Publications
20 results found
Kallol S, Martin-Sancho L, Morey R, et al., 2023, Activation of the interferon pathway in trophoblast cells productively infected with SARS-CoV-2, Stem Cells and Development, Vol: 32, Pages: 225-236, ISSN: 1547-3287
SARS-CoV-2 infection during pregnancy has been associated with poor maternal and neonatal outcomes and placental defects. The placenta, which acts as a physical and immunological barrier at the maternal–fetal interface, is not established until the end of the first trimester. Therefore, localized viral infection of the trophoblast compartment early in gestation could trigger an inflammatory response resulting in altered placental function and consequent suboptimal conditions for fetal growth and development. In this study, we investigated the effect of SARS-CoV-2 infection in early gestation placentae using placenta-derived human trophoblast stem cells (TSCs), a novel in vitro model, and their extravillous trophoblast (EVT) and syncytiotrophoblast (STB) derivatives. SARS-CoV-2 was able to productively replicate in TSC-derived STB and EVT, but not undifferentiated TSCs, which is consistent with the expression of SARS-CoV-2 entry host factors, ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane cellular serine protease) in these cells. In addition, both TSC-derived EVT and STB infected with SARS-CoV-2 elicited an interferon-mediated innate immune response. Combined, these results suggest that placenta-derived TSCs are a robust in vitro model to investigate the effect of SARS-CoV-2 infection in the trophoblast compartment of the early placenta and that SARS-CoV-2 infection in early gestation activates the innate immune response and inflammation pathways. Therefore, placental development could be adversely affected by early SARS-CoV-2 infection by directly infecting the developing differentiated trophoblast compartment, posing a higher risk for poor pregnancy outcomes.
Mesci P, de Souza JS, Martin-Sancho L, et al., 2022, SARS-CoV-2 infects human brain organoids causing cell death and loss of synapses that can be rescued by treatment with Sofosbuvir, PLOS Biology, Vol: 20, Pages: e3001845-e3001845
<jats:p>The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which was rapidly declared a pandemic by the World Health Organization (WHO). Early clinical symptomatology focused mainly on respiratory illnesses. However, a variety of neurological manifestations in both adults and newborns are now well-documented. To experimentally determine whether SARS-CoV-2 could replicate in and affect human brain cells, we infected iPSC-derived human brain organoids. Here, we show that SARS-CoV-2 can productively replicate and promote death of neural cells, including cortical neurons. This phenotype was accompanied by loss of excitatory synapses in neurons. Notably, we found that the U.S. Food and Drug Administration (FDA)-approved antiviral Sofosbuvir was able to inhibit SARS-CoV-2 replication and rescued these neuronal alterations in infected brain organoids. Given the urgent need for readily available antivirals, these results provide a cellular basis supporting repurposed antivirals as a strategic treatment to alleviate neurocytological defects that may underlie COVID-19- related neurological symptoms.</jats:p>
Forst CV, Martin-Sancho L, Tripathi S, et al., 2022, Common and species-specific molecular signatures, networks, and regulators of influenza virus infection in mice, ferrets, and humans, Science Advances, Vol: 8
<jats:p> Molecular responses to influenza A virus (IAV) infections vary between mammalian species. To identify conserved and species-specific molecular responses, we perform a comparative study of transcriptomic data derived from blood cells, primary epithelial cells, and lung tissues collected from IAV-infected humans, ferrets, and mice. The molecular responses in the human host have unique functions such as antigen processing that are not observed in mice or ferrets. Highly conserved gene coexpression modules across the three species are enriched for IAV infection–induced pathways including cell cycle and interferon (IFN) signaling. <jats:italic>TDRD7</jats:italic> is predicted as an IFN-inducible host factor that is up-regulated upon IAV infection in the three species. <jats:italic>TDRD7</jats:italic> is required for antiviral IFN response, potentially modulating IFN signaling via the JAK/STAT/IRF9 pathway. Identification of the common and species-specific molecular signatures, networks, and regulators of IAV infection provides insights into host-defense mechanisms and will facilitate the development of novel therapeutic interventions against IAV infection. </jats:p>
Pohl MO, Martin-Sancho L, Ratnayake R, et al., 2022, Sec61 Inhibitor Apratoxin S4 Potently Inhibits SARS-CoV-2 and Exhibits Broad-Spectrum Antiviral Activity, ACS Infectious Diseases, Vol: 8, Pages: 1265-1279, ISSN: 2373-8227
Pal LR, Cheng K, Nair NU, et al., 2022, Synthetic lethality-based prediction of anti-SARS-CoV-2 targets, iScience, Vol: 25, Pages: 104311-104311, ISSN: 2589-0042
May DG, Martin-Sancho L, Anschau V, et al., 2022, A BioID-Derived Proximity Interactome for SARS-CoV-2 Proteins, Viruses, Vol: 14, Pages: 611-611
<jats:p>The novel coronavirus SARS-CoV-2 is responsible for the ongoing COVID-19 pandemic and has caused a major health and economic burden worldwide. Understanding how SARS-CoV-2 viral proteins behave in host cells can reveal underlying mechanisms of pathogenesis and assist in development of antiviral therapies. Here, the cellular impact of expressing SARS-CoV-2 viral proteins was studied by global proteomic analysis, and proximity biotinylation (BioID) was used to map the SARS-CoV-2 virus–host interactome in human lung cancer-derived cells. Functional enrichment analyses revealed previously reported and unreported cellular pathways that are associated with SARS-CoV-2 proteins. We have established a website to host the proteomic data to allow for public access and continued analysis of host–viral protein associations and whole-cell proteomes of cells expressing the viral–BioID fusion proteins. Furthermore, we identified 66 high-confidence interactions by comparing this study with previous reports, providing a strong foundation for future follow-up studies. Finally, we cross-referenced candidate interactors with the CLUE drug library to identify potential therapeutics for drug-repurposing efforts. Collectively, these studies provide a valuable resource to uncover novel SARS-CoV-2 biology and inform development of antivirals.</jats:p>
Madden PJ, Arif MS, Becker ME, et al., 2021, Development of an In Vivo Probe to Track SARS-CoV-2 Infection in Rhesus Macaques, Frontiers in Immunology, Vol: 12
<jats:p>Infection with the novel coronavirus, SARS-CoV-2, results in pneumonia and other respiratory symptoms as well as pathologies at diverse anatomical sites. An outstanding question is whether these diverse pathologies are due to replication of the virus in these anatomical compartments and how and when the virus reaches those sites. To answer these outstanding questions and study the spatiotemporal dynamics of SARS-CoV-2 infection a method for tracking viral spread <jats:italic>in vivo</jats:italic> is needed. We developed a novel, fluorescently labeled, antibody-based <jats:italic>in vivo</jats:italic> probe system using the anti-spike monoclonal antibody CR3022 and demonstrated that it could successfully identify sites of SARS-CoV-2 infection in a rhesus macaque model of COVID-19. Our results showed that the fluorescent signal from our antibody-based probe could differentiate whole lungs of macaques infected for 9 days from those infected for 2 or 3 days. Additionally, the probe signal corroborated the frequency and density of infected cells in individual tissue blocks from infected macaques. These results provide proof of concept for the use of <jats:italic>in vivo</jats:italic> antibody-based probes to study SARS-CoV-2 infection dynamics in rhesus macaques.</jats:p>
Cheng K, MartinSancho L, Pal LR, et al., 2021, Genome‐scale metabolic modeling reveals SARS‐CoV‐2‐induced metabolic changes and antiviral targets, Molecular Systems Biology, Vol: 17, ISSN: 1744-4292
Riva L, Goellner S, Biering SB, et al., 2021, The Compound SBI-0090799 Inhibits Zika Virus Infection by Blocking <i>De Novo</i> Formation of the Membranous Replication Compartment, Journal of Virology, Vol: 95, ISSN: 0022-538X
<jats:p>This study describes the elucidation of (2E)-N-benzyl-3-(4-butoxyphenyl)prop-2-enamide (SBI-0090799) as a selective and potent inhibitor of Zika virus (ZIKV) replication using a high-throughput screening approach. Mapping and resistance studies, supported by electron microscopy observations, indicate that the small molecule is functioning through inhibition of NS4A-mediated formation of ZIKV replication compartments in the endoplasmic reticulum (ER).</jats:p>
Martin-Sancho L, Tripathi S, Rodriguez-Frandsen A, et al., 2021, Restriction factor compendium for influenza A virus reveals a mechanism for evasion of autophagy, Nature Microbiology, Vol: 6, Pages: 1319-1333
, 2021, Meet the authors: Laura Martin-Sancho and Sumit K. Chanda, Molecular Cell, Vol: 81, Pages: 2497-2498, ISSN: 1097-2765
Stern-Ginossar N, Kanneganti T-D, Cameron CE, et al., 2021, Rising to the challenge of COVID-19: Working on SARS-CoV-2 during the pandemic, Molecular Cell, Vol: 81, Pages: 2261-2265, ISSN: 1097-2765
Martin-Sancho L, Lewinski MK, Pache L, et al., 2021, Functional landscape of SARS-CoV-2 cellular restriction, Molecular Cell, Vol: 81, Pages: 2656-2668.e8, ISSN: 1097-2765
Yin X, Riva L, Pu Y, et al., 2021, MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells, Cell Reports, Vol: 34, Pages: 108628-108628, ISSN: 2211-1247
Miorin L, Kehrer T, Sanchez-Aparicio MT, et al., 2020, SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling, Proceedings of the National Academy of Sciences, Vol: 117, Pages: 28344-28354, ISSN: 0027-8424
<jats:title>Significance</jats:title> <jats:p>To successfully establish infection, viral pathogens have to overcome the interferon (IFN)-mediated antiviral response. Previous studies revealed that the viral accessory protein Orf6 of SARS-CoV and SARS-CoV-2 is able to inhibit STAT1 nuclear translocation to block IFN signaling. In this study, we report that Orf6 localizes at the nuclear pore complex (NPC) where it binds directly to the Nup98-Rae1 complex to target the nuclear import pathway and mediate this inhibition. A better understanding of the strategies used by viruses to subvert host immune responses is critical for the design of novel antivirals and vaccines.</jats:p>
Riva L, Yuan S, Yin X, et al., 2020, Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing, Nature, Vol: 586, Pages: 113-119, ISSN: 0028-0836
Du Y, Hultquist JF, Zhou Q, et al., 2020, mRNA display with library of even-distribution reveals cellular interactors of influenza virus NS1, Nature Communications, Vol: 11
<jats:title>Abstract</jats:title><jats:p>A comprehensive examination of protein-protein interactions (PPIs) is fundamental for the understanding of cellular machineries. However, limitations in current methodologies often prevent the detection of PPIs with low abundance proteins. To overcome this challenge, we develop a mRNA display with library of even-distribution (md-LED) method that facilitates the detection of low abundance binders with high specificity and sensitivity. As a proof-of-principle, we apply md-LED to IAV NS1 protein. Complementary to AP-MS, md-LED enables us to validate previously described PPIs as well as to identify novel NS1 interactors. We show that interacting with FASN allows NS1 to directly regulate the synthesis of cellular fatty acids. We also use md-LED to identify a mutant of NS1, D92Y, results in a loss of interaction with CPSF1. The use of high-throughput sequencing as the readout for md-LED enables sensitive quantification of interactions, ultimately enabling massively parallel experimentation for the investigation of PPIs.</jats:p>
Rodriguez-Frandsen A, Martin-Sancho L, Gounder AP, et al., 2020, Viral Determinants in H5N1 Influenza A Virus Enable Productive Infection of HeLa Cells, Journal of Virology, Vol: 94, ISSN: 0022-538X
<jats:p>Many zoonotic avian influenza A viruses have successfully crossed the species barrier and caused mild to life-threatening disease in humans. While human-to-human transmission is limited, there is a risk that these zoonotic viruses may acquire adaptive mutations enabling them to propagate efficiently and cause devastating human pandemics. Therefore, it is important to identify viral determinants that provide these viruses with a replicative advantage in human cells. Here, we tested the growth of influenza A virus in a subset of human cell lines and found that abortive replication of H1N1 viruses in HeLa cells can be circumvented upon the introduction of H5N1 virus HA and NP. Overall, this work leverages the genetic diversity of multiple human cell lines to highlight viral determinants that could contribute to H5N1 virus pathogenesis and tropism.</jats:p>
Lesch M, Luckner M, Meyer M, et al., 2019, RNAi-based small molecule repositioning reveals clinically approved urea-based kinase inhibitors as broadly active antivirals, PLoS Pathogens, Vol: 15, Pages: 1-34, ISSN: 1553-7366
Influenza viruses (IVs) tend to rapidly develop resistance to virus-directed vaccines and common antivirals targeting pathogen determinants, but novel host-directed approaches might preclude resistance development. To identify the most promising cellular targets for a host-directed approach against influenza, we performed a comparative small interfering RNA (siRNA) loss-of-function screen of IV replication in A549 cells. Analysis of four different IV strains including a highly pathogenic avian H5N1 strain, an influenza B virus (IBV) and two human influenza A viruses (IAVs) revealed 133 genes required by all four IV strains. According to gene enrichment analyses, these strain-independent host genes were particularly enriched for nucleocytoplasmic trafficking. In addition, 360 strain-specific genes were identified with distinct patterns of usage for IAVs versus IBV and human versus avian IVs. The strain-independent host genes served to define 43 experimental and otherwise clinically approved drugs, targeting reportedly fourteen of the encoded host factors. Amongst the approved drugs, the urea-based kinase inhibitors (UBKIs) regorafenib and sorafenib exhibited a superior therapeutic window of high IV antiviral activity and low cytotoxicity. Both UBKIs appeared to block a cell signaling pathway involved in IV replication after internalization, yet prior to vRNP uncoating. Interestingly, both compounds were active also against unrelated viruses including cowpox virus (CPXV), hantavirus (HTV), herpes simplex virus 1 (HSV1) and vesicular stomatitis virus (VSV) and showed antiviral efficacy in human primary respiratory cells. An in vitro resistance development analysis for regorafenib failed to detect IV resistance development against this drug. Taken together, the otherwise clinically approved UBKIs regorafenib and sorafenib possess high and broad-spectrum antiviral activity along with substantial robustness against resistance development and thus constitute attractive hos
Imai-Matsushima A, Martin-Sancho L, Karlas A, et al., 2018, Long-Term Culture of Distal Airway Epithelial Cells Allows Differentiation Towards Alveolar Epithelial Cells Suited for Influenza Virus Studies, EBioMedicine, Vol: 33, Pages: 230-241, ISSN: 2352-3964
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.