sexton, Jonathan Z., additional, Alysandratos, Konstantinos D., additional, Kotton, Darrell N., additional, Pittaluga, Stefania, additional, Bibby, Jack, additional, Niyonzima, Nathalie, additional, Olson, Matthew R., additional, Kordasti, Shahram, additional, Portilla, Didier, additional, Wobus, Christiane E., additional, Laurence, Arian, additional, Lionakis, Michail S., additional, Kemper, Claudia, additional, Afzali, Behdad, additional, and Kazemian, Majid, additional

Published
2021
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26. Host-virus chimeric events in SARS-CoV2 infected cells are infrequent and artifactual

Author

Yan, Bingyu, primary, Chakravorty, Srishti, additional, Mirabelli, Carmen, additional, Wang, Luopin, additional, Trujillo-Ochoa, Jorge L., additional, Chauss, Daniel, additional, Kumar, Dhaneshwar, additional, Lionakis, Michail S., additional, Olson, Matthew R, additional, Wobus, Christiane E., additional, Afzali, Behdad, additional, and Kazemian, Majid, additional

Published
2021
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29. An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19

Author

McGregor, Reuben, primary, Chauss, Daniel, additional, Freiwald, Tilo, additional, Yan, Bingyu, additional, Wang, Luopin, additional, Nova-Lamperti, Estefania, additional, Zhang, Zonghao, additional, Teague, Heather, additional, West, Erin E, additional, Bibby, Jack, additional, Kelly, Audrey, additional, Malik, Amna, additional, Freeman, Alexandra F, additional, Schwartz, Daniella, additional, Portilla, Didier, additional, John, Susan, additional, Lavender, Paul, additional, Lionakis, Michail S, additional, Mehta, Nehal N, additional, Kemper, Claudia, additional, Cooper, Nichola, additional, Lombardi, Giovanna, additional, Laurence, Arian, additional, Kazemian, Majid, additional, and Afzali, Behdad, additional

Published
2020
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30. SARS-CoV2 drives JAK1/2-dependent local and systemic complement hyper-activation

Author

Yan, Bingyu, primary, Freiwald, Tilo, additional, Chauss, Daniel, additional, Wang, Luopin, additional, West, Erin, additional, Bibby, Jack, additional, Olson, Matthew, additional, Kordasti, Shahram, additional, Portilla, Didier, additional, Laurence, Arian, additional, Lionakis, Michail S, additional, Kemper, Claudia, additional, Afzali, Behdad, additional, and Kazemian, Majid, additional

Published
2020
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32. Diapedesis and LFA-1 mediate tissue immune cell effector activity via intrinsic complement C3 licensing

Author

Kemper, Claudia, primary, Kolev, Martin, additional, West, Erin E, additional, Kunz, Natalia, additional, Rahman, Jubayer, additional, Chauss, Daniel, additional, Moutsopoulos, Niki, additional, Holland, Steven M, additional, Kaplan, Mariana J, additional, Wang, Luopin, additional, Kazemian, Majid, additional, and Afzali, Behdad, additional

Published
2020
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33. The role of Virostatic genes in modulating Immune Checkpoints in Epstein-Barr Virus associated Tumors

Author

Chakravorty, Srishti, primary, Yan, Bingyu, additional, Chauss, Daniel, additional, Wang, Luopin, additional, Canaria, D. Alejandro, additional, Jethava, Krupal, additional, Chopra, Gaurav, additional, Briggs, Scott D, additional, Zhao, Bo, additional, Olson, Matthew R., additional, Afzali, Behdad, additional, and Kazemian, Majid, additional

Published
2020
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34. Diapedesis-Induced Integrin Signaling via LFA-1 Facilitates Tissue Immunity by Inducing Intrinsic Complement C3 Expression in Immune Cells

Author

Kolev, Martin, primary, West, Erin E., additional, Kunz, Natalia, additional, Chauss, Daniel, additional, Moseman, E. Ashley, additional, Rahman, Jubayer, additional, Freiwald, Tilo, additional, Balmer, Maria L., additional, Lötscher, Jonas, additional, Dimeloe, Sarah, additional, Rosser, Elizabeth C., additional, Wedderburn, Lucy R., additional, Mayer-Barber, Katrin D., additional, Bohrer, Andrea, additional, Lavender, Paul, additional, Cope, Andrew, additional, Wang, Luopin, additional, Kaplan, Mariana J., additional, Moutsopoulos, Niki M., additional, McGavern, Dorian, additional, Holland, Steven M., additional, Hess, Christoph, additional, Kazemian, Majid, additional, Afzali, Behdad, additional, and Kemper, Claudia, additional

Published
2020
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35. Integrated Pan-Cancer Map of EBV-Associated Neoplasms Reveals Functional Host–Virus Interactions

Author

Chakravorty, Srishti, primary, Yan, Bingyu, additional, Wang, Chong, additional, Wang, Luopin, additional, Quaid, Joseph Taylor, additional, Lin, Chin Fang, additional, Briggs, Scott D., additional, Majumder, Joydeb, additional, Canaria, D. Alejandro, additional, Chauss, Daniel, additional, Chopra, Gaurav, additional, Olson, Matthew R., additional, Zhao, Bo, additional, Afzali, Behdad, additional, and Kazemian, Majid, additional

Published
2019
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36. Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

Author

Martinez-Fabregas, Jonathan, primary, Wilmes, Stephan, additional, Wang, Luopin, additional, Hafer, Maximillian, additional, Pohler, Elizabeth, additional, Lokau, Juliane, additional, Garbers, Christoph, additional, Cozzani, Adeline, additional, Fyfe, Paul K, additional, Piehler, Jacob, additional, Kazemian, Majid, additional, Mitra, Suman, additional, and Moraga, Ignacio, additional

Published
2019
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37. Author response: Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

Author

Martinez-Fabregas, Jonathan, primary, Wilmes, Stephan, additional, Wang, Luopin, additional, Hafer, Maximillian, additional, Pohler, Elizabeth, additional, Lokau, Juliane, additional, Garbers, Christoph, additional, Cozzani, Adeline, additional, Fyfe, Paul K, additional, Piehler, Jacob, additional, Kazemian, Majid, additional, Mitra, Suman, additional, and Moraga, Ignacio, additional

Published
2019
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39. Folic acid-mediated fibrosis is driven by C5a receptor 1-mediated activation of kidney myeloid cells.

Author

Sahu RK, Xavier S, Chauss D, Wang L, Chew C, Taylor R, Stallcup WB, Ma JZ, Kazemian M, Afzali B, Köhl J, and Portilla D

Subjects
Animals, Cicatrix, Fibrosis, Green Fluorescent Proteins, Kidney pathology, Mice, Mice, Knockout, Myeloid Cells pathology, Receptors, Platelet-Derived Growth Factor, Folic Acid pharmacology, Receptor, Anaphylatoxin C5a genetics
Abstract

We have previously reported that increased expression and activation of kidney cell complement components play an important role in the pathogenesis of renal scarring. Here, we used floxed green fluorescent protein (GFP)-C5a receptor 1 (C5aR1) knockin mice (GFP- C5ar1 fl/fl ) and the model of folic acid (FA)-induced kidney injury to define the cell types and potential mechanisms by which increased C5aR1 activation leads to fibrosis. Using flow cytometry and confocal microscopy, we identified macrophages as the major interstitial cell type showing increased expression of C5aR1 in FA-treated mice. C5ar1 fl/fl . Lyz2 Cre +/- mice, in which C5aR1 has been specifically deleted in lysozyme M-expressing myeloid cells, experienced reduced fibrosis compared with control C5ar1 fl/fl mice. Examination of C5aR1-expressing macrophage transcriptomes by gene set enrichment analysis demonstrated that these cells were enriched in pathways corresponding to the complement cascade, collagen formation, and the NABA matrisome, strongly pointing to their critical roles in tissue repair/scarring. Since C5aR1 was also detected in a small population of platelet-derived growth factor receptor-β + GFP + cells, we developed C5ar1 fl/fl . Foxd1 Cre +/- mice, in which C5aR1 is deleted specifically in pericytes, and found reduced FA-induced fibrosis. Primary cell cultures of platelet-derived growth factor receptor-β + pericytes isolated from FA-treated C5ar1 fl/fl . Foxd1 Cre +/- mice showed reduced secretion of several cytokines, including IL-6 and macrophage inflammatory protein-2, compared with pericytes isolated from FA-treated control GFP- C5ar1 fl/fl mice. Collectively, these data imply that C5a/C5aR1 axis activation primarily in interstitial cells contributes to the development of renal fibrosis. NEW & NOTEWORTHY This study used novel green fluorescent protein C5a receptor 1 floxed mice and the model of folic acid-mediated kidney fibrosis to demonstrate the pathogenic role of increased expression of this complement receptor on macrophages.

Published
2022
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40. Host-virus chimeric events in SARS-CoV2 infected cells are infrequent and artifactual.

Author

Yan B, Chakravorty S, Mirabelli C, Wang L, Trujillo-Ochoa JL, Chauss D, Kumar D, Lionakis MS, Olson MR, Wobus CE, Afzali B, and Kazemian M

Abstract

Pathogenic mechanisms underlying severe SARS-CoV2 infection remain largely unelucidated. High throughput sequencing technologies that capture genome and transcriptome information are key approaches to gain detailed mechanistic insights from infected cells. These techniques readily detect both pathogen and host-derived sequences, providing a means of studying host-pathogen interactions. Recent studies have reported the presence of host-virus chimeric (HVC) RNA in RNA-seq data from SARS-CoV2 infected cells and interpreted these findings as evidence of viral integration in the human genome as a potential pathogenic mechanism. Since SARS-CoV2 is a positive sense RNA virus that replicates in the cytoplasm it does not have a nuclear phase in its life cycle, it is biologically unlikely to be in a location where splicing events could result in genome integration. Here, we investigated the biological authenticity of HVC events. In contrast to true biological events such as mRNA splicing and genome rearrangement events, which generate reproducible chimeric sequencing fragments across different biological isolates, we found that HVC events across >100 RNA-seq libraries from patients with COVID-19 and infected cell lines, were highly irreproducible. RNA-seq library preparation is inherently error-prone due to random template switching during reverse transcription of RNA to cDNA. By counting chimeric events observed when constructing an RNA-seq library from human RNA and spike-in RNA from an unrelated species, such as fruit-fly, we estimated that ~1% of RNA-seq reads are artifactually chimeric. In SARS-CoV2 RNA-seq we found that the frequency of HVC events was, in fact, not greater than this background "noise". Finally, we developed a novel experimental approach to enrich SARS-CoV2 sequences from bulk RNA of infected cells. This method enriched viral sequences but did not enrich for HVC events, suggesting that the majority of HVC events are, in all likelihood, artifacts of library construction. In conclusion, our findings indicate that HVC events observed in RNA-sequencing libraries from SARS-CoV2 infected cells are extremely rare and are likely artifacts arising from either random template switching of reverse-transcriptase and/or sequence alignment errors. Therefore, the observed HVC events do not support SARS-CoV2 fusion to cellular genes and/or integration into human genomes.

Published
2021
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41. An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19.

Author

McGregor R, Chauss D, Freiwald T, Yan B, Wang L, Nova-Lamperti E, Zhang Z, Teague H, West EE, Bibby J, Kelly A, Malik A, Freeman AF, Schwartz D, Portilla D, John S, Lavender P, Lionakis MS, Mehta NN, Kemper C, Cooper N, Lombardi G, Laurence A, Kazemian M, and Afzali B

Abstract

Pro-inflammatory immune responses are necessary for effective pathogen clearance, but cause severe tissue damage if not shut down in a timely manner 1,2 . Excessive complement and IFN-γ-associated responses are known drivers of immunopathogenesis 3 and are among the most highly induced immune programs in hyper-inflammatory SARS-CoV2 lung infection 4 . The molecular mechanisms that govern orderly shutdown and retraction of these responses remain poorly understood. Here, we show that complement triggers contraction of IFN-γ producing CD4 + T helper (Th) 1 cell responses by inducing expression of the vitamin D (VitD) receptor (VDR) and CYP27B1, the enzyme that activates VitD, permitting T cells to both activate and respond to VitD. VitD then initiates the transition from pro-inflammatory IFN-γ + Th1 cells to suppressive IL-10 + Th1 cells. This process is primed by dynamic changes in the epigenetic landscape of CD4 + T cells, generating superenhancers and recruiting c-JUN and BACH2, a key immunoregulatory transcription factor 5-7 . Accordingly, cells in psoriatic skin treated with VitD increased BACH2 expression, and BACH2 haplo-insufficient CD4 + T cells were defective in IL-10 production. As proof-of-concept, we show that CD4 + T cells in the bronchoalveolar lavage fluid (BALF) of patients with COVID-19 are Th1-skewed and that VDR is among the top regulators of genes induced by SARS-CoV2. Importantly, genes normally down-regulated by VitD were de-repressed in CD4 + BALF T cells of COVID-19, indicating that the VitD-driven shutdown program is impaired in this setting. The active metabolite of VitD, alfacalcidol, and cortico-steroids were among the top predicted pharmaceuticals that could normalize SARS-CoV2 induced genes. These data indicate that adjunct therapy with VitD in the context of other immunomodulatory drugs may be a beneficial strategy to dampen hyperinflammation in severe COVID-19.

Published
2020
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42. SARS-CoV2 drives JAK1/2-dependent local and systemic complement hyper-activation.

Author

Yan B, Freiwald T, Chauss D, Wang L, West E, Bibby J, Olson M, Kordasti S, Portilla D, Laurence A, Lionakis MS, Kemper C, Afzali B, and Kazemian M

Abstract

Patients with coronavirus disease 2019 (COVID-19) present with a range of devastating acute clinical manifestations affecting the lungs, liver, kidneys and gut. The best-characterized entry receptor for the disease-causing virus SARS-CoV2, angiotensin converting enzyme (ACE) 2, is highly expressed in these tissues. However, the pathways that underlie the disease are still poorly understood. Here we show that the complement system is unexpectedly one of the intracellular pathways most highly induced by SARS-CoV2 infection in lung epithelial and liver cells. Within cells of the bronchoalveolar lavage of patients, distinct signatures of complement activation in myeloid, lymphoid and epithelial cells tracked with disease severity. Modelling the regulome of host genes induced by COVID-19 and the drugs that could normalize these genes both implicated the JAK1/2-STAT1 signaling system downstream of type I interferon receptors, and NF-kB. Ruxolitinib, a JAK1/2 inhibitor and the top predicted pharmaceutical candidate, normalized interferon signature genes, IL-6 (the best characterized severity marker in COVID-19) and all complement genes induced by SARS-CoV2, but did not affect NF-kB-regulated genes. We predict that combination therapy with JAK inhibitors and other agents with the potential to normalize NF-kB-signaling, such as anti-viral agents, may serve as an effective clinical strategy.

Published
2020
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