Imperial College London

Dr Laura Martin-Sancho

Faculty of MedicineDepartment of Infectious Disease

Lecturer in Molecular Virology
 
 
 
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Contact

 

+44 (0)20 7594 9032 ext 49032laura.martin-sancho Website

 
 
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Location

 

315Medical SchoolSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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21 results found

Haas KM, McGregor MJ, Bouhaddou M, Polacco BJ, Kim E-Y, Nguyen TT, Newton BW, Urbanowski M, Kim H, Williams MAP, Rezelj VV, Hardy A, Fossati A, Stevenson EJ, Sukerman E, Kim T, Penugonda S, Moreno E, Braberg H, Zhou Y, Metreveli G, Harjai B, Tummino TA, Melnyk JE, Soucheray M, Batra J, Pache L, Martin-Sancho L, Carlson-Stevermer J, Jureka AS, Basler CF, Shokat KM, Shoichet BK, Shriver LP, Johnson JR, Shaw ML, Chanda SK, Roden DM, Carter TC, Kottyan LC, Chisholm RL, Pacheco JA, Smith ME, Schrodi SJ, Albrecht RA, Vignuzzi M, Zuliani-Alvarez L, Swaney DL, Eckhardt M, Wolinsky SM, White KM, Hultquist JF, Kaake RM, García-Sastre A, Krogan NJet al., 2023, Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets., Nat Commun, Vol: 14

Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

Journal article

Kallol S, Martin-Sancho L, Morey R, Aisagbonhi O, Pizzo D, Meads M, Chanda SK, Soncin Fet 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.

Journal article

Mesci P, de Souza JS, Martin-Sancho L, Macia A, Saleh A, Yin X, Snethlage C, Adams JW, Avansini SH, Herai RH, Almenar-Queralt A, Pu Y, Szeto RA, Goldberg G, Bruck PT, Papes F, Chanda SK, Muotri ARet 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>

Journal article

Forst CV, Martin-Sancho L, Tripathi S, Wang G, Dos Anjos Borges LG, Wang M, Geber A, Lashua L, Ding T, Zhou X, Carter CE, Metreveli G, Rodriguez-Frandsen A, Urbanowski MD, White KM, Stein DA, Moulton H, Chanda SK, Pache L, Shaw ML, Ross TM, Ghedin E, García-Sastre A, Zhang Bet 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>

Journal article

Pohl MO, Martin-Sancho L, Ratnayake R, White KM, Riva L, Chen Q-Y, Lieber G, Busnadiego I, Yin X, Lin S, Pu Y, Pache L, Rosales R, Déjosez M, Qin Y, De Jesus PD, Beall A, Yoh S, Hale BG, Zwaka TP, Matsunaga N, García-Sastre A, Stertz S, Chanda SK, Luesch Het 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

Journal article

Pal LR, Cheng K, Nair NU, Martin-Sancho L, Sinha S, Pu Y, Riva L, Yin X, Schischlik F, Lee JS, Chanda SK, Ruppin Eet al., 2022, Synthetic lethality-based prediction of anti-SARS-CoV-2 targets, iScience, Vol: 25, Pages: 104311-104311, ISSN: 2589-0042

Journal article

May DG, Martin-Sancho L, Anschau V, Liu S, Chrisopulos RJ, Scott KL, Halfmann CT, Díaz Peña R, Pratt D, Campos AR, Roux KJet 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>

Journal article

Madden PJ, Arif MS, Becker ME, McRaven MD, Carias AM, Lorenzo-Redondo R, Xiao S, Midkiff CC, Blair RV, Potter EL, Martin-Sancho L, Dodson A, Martinelli E, Todd J-PM, Villinger FJ, Chanda SK, Aye PP, Roy CJ, Roederer M, Lewis MG, Veazey RS, Hope TJet 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>

Journal article

Cheng K, MartinSancho L, Pal LR, Pu Y, Riva L, Yin X, Sinha S, Nair NU, Chanda SK, Ruppin Eet al., 2021, Genome‐scale metabolic modeling reveals SARS‐CoV‐2‐induced metabolic changes and antiviral targets, Molecular Systems Biology, Vol: 17, ISSN: 1744-4292

Journal article

Riva L, Goellner S, Biering SB, Huang C-T, Rubanov AN, Haselmann U, Warnes CM, De Jesus PD, Martin-Sancho L, Terskikh AV, Harris E, Pinkerton AB, Bartenschlager R, Chanda SKet 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>

Journal article

Martin-Sancho L, Tripathi S, Rodriguez-Frandsen A, Pache L, Sanchez-Aparicio M, McGregor MJ, Haas KM, Swaney DL, Nguyen TT, Mamede JI, Churas C, Pratt D, Rosenthal SB, Riva L, Nguyen C, Beltran-Raygoza N, Soonthornvacharin S, Wang G, Jimenez-Morales D, De Jesus PD, Moulton HM, Stein DA, Chang MW, Benner C, Ideker T, Albrecht RA, Hultquist JF, Krogan NJ, García-Sastre A, Chanda SKet al., 2021, Restriction factor compendium for influenza A virus reveals a mechanism for evasion of autophagy, Nature Microbiology, Vol: 6, Pages: 1319-1333

Journal article

Stern-Ginossar N, Kanneganti T-D, Cameron CE, Lou Z, Cherry S, Abraham J, Martin-Sancho Let 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

Journal article

, 2021, Meet the authors: Laura Martin-Sancho and Sumit K. Chanda, Molecular Cell, Vol: 81, Pages: 2497-2498, ISSN: 1097-2765

Journal article

Martin-Sancho L, Lewinski MK, Pache L, Stoneham CA, Yin X, Becker ME, Pratt D, Churas C, Rosenthal SB, Liu S, Weston S, De Jesus PD, ONeill AM, Gounder AP, Nguyen C, Pu Y, Curry HM, Oom AL, Miorin L, Rodriguez-Frandsen A, Zheng F, Wu C, Xiong Y, Urbanowski M, Shaw ML, Chang MW, Benner C, Hope TJ, Frieman MB, García-Sastre A, Ideker T, Hultquist JF, Guatelli J, Chanda SKet al., 2021, Functional landscape of SARS-CoV-2 cellular restriction, Molecular Cell, Vol: 81, Pages: 2656-2668.e8, ISSN: 1097-2765

Journal article

Yin X, Riva L, Pu Y, Martin-Sancho L, Kanamune J, Yamamoto Y, Sakai K, Gotoh S, Miorin L, De Jesus PD, Yang C-C, Herbert KM, Yoh S, Hultquist JF, García-Sastre A, Chanda SKet 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

Journal article

Miorin L, Kehrer T, Sanchez-Aparicio MT, Zhang K, Cohen P, Patel RS, Cupic A, Makio T, Mei M, Moreno E, Danziger O, White KM, Rathnasinghe R, Uccellini M, Gao S, Aydillo T, Mena I, Yin X, Martin-Sancho L, Krogan NJ, Chanda SK, Schotsaert M, Wozniak RW, Ren Y, Rosenberg BR, Fontoura BMA, García-Sastre Aet 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>

Journal article

Riva L, Yuan S, Yin X, Martin-Sancho L, Matsunaga N, Pache L, Burgstaller-Muehlbacher S, De Jesus PD, Teriete P, Hull MV, Chang MW, Chan JF-W, Cao J, Poon VK-M, Herbert KM, Cheng K, Nguyen T-TH, Rubanov A, Pu Y, Nguyen C, Choi A, Rathnasinghe R, Schotsaert M, Miorin L, Dejosez M, Zwaka TP, Sit K-Y, Martinez-Sobrido L, Liu W-C, White KM, Chapman ME, Lendy EK, Glynne RJ, Albrecht R, Ruppin E, Mesecar AD, Johnson JR, Benner C, Sun R, Schultz PG, Su AI, García-Sastre A, Chatterjee AK, Yuen K-Y, Chanda SKet al., 2020, Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing, Nature, Vol: 586, Pages: 113-119, ISSN: 0028-0836

Journal article

Du Y, Hultquist JF, Zhou Q, Olson A, Tseng Y, Zhang T-H, Hong M, Tang K, Chen L, Meng X, McGregor MJ, Dai L, Gong D, Martin-Sancho L, Chanda S, Li X, Bensenger S, Krogan NJ, Sun Ret 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>

Journal article

Rodriguez-Frandsen A, Martin-Sancho L, Gounder AP, Chang MW, Liu W-C, De Jesus PD, von Recum-Knepper J, Dutra MS, Huffmaster NJ, Chavarria M, Mena I, Riva L, Nguyen CB, Dobariya S, Herbert KM, Benner C, Albrecht RA, García-Sastre A, Chanda SKet 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>

Journal article

Lesch M, Luckner M, Meyer M, Weege F, Gravenstein I, Raftery M, Sieben C, Martin-Sancho L, Imai-Matsushima A, Welke R-W, Frise R, Barclay W, Schoenrich G, Herrmann A, Meyer TF, Karlas Aet 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

Journal article

Imai-Matsushima A, Martin-Sancho L, Karlas A, Imai S, Zoranovic T, Hocke AC, Mollenkopf H-J, Berger H, Meyer TFet 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

Journal article

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