Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell
Puray-Chavez, M;LaPak, KM;Schrank, TP;Elliott, JL;Bhatt, DP;Agajanian, MJ;Jasuja, R;Lawson, DQ;Davis, K;Rothlauf, PW;Liu, Z;Jo, H;Lee, N;Tenneti, K;Eschbach, JE;Shema Mugisha, C;Cousins, EM;Cloer, EW;Vuong, HR;VanBlargan, LA;Bailey, AL;Gilchuk, P;Crowe, JE;Diamond, MS;Hayes, DN;Whelan, SPJ;Horani, A;Brody, SL;Goldfarb, D;Major, MB;Kutluay, SB;
PMID: 34214467 | DOI: 10.1016/j.celrep.2021.109364
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) variants govern transmissibility, responsiveness to vaccination, and disease severity. In a screen for new models of SARS-CoV-2 infection, we identify human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of angiotensin-converting enzyme 2 (ACE2) expression. Remarkably, H522 infection requires the E484D S variant; viruses expressing wild-type S are not infectious. Anti-S monoclonal antibodies differentially neutralize SARS-CoV-2 E484D S in H522 cells as compared to ACE2-expressing cells. Sera from vaccinated individuals block this alternative entry mechanism, whereas convalescent sera are less effective. Although the H522 receptor remains unknown, depletion of surface heparan sulfates block H522 infection. Temporally resolved transcriptomic and proteomic profiling reveal alterations in cell cycle and the antiviral host cell response, including MDA5-dependent activation of type I interferon signaling. These findings establish an alternative SARS-CoV-2 host cell receptor for the E484D SARS-CoV-2 variant, which may impact tropism of SARS-CoV-2 and consequently human disease pathogenesis.
Molecular Pathology Analysis of SARS-CoV-2 in Syncytiotrophoblast and Hofbauer Cells in Placenta from a Pregnant Woman and Fetus with COVID-19
Pathogens (Basel, Switzerland)
Morotti, D;Cadamuro, M;Rigoli, E;Sonzogni, A;Gianatti, A;Parolin, C;Patanè, L;Schwartz, DA;
PMID: 33920814 | DOI: 10.3390/pathogens10040479
A small number of neonates delivered to women with SARS-CoV-2 infection have been found to become infected through intrauterine transplacental transmission. These cases are associated with a group of unusual placental pathology abnormalities that include chronic histiocytic intervillositis, syncytiotrophoblast necrosis, and positivity of the syncytiotrophoblast for SARS-CoV-2 antigen or RNA. Hofbauer cells constitute a heterogeneous group of immunologically active macrophages that have been involved in transplacental infections that include such viral agents as Zika virus and human immunodeficiency virus. The role of Hofbauer cells in placental infection with SARS-CoV-2 and maternal-fetal transmission is unknown. This study uses molecular pathology techniques to evaluate the placenta from a neonate infected with SARS-CoV-2 via the transplacental route to determine whether Hofbauer cells have evidence of infection. We found that the placenta had chronic histiocytic intervillositis and syncytiotrophoblast necrosis, with the syncytiotrophoblast demonstrating intense positive staining for SARS-CoV-2. Immunohistochemistry using the macrophage marker CD163, SARS-CoV-2 nucleocapsid protein, and double staining for SARS-CoV-2 with RNAscope and anti-CD163 antibody, revealed that no demonstrable virus could be identified within Hofbauer cells, despite these cells closely approaching the basement membrane zone of the infected trophoblast. Unlike some other viruses, there was no evidence from this transmitting placenta for infection of Hofbauer cells with SARS-CoV-2.
NOTCH3-targeted antibody drug conjugates regress tumors by inducing apoptosis in receptor cells and through transendocytosis into ligand cells
Geles, K;Gao, Y;Giannakou, A;Sridharan, L;Yamin, T;Zhang, J;Karim, R;Bard, J;Piche-Nicholas, N;Charati, M;Maderna, A;Lucas, J;Golas, J;Guffroy, M;Pirie-Shepherd, S;Roy, M;Qian, J;Franks, T;Zhong, W;O’Donnell, C;Tchistiakova, L;Gerber, H;Sapra, P;
| DOI: 10.1016/j.xcrm.2021.100279
Aberrant NOTCH3 signaling and overexpression is oncogenic, associated with cancer stem cells and drug resistance, yet therapeutic targeting remains elusive. Here, we develop NOTCH3-targeted antibody drug conjugates (NOTCH3-ADCs) by bioconjugation of an auristatin microtubule inhibitor through a protease cleavable linker to two antibodies with differential abilities to inhibit signaling. The signaling inhibitory antibody rapidly induces ligand-independent receptor clustering and internalization through both caveolin and clathrin-mediated pathways. The non-inhibitory antibody also efficiently endocytoses via clathrin without inducing receptor clustering but with slower lysosomal co-localization kinetics. In addition, DLL4 ligand binding to the NOTCH3 receptor mediates transendocytosis of NOTCH3-ADCs into ligand-expressing cells. NOTCH3-ADCs internalize into receptor and ligand cells independent of signaling and induce cell death in both cell types representing an atypical mechanism of ADC cytotoxicity. Treatment of xenografts with NOTCH3-ADCs leads to sustained tumor regressions, outperforms standard-of-care chemotherapy, and allows targeting of tumors that overexpress NOTCH3 independent of signaling inhibition.
Gajewski, T;Rouhani, S;Trujillo, J;Pyzer, A;Yu, J;Fessler, J;Cabanov, A;Higgs, E;Cron, K;Zha, Y;Lu, Y;Bloodworth, J;Abasiyanik, M;Okrah, S;Flood, B;Hatogai, K;Leung, M;Pezeshk, A;Kozloff, L;Reschke, R;Strohbehn, G;Chervin, CS;Kumar, M;Schrantz, S;Madariaga, ML;Beavis, K;Yeo, KT;Sweis, R;Segal, J;Tay, S;Izumchenko, E;Mueller, J;Chen, L;
PMID: 34845442 | DOI: 10.21203/rs.3.rs-1083825/v1
The mechanisms explaining progression to severe COVID-19 remain poorly understood. It has been proposed that immune system dysregulation/over-stimulation may be implicated, but it is not clear how such processes would lead to respiratory failure. We performed comprehensive multiparameter immune monitoring in a tightly controlled cohort of 128 COVID-19 patients, and used the ratio of oxygen saturation to fraction of inspired oxygen (SpO2 / FiO2) as a physiologic measure of disease severity. Machine learning algorithms integrating 139 parameters identified IL-6 and CCL2 as two factors predictive of severe disease, consistent with the therapeutic benefit observed with anti-IL6-R antibody treatment. However, transcripts encoding these cytokines were not detected among circulating immune cells. Rather, in situ analysis of lung specimens using RNAscope and immunofluorescent staining revealed that elevated IL-6 and CCL2 were dominantly produced by infected lung type II pneumocytes. Severe disease was not associated with higher viral load, deficient antibody responses, or dysfunctional T cell responses. These results refine our understanding of severe COVID-19 pathophysiology, indicating that aberrant cytokine production by infected lung epithelial cells is a major driver of immunopathology. We propose that these factors cause local immune regulation towards the benefit of the virus.
Bewley, D;Lee, J;Popescu, O;Oviedo, A;
| DOI: 10.7759/cureus.20833
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Favre, G;Mazzetti, S;Gengler, C;Bertelli, C;Schneider, J;Laubscher, B;Capoccia, R;Pakniyat, F;Ben Jazia, I;Eggel-Hort, B;de Leval, L;Pomar, L;Greub, G;Baud, D;Giannoni, E;
PMID: 34960786 | DOI: 10.3390/v13122517
Neonatal COVID-19 is rare and mainly results from postnatal transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, can infect the placenta and compromise its function. We present two cases of decreased fetal movements and abnormal fetal heart rhythm 5 days after mild maternal COVID-19, requiring emergency caesarean section at 29 + 3 and 32 + 1 weeks of gestation, and leading to brain injury. Placental examination revealed extensive and multifocal chronic intervillositis, with intense cytoplasmic positivity for SARS-CoV-2 spike antibody and SARS-CoV-2 detection by RT-qPCR. Vertical transmission was confirmed in one case, and both neonates developed extensive cystic peri-ventricular leukomalacia.
Karras, P;Bordeu, I;Pozniak, J;Nowosad, A;Pazzi, C;Van Raemdonck, N;Landeloos, E;Van Herck, Y;Pedri, D;Bervoets, G;Makhzami, S;Khoo, JH;Pavie, B;Lamote, J;Marin-Bejar, O;Dewaele, M;Liang, H;Zhang, X;Hua, Y;Wouters, J;Browaeys, R;Bergers, G;Saeys, Y;Bosisio, F;van den Oord, J;Lambrechts, D;Rustgi, AK;Bechter, O;Blanpain, C;Simons, BD;Rambow, F;Marine, JC;
PMID: 36131018 | DOI: 10.1038/s41586-022-05242-7
Although melanoma is notorious for its high degree of heterogeneity and plasticity1,2, the origin and magnitude of cell-state diversity remains poorly understood. Equally, it is unclear whether growth and metastatic dissemination are supported by overlapping or distinct melanoma subpopulations. Here, by combining mouse genetics, single-cell and spatial transcriptomics, lineage tracing and quantitative modelling, we provide evidence of a hierarchical model of tumour growth that mirrors the cellular and molecular logic underlying the cell-fate specification and differentiation of the embryonic neural crest. We show that tumorigenic competence is associated with a spatially localized perivascular niche, a phenotype acquired through an intercellular communication pathway established by endothelial cells. Consistent with a model in which only a fraction of cells are fated to fuel growth, temporal single-cell tracing of a population of melanoma cells with a mesenchymal-like state revealed that these cells do not contribute to primary tumour growth but, instead, constitute a pool of metastatic initiating cells that switch cell identity while disseminating to secondary organs. Our data provide a spatially and temporally resolved map of the diversity and trajectories of melanoma cell states and suggest that the ability to support growth and metastasis are limited to distinct pools of cells. The observation that these phenotypic competencies can be dynamically acquired after exposure to specific niche signals warrant the development of therapeutic strategies that interfere with the cancer cell reprogramming activity of such microenvironmental cues.
