Browsing by Author "Sinha, Rahul"
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Item Open Access Microglia are effector cells of CD47-SIRPα antiphagocytic axis disruption against glioblastoma.(Proceedings of the National Academy of Sciences of the United States of America, 2019-01) Hutter, Gregor; Theruvath, Johanna; Graef, Claus Moritz; Zhang, Michael; Schoen, Matthew Kenneth; Manz, Eva Maria; Bennett, Mariko L; Olson, Andrew; Azad, Tej D; Sinha, Rahul; Chan, Carmel; Assad Kahn, Suzana; Gholamin, Sharareh; Wilson, Christy; Grant, Gerald; He, Joy; Weissman, Irving L; Mitra, Siddhartha S; Cheshier, Samuel HGlioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor with fatal outcome. Tumor-associated macrophages and microglia (TAMs) have been found to be major tumor-promoting immune cells in the tumor microenvironment. Hence, modulation and reeducation of tumor-associated macrophages and microglia in GBM is considered a promising antitumor strategy. Resident microglia and invading macrophages have been shown to have distinct origin and function. Whereas yolk sac-derived microglia reside in the brain, blood-derived monocytes invade the central nervous system only under pathological conditions like tumor formation. We recently showed that disruption of the SIRPα-CD47 signaling axis is efficacious against various brain tumors including GBM primarily by inducing tumor phagocytosis. However, most effects are attributed to macrophages recruited from the periphery but the role of the brain resident microglia is unknown. Here, we sought to utilize a model to distinguish resident microglia and peripheral macrophages within the GBM-TAM pool, using orthotopically xenografted, immunodeficient, and syngeneic mouse models with genetically color-coded macrophages (Ccr2 RFP) and microglia (Cx3cr1 GFP). We show that even in the absence of phagocytizing macrophages (Ccr2 RFP/RFP), microglia are effector cells of tumor cell phagocytosis in response to anti-CD47 blockade. Additionally, macrophages and microglia show distinct morphological and transcriptional changes. Importantly, the transcriptional profile of microglia shows less of an inflammatory response which makes them a promising target for clinical applications.Item Open Access Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics.(Nature medicine, 2021-03) Muus, Christoph; Luecken, Malte D; Eraslan, Gökcen; Sikkema, Lisa; Waghray, Avinash; Heimberg, Graham; Kobayashi, Yoshihiko; Vaishnav, Eeshit Dhaval; Subramanian, Ayshwarya; Smillie, Christopher; Jagadeesh, Karthik A; Duong, Elizabeth Thu; Fiskin, Evgenij; Torlai Triglia, Elena; Ansari, Meshal; Cai, Peiwen; Lin, Brian; Buchanan, Justin; Chen, Sijia; Shu, Jian; Haber, Adam L; Chung, Hattie; Montoro, Daniel T; Adams, Taylor; Aliee, Hananeh; Allon, Samuel J; Andrusivova, Zaneta; Angelidis, Ilias; Ashenberg, Orr; Bassler, Kevin; Bécavin, Christophe; Benhar, Inbal; Bergenstråhle, Joseph; Bergenstråhle, Ludvig; Bolt, Liam; Braun, Emelie; Bui, Linh T; Callori, Steven; Chaffin, Mark; Chichelnitskiy, Evgeny; Chiou, Joshua; Conlon, Thomas M; Cuoco, Michael S; Cuomo, Anna SE; Deprez, Marie; Duclos, Grant; Fine, Denise; Fischer, David S; Ghazanfar, Shila; Gillich, Astrid; Giotti, Bruno; Gould, Joshua; Guo, Minzhe; Gutierrez, Austin J; Habermann, Arun C; Harvey, Tyler; He, Peng; Hou, Xiaomeng; Hu, Lijuan; Hu, Yan; Jaiswal, Alok; Ji, Lu; Jiang, Peiyong; Kapellos, Theodoros S; Kuo, Christin S; Larsson, Ludvig; Leney-Greene, Michael A; Lim, Kyungtae; Litviňuková, Monika; Ludwig, Leif S; Lukassen, Soeren; Luo, Wendy; Maatz, Henrike; Madissoon, Elo; Mamanova, Lira; Manakongtreecheep, Kasidet; Leroy, Sylvie; Mayr, Christoph H; Mbano, Ian M; McAdams, Alexi M; Nabhan, Ahmad N; Nyquist, Sarah K; Penland, Lolita; Poirion, Olivier B; Poli, Sergio; Qi, CanCan; Queen, Rachel; Reichart, Daniel; Rosas, Ivan; Schupp, Jonas C; Shea, Conor V; Shi, Xingyi; Sinha, Rahul; Sit, Rene V; Slowikowski, Kamil; Slyper, Michal; Smith, Neal P; Sountoulidis, Alex; Strunz, Maximilian; Sullivan, Travis B; Sun, Dawei; Talavera-López, Carlos; Tan, Peng; Tantivit, Jessica; Travaglini, Kyle J; Tucker, Nathan R; Vernon, Katherine A; Wadsworth, Marc H; Waldman, Julia; Wang, Xiuting; Xu, Ke; Yan, Wenjun; Zhao, William; Ziegler, Carly GK; NHLBI LungMap Consortium; Human Cell Atlas Lung Biological NetworkAngiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.