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A serpin shapes the extracellular environment to prevent influenza A virus maturation

Dittmann, Meike; Hoffmann, Hans-Heinrich; Scull, Margaret A; Gilmore, Rachel H; Bell, Kierstin L; Ciancanelli, Michael; Wilson, Sam J; Crotta, Stefania; Yu, Yingpu; Flatley, Brenna; Xiao, Jing W; Casanova, Jean-Laurent; Wack, Andreas; Bieniasz, Paul D; Rice, Charles M
Interferon-stimulated genes (ISGs) act in concert to provide a tight barrier against viruses. Recent studies have shed light on the contribution of individual ISG effectors to the antiviral state, but most have examined those acting on early, intracellular stages of the viral life cycle. Here, we applied an image-based screen to identify ISGs inhibiting late stages of influenza A virus (IAV) infection. We unraveled a directly antiviral function for the gene SERPINE1, encoding plasminogen activator inhibitor 1 (PAI-1). By targeting extracellular airway proteases, PAI-1 inhibits IAV glycoprotein cleavage, thereby reducing infectivity of progeny viruses. This was biologically relevant for IAV restriction in vivo. Further, partial PAI-1 deficiency, attributable to a polymorphism in human SERPINE1, conferred increased susceptibility to IAV in vitro. Together, our findings reveal that manipulating the extracellular environment to inhibit the last step in a virus life cycle is an important mechanism of the antiviral response.
PMID: 25679759
ISSN: 1097-4172
CID: 2162472

ATP-dependent effector-like functions of RIG-I-like receptors

Yao, Hui; Dittmann, Meike; Peisley, Alys; Hoffmann, Hans-Heinrich; Gilmore, Rachel H; Schmidt, Tobias; Schmid-Burgk, Jonathan L; Hornung, Veit; Rice, Charles M; Hur, Sun
The vertebrate antiviral innate immune system is often considered to consist of two distinct groups of proteins: pattern recognition receptors (PRRs) that detect viral infection and induce the interferon (IFN) signaling, and effectors that directly act against viral replication. Accordingly, previous studies on PRRs, such as RIG-I and MDA5, have primarily focused on their functions in viral double-stranded RNA (dsRNA) detection and consequent antiviral signaling. We report here that both RIG-I and MDA5 efficiently displace viral proteins pre-bound to dsRNA in a manner dependent on their ATP hydrolysis, and that this activity assists a dsRNA-dependent antiviral effector protein, PKR, and allows RIG-I to promote MDA5 signaling. Furthermore, truncated RIG-I/MDA5 lacking the signaling domain, and hence the IFN stimulatory activity, displaces viral proteins and suppresses replication of certain viruses in an ATP-dependent manner. Thus, this study reveals novel "effector-like" functions of RIG-I and MDA5 that challenge the conventional view of PRRs.
PMID: 25891073
ISSN: 1097-4164
CID: 2162462

Gut microbiome dysbiosis in antibiotic-treated COVID-19 patients is associated with microbial translocation and bacteremia

Bernard-Raichon, Lucie; Venzon, Mericien; Klein, Jon; Axelrad, Jordan E; Zhang, Chenzhen; Sullivan, Alexis P; Hussey, Grant A; Casanovas-Massana, Arnau; Noval, Maria G; Valero-Jimenez, Ana M; Gago, Juan; Putzel, Gregory; Pironti, Alejandro; Wilder, Evan; Thorpe, Lorna E; Littman, Dan R; Dittmann, Meike; Stapleford, Kenneth A; Shopsin, Bo; Torres, Victor J; Ko, Albert I; Iwasaki, Akiko; Cadwell, Ken; Schluter, Jonas
Although microbial populations in the gut microbiome are associated with COVID-19 severity, a causal impact on patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. We first demonstrate SARS-CoV-2 infection induces gut microbiome dysbiosis in mice, which correlated with alterations to Paneth cells and goblet cells, and markers of barrier permeability. Samples collected from 96 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, including blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicates that bacteria may translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19.
PMID: 36319618
ISSN: 2041-1723
CID: 5358262

DDX60 selectively reduces translation off viral type II internal ribosome entry sites

Sadic, Mohammad; Schneider, William M; Katsara, Olga; Medina, Gisselle N; Fisher, Ashley; Mogulothu, Aishwarya; Yu, Yingpu; Gu, Meigang; de Los Santos, Teresa; Schneider, Robert J; Dittmann, Meike
Co-opting host cell protein synthesis is a hallmark of many virus infections. In response, certain host defense proteins limit mRNA translation globally, albeit at the cost of the host cell's own protein synthesis. Here, we describe an interferon-stimulated helicase, DDX60, that decreases translation from viral internal ribosome entry sites (IRESs). DDX60 acts selectively on type II IRESs of encephalomyocarditis virus (EMCV) and foot and mouth disease virus (FMDV), but not by other IRES types or by 5' cap. Correspondingly, DDX60 reduces EMCV and FMDV (type II IRES) replication, but not that of poliovirus or bovine enterovirus 1 (BEV-1; type I IRES). Furthermore, replacing the IRES of poliovirus with a type II IRES is sufficient for DDX60 to inhibit viral replication. Finally, DDX60 selectively modulates the amount of translating ribosomes on viral and in vitro transcribed type II IRES mRNAs, but not 5' capped mRNA. Our study identifies a novel facet in the repertoire of interferon-stimulated effector genes, the selective downregulation of translation from viral type II IRES elements.
PMID: 36256515
ISSN: 1469-3178
CID: 5360422

Long noncoding RNA CHROMR regulates antiviral immunity in humans

van Solingen, Coen; Cyr, Yannick; Scacalossi, Kaitlyn R; de Vries, Maren; Barrett, Tessa J; de Jong, Annika; Gourvest, Morgane; Zhang, Tracy; Peled, Daniel; Kher, Raadhika; Cornwell, MacIntosh; Gildea, Michael A; Brown, Emily J; Fanucchi, Stephanie; Mhlanga, Musa M; Berger, Jeffrey S; Dittmann, Meike; Moore, Kathryn J
Long noncoding RNAs (lncRNAs) have emerged as critical regulators of gene expression, yet their contribution to immune regulation in humans remains poorly understood. Here, we report that the primate-specific lncRNA CHROMR is induced by influenza A virus and SARS-CoV-2 infection and coordinates the expression of interferon-stimulated genes (ISGs) that execute antiviral responses. CHROMR depletion in human macrophages reduces histone acetylation at regulatory regions of ISG loci and attenuates ISG expression in response to microbial stimuli. Mechanistically, we show that CHROMR sequesters the interferon regulatory factor (IRF)-2-dependent transcriptional corepressor IRF2BP2, thereby licensing IRF-dependent signaling and transcription of the ISG network. Consequently, CHROMR expression is essential to restrict viral infection of macrophages. Our findings identify CHROMR as a key arbitrator of antiviral innate immune signaling in humans.
PMID: 36001732
ISSN: 1091-6490
CID: 5331652

ACE2-containing defensosomes serve as decoys to inhibit SARS-CoV-2 infection

Ching, Krystal L; de Vries, Maren; Gago, Juan; Dancel-Manning, Kristen; Sall, Joseph; Rice, William J; Barnett, Clea; Khodadadi-Jamayran, Alireza; Tsirigos, Aristotelis; Liang, Feng-Xia; Thorpe, Lorna E; Shopsin, Bo; Segal, Leopoldo N; Dittmann, Meike; Torres, Victor J; Cadwell, Ken
Extracellular vesicles of endosomal origin, exosomes, mediate intercellular communication by transporting substrates with a variety of functions related to tissue homeostasis and disease. Their diagnostic and therapeutic potential has been recognized for diseases such as cancer in which signaling defects are prominent. However, it is unclear to what extent exosomes and their cargo inform the progression of infectious diseases. We recently defined a subset of exosomes termed defensosomes that are mobilized during bacterial infection in a manner dependent on autophagy proteins. Through incorporating protein receptors on their surface, defensosomes mediated host defense by binding and inhibiting pore-forming toxins secreted by bacterial pathogens. Given this capacity to serve as decoys that interfere with surface protein interactions, we investigated the role of defensosomes during infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of Coronavirus Disease 2019 (COVID-19). Consistent with a protective function, exosomes containing high levels of the viral receptor ACE2 in bronchoalveolar lavage fluid (BALF) from critically ill COVID-19 patients was associated with reduced intensive care unit (ICU) and hospitalization times. We found ACE2+ exosomes were induced by SARS-CoV-2 infection and activation of viral sensors in cell culture, which required the autophagy protein ATG16L1, defining these as defensosomes. We further demonstrate that ACE2+ defensosomes directly bind and block viral entry. These findings suggest that defensosomes may contribute to the antiviral response against SARS-CoV-2 and expand our knowledge on the regulation and effects of extracellular vesicles during infection.
PMID: 36099266
ISSN: 1545-7885
CID: 5335192

Clinical and genomic signatures of SARS-CoV-2 Delta breakthrough infections in New York

Duerr, Ralf; Dimartino, Dacia; Marier, Christian; Zappile, Paul; Levine, Samuel; Francois, Fritz; Iturrate, Eduardo; Wang, Guiqing; Dittmann, Meike; Lighter, Jennifer; Elbel, Brian; Troxel, Andrea B; Goldfeld, Keith S; Heguy, Adriana
BACKGROUND:In 2021, Delta became the predominant SARS-CoV-2 variant worldwide. While vaccines have effectively prevented COVID-19 hospitalization and death, vaccine breakthrough infections increasingly occurred. The precise role of clinical and genomic determinants in Delta infections is not known, and whether they contributed to increased rates of breakthrough infections compared to unvaccinated controls. METHODS:We studied SARS-CoV-2 variant distribution, dynamics, and adaptive selection over time in relation to vaccine status, phylogenetic relatedness of viruses, full genome mutation profiles, and associated clinical and demographic parameters. FINDINGS/RESULTS:We show a steep and near-complete replacement of circulating variants with Delta between May and August 2021 in metropolitan New York. We observed an increase of the Delta sublineage AY.25 (14% in vaccinated, 7% in unvaccinated), its spike mutation S112L, and AY.44 (8% in vaccinated, 2% in unvaccinated) with its nsp12 mutation F192V in breakthroughs. Delta infections were associated with younger age and lower hospitalization rates than Alpha. Delta breakthrough infections increased significantly with time since vaccination, and, after adjusting for confounders, they rose at similar rates as in unvaccinated individuals. INTERPRETATION/CONCLUSIONS:We observed a modest adaptation of Delta genomes in breakthrough infections in New York, suggesting an improved genomic framework to support Delta's epidemic growth in times of waning vaccine protection despite limited impact on vaccine escape. FUNDING/BACKGROUND:The study was supported by NYU institutional funds. The NYULH Genome Technology Center is partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center.
PMID: 35906172
ISSN: 2352-3964
CID: 5277042

Defining the risk of SARS-CoV-2 variants on immune protection

DeGrace, Marciela M; Ghedin, Elodie; Frieman, Matthew B; Krammer, Florian; Grifoni, Alba; Alisoltani, Arghavan; Alter, Galit; Amara, Rama R; Baric, Ralph S; Barouch, Dan H; Bloom, Jesse D; Bloyet, Louis-Marie; Bonenfant, Gaston; Boon, Adrianus C M; Boritz, Eli A; Bratt, Debbie L; Bricker, Traci L; Brown, Liliana; Buchser, William J; Carreño, Juan Manuel; Cohen-Lavi, Liel; Darling, Tamarand L; Davis-Gardner, Meredith E; Dearlove, Bethany L; Di, Han; Dittmann, Meike; Doria-Rose, Nicole A; Douek, Daniel C; Drosten, Christian; Edara, Venkata-Viswanadh; Ellebedy, Ali; Fabrizio, Thomas P; Ferrari, Guido; Florence, William C; Fouchier, Ron A M; Franks, John; García-Sastre, Adolfo; Godzik, Adam; Gonzalez-Reiche, Ana Silvia; Gordon, Aubree; Haagmans, Bart L; Halfmann, Peter J; Ho, David D; Holbrook, Michael R; Huang, Yaoxing; James, Sarah L; Jaroszewski, Lukasz; Jeevan, Trushar; Johnson, Robert M; Jones, Terry C; Joshi, Astha; Kawaoka, Yoshihiro; Kercher, Lisa; Koopmans, Marion P G; Korber, Bette; Koren, Eilay; Koup, Richard A; LeGresley, Eric B; Lemieux, Jacob E; Liebeskind, Mariel J; Liu, Zhuoming; Livingston, Brandi; Logue, James P; Luo, Yang; McDermott, Adrian B; McElrath, Margaret J; Meliopoulos, Victoria A; Menachery, Vineet D; Montefiori, David C; Mühlemann, Barbara; Munster, Vincent J; Munt, Jenny E; Nair, Manoj S; Netzl, Antonia; Niewiadomska, Anna M; O'Dell, Sijy; Pekosz, Andrew; Perlman, Stanley; Pontelli, Marjorie C; Rockx, Barry; Rolland, Morgane; Rothlauf, Paul W; Sacharen, Sinai; Scheuermann, Richard H; Schmidt, Stephen D; Schotsaert, Michael; Schultz-Cherry, Stacey; Seder, Robert A; Sedova, Mayya; Sette, Alessandro; Shabman, Reed S; Shen, Xiaoying; Shi, Pei-Yong; Shukla, Maulik; Simon, Viviana; Stumpf, Spencer; Sullivan, Nancy J; Thackray, Larissa B; Theiler, James; Thomas, Paul G; Trifkovic, Sanja; Türeli, Sina; Turner, Samuel A; Vakaki, Maria A; van Bakel, Harm; VanBlargan, Laura A; Vincent, Leah R; Wallace, Zachary S; Wang, Li; Wang, Maple; Wang, Pengfei; Wang, Wei; Weaver, Scott C; Webby, Richard J; Weiss, Carol D; Wentworth, David E; Weston, Stuart M; Whelan, Sean P J; Whitener, Bradley M; Wilks, Samuel H; Xie, Xuping; Ying, Baoling; Yoon, Hyejin; Zhou, Bin; Hertz, Tomer; Smith, Derek J; Diamond, Michael S; Post, Diane J; Suthar, Mehul S
The global emergence of many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants jeopardizes the protective antiviral immunity induced following infection or vaccination. To address the public health threat caused by the increasing SARS-CoV-2 genomic diversity, the National Institute of Allergy and Infectious Diseases (NIAID) within the National Institutes of Health (NIH) established the SARS-CoV-2 Assessment of Viral Evolution (SAVE) program. This effort was designed to provide a real-time risk assessment of SARS-CoV-2 variants potentially impacting transmission, virulence, and resistance to convalescent and vaccine-induced immunity. The SAVE program serves as a critical data-generating component of the United States Government SARS-CoV-2 Interagency Group to assess implications of SARS-CoV-2 variants on diagnostics, vaccines, and therapeutics and for communicating public health risk. Here we describe the coordinated approach used to identify and curate data about emerging variants, their impact on immunity, and effects on vaccine protection using animal models. We report the development of reagents, methodologies, models, and pivotal findings facilitated by this collaborative approach and identify future challenges. This program serves as a template for the response against rapidly evolving pandemic pathogens by monitoring viral evolution in the human population to identify variants that could erode the effectiveness of countermeasures.
PMID: 35361968
ISSN: 1476-4687
CID: 5220052

Delta-Omicron recombinant SARS-CoV-2 in a transplant patient treated with Sotrovimab [PrePrint]

Duerr, Ralf; Dimartino, Dacia; Marier, Christian; Zappile, Paul; Wang, Guiqing; Plitnick, Jonathan; Griesemer, Sara B; Lasek-Nesselquist, Erica; Dittmann, Meike; Ortigoza, Mila B; Prasad, Prithiv J; St George, Kirsten; Heguy, Adriana
We identified a Delta-Omicron SARS-CoV-2 recombinant in an unvaccinated, immunosuppressed kidney transplant recipient who had positive COVID-19 tests in December 2021 and February 2022 and was initially treated with Sotrovimab. Viral sequencing in February 2022 revealed a 5' Delta AY.45 portion and a 3' Omicron BA.1 portion with a recombination breakpoint in the spike N-terminal domain, adjacent to the Sotrovimab quaternary binding site. The recombinant virus induced cytopathic effects with characteristics of both Delta (large cells) and Omicron (cell rounding/detachment). Monitoring of immunosuppressed COVID-19 patients treated with antiviral monoclonal antibodies is crucial to detect potential selection of recombinant variants.
PMID: 35411351
ISSN: 2692-8205
CID: 5192442

The NSP14/NSP10 RNA repair complex as a Pan-coronavirus therapeutic target

Rona, Gergely; Zeke, Andras; Miwatani-Minter, Bearach; de Vries, Maren; Kaur, Ramanjit; Schinlever, Austin; Garcia, Sheena Faye; Goldberg, Hailey V; Wang, Hui; Hinds, Thomas R; Bailly, Fabrice; Zheng, Ning; Cotelle, Philippe; Desmaële, Didier; Landau, Nathaniel R; Dittmann, Meike; Pagano, Michele
The risk of zoonotic coronavirus spillover into the human population, as highlighted by the SARS-CoV-2 pandemic, demands the development of pan-coronavirus antivirals. The efficacy of existing antiviral ribonucleoside/ribonucleotide analogs, such as remdesivir, is decreased by the viral proofreading exonuclease NSP14-NSP10 complex. Here, using a novel assay and in silico modeling and screening, we identified NSP14-NSP10 inhibitors that increase remdesivir's potency. A model compound, sofalcone, both inhibits the exonuclease activity of SARS-CoV-2, SARS-CoV, and MERS-CoV in vitro, and synergistically enhances the antiviral effect of remdesivir, suppressing the replication of SARS-CoV-2 and the related human coronavirus OC43. The validation of top hits from our primary screenings using cellular systems provides proof-of-concept for the NSP14 complex as a therapeutic target.
PMID: 34862481
ISSN: 1476-5403
CID: 5069282