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1.
Cell ; 186(16): 3427-3442.e22, 2023 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-37421949

RESUMO

SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, a lysosomal transmembrane protein, can serve as an alternative receptor for SARS-CoV-2 entry into angiotensin-converting enzyme 2 (ACE2)-negative cells. Spike substitution E484D increased TMEM106B binding, thereby enhancing TMEM106B-mediated entry. TMEM106B-specific monoclonal antibodies blocked SARS-CoV-2 infection, demonstrating a role of TMEM106B in viral entry. Using X-ray crystallography, cryogenic electron microscopy (cryo-EM), and hydrogen-deuterium exchange mass spectrometry (HDX-MS), we show that the luminal domain (LD) of TMEM106B engages the receptor-binding motif of SARS-CoV-2 spike. Finally, we show that TMEM106B promotes spike-mediated syncytium formation, suggesting a role of TMEM106B in viral fusion. Together, our findings identify an ACE2-independent SARS-CoV-2 infection mechanism that involves cooperative interactions with the receptors heparan sulfate and TMEM106B.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Receptores Virais/metabolismo , Internalização do Vírus , Ligação Proteica , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo
2.
Nature ; 541(7637): 412-416, 2017 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-28077878

RESUMO

Picornaviruses are a leading cause of human and veterinary infections that result in various diseases, including polio and the common cold. As archetypical non-enveloped viruses, their biology has been extensively studied. Although a range of different cell-surface receptors are bound by different picornaviruses, it is unclear whether common host factors are needed for them to reach the cytoplasm. Using genome-wide haploid genetic screens, here we identify the lipid-modifying enzyme PLA2G16 (refs 8, 9, 10, 11) as a picornavirus host factor that is required for a previously unknown event in the viral life cycle. We find that PLA2G16 functions early during infection, enabling virion-mediated genome delivery into the cytoplasm, but not in any virion-assigned step, such as cell binding, endosomal trafficking or pore formation. To resolve this paradox, we screened for suppressors of the ΔPLA2G16 phenotype and identified a mechanism previously implicated in the clearance of intracellular bacteria. The sensor of this mechanism, galectin-8 (encoded by LGALS8), detects permeated endosomes and marks them for autophagic degradation, whereas PLA2G16 facilitates viral genome translocation and prevents clearance. This study uncovers two competing processes triggered by virus entry: activation of a pore-activated clearance pathway and recruitment of a phospholipase to enable genome release.


Assuntos
Citoplasma/virologia , Genoma Viral , Fatores Celulares Derivados do Hospedeiro/metabolismo , Fosfolipases A2 Independentes de Cálcio/metabolismo , Picornaviridae/genética , Picornaviridae/fisiologia , Proteínas Supressoras de Tumor/metabolismo , Internalização do Vírus , Animais , Autofagia , Transporte Biológico , Linhagem Celular , Citoplasma/genética , Endossomos/metabolismo , Feminino , Galectinas/genética , Galectinas/metabolismo , Fatores Celulares Derivados do Hospedeiro/deficiência , Fatores Celulares Derivados do Hospedeiro/genética , Humanos , Masculino , Camundongos , Mutação , Fenótipo , Fosfolipases A2 Independentes de Cálcio/deficiência , Fosfolipases A2 Independentes de Cálcio/genética , Supressão Genética , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/genética , Vírion/genética , Vírion/metabolismo , Replicação Viral
3.
Proc Natl Acad Sci U S A ; 115(2): 397-402, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29284752

RESUMO

Acute hemorrhagic conjunctivitis (AHC) is a painful, contagious eye disease, with millions of cases in the last decades. Coxsackievirus A24 (CV-A24) was not originally associated with human disease, but in 1970 a pathogenic "variant" (CV-A24v) emerged, which is now the main cause of AHC. Initially, this variant circulated only in Southeast Asia, but it later spread worldwide, accounting for numerous AHC outbreaks and two pandemics. While both CV-A24 variant and nonvariant strains still circulate in humans, only variant strains cause AHC for reasons that are yet unknown. Since receptors are important determinants of viral tropism, we set out to map the CV-A24 receptor repertoire and establish whether changes in receptor preference have led to the increased pathogenicity and rapid spread of CV-A24v. Here, we identify ICAM-1 as an essential receptor for both AHC-causing and non-AHC strains. We provide a high-resolution cryo-EM structure of a virus-ICAM-1 complex, which revealed critical ICAM-1-binding residues. These data could help identify a possible conserved mode of receptor engagement among ICAM-1-binding enteroviruses and rhinoviruses. Moreover, we identify a single capsid substitution that has been adopted by all pandemic CV-A24v strains and we reveal that this adaptation enhances the capacity of CV-A24v to bind sialic acid. Our data elucidate the CV-A24v receptor repertoire and point to a role of enhanced receptor engagement in the adaptation to the eye, possibly enabling pandemic spread.


Assuntos
Conjuntivite Hemorrágica Aguda/metabolismo , Enterovirus Humano C/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Receptores Virais/metabolismo , Sequência de Aminoácidos , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Conjuntivite Hemorrágica Aguda/epidemiologia , Conjuntivite Hemorrágica Aguda/virologia , Microscopia Crioeletrônica , Surtos de Doenças , Enterovirus Humano C/genética , Enterovirus Humano C/fisiologia , Humanos , Molécula 1 de Adesão Intercelular/química , Mutação , Ácido N-Acetilneuramínico/metabolismo , Pandemias , Filogenia , Ligação Proteica , Receptores Virais/química , Homologia de Sequência de Aminoácidos , Tropismo Viral/fisiologia
4.
Proc Natl Acad Sci U S A ; 113(5): 1399-404, 2016 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-26787879

RESUMO

Enterovirus D68 (EV-D68) is an emerging pathogen that can cause severe respiratory disease and is associated with cases of paralysis, especially among children. Heretofore, information on host factor requirements for EV-D68 infection is scarce. Haploid genetic screening is a powerful tool to reveal factors involved in the entry of pathogens. We performed a genome-wide haploid screen with the EV-D68 prototype Fermon strain to obtain a comprehensive overview of cellular factors supporting EV-D68 infection. We identified and confirmed several genes involved in sialic acid (Sia) biosynthesis, transport, and conjugation to be essential for infection. Moreover, by using knockout cell lines and gene reconstitution, we showed that both α2,6- and α2,3-linked Sia can be used as functional cellular EV-D68 receptors. Importantly, the screen did not reveal a specific protein receptor, suggesting that EV-D68 can use multiple redundant sialylated receptors. Upon testing recent clinical strains, we identified strains that showed a similar Sia dependency, whereas others could infect cells lacking surface Sia, indicating they can use an alternative, nonsialylated receptor. Nevertheless, these Sia-independent strains were still able to bind Sia on human erythrocytes, raising the possibility that these viruses can use multiple receptors. Sequence comparison of Sia-dependent and Sia-independent EV-D68 strains showed that many changes occurred near the canyon that might allow alternative receptor binding. Collectively, our findings provide insights into the identity of the EV-D68 receptor and suggest the possible existence of Sia-independent viruses, which are essential for understanding tropism and disease.


Assuntos
Enterovirus Humano D/metabolismo , Receptores Virais/metabolismo , Animais , Linhagem Celular , Haploidia , Humanos , Receptores Virais/genética
5.
Antimicrob Agents Chemother ; 59(12): 7782-5, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26369972

RESUMO

We investigated the susceptibility of 10 enterovirus D68 (EV-D68) isolates (belonging to clusters A, B, and C) to (entero)virus inhibitors with different mechanisms of action. The 3C-protease inhibitors proved to be more efficient than enviroxime and pleconaril, which in turn were more effective than vapendavir and pirodavir. Favipiravir proved to be a weak inhibitor. Resistance to pleconaril maps to V69A in the VP1 protein, and resistance to rupintrivir maps to V104I in the 3C protease. A structural explanation of why both substitutions may cause resistance is provided.


Assuntos
Antivirais/farmacologia , Enterovirus Humano D/efeitos dos fármacos , Infecções por Enterovirus/virologia , Farmacorresistência Viral , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Oxidiazóis/farmacologia , Oxazóis , Receptores de Droga/química , Receptores de Droga/efeitos dos fármacos , Infecções Respiratórias/virologia , Proteínas Virais/química , Replicação Viral/efeitos dos fármacos
6.
J Virol ; 86(19): 10873-9, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22837213

RESUMO

Chikungunya virus nonstructural protein nsP3 has an essential but unknown role in alphavirus replication and interacts with Ras-GAP SH3 domain-binding protein (G3BP). Here we describe the first known function of nsP3, to inhibit stress granule assembly by recruiting G3BP into cytoplasmic foci. A conserved SH3 domain-binding motif in nsP3 is essential for both nsP3-G3BP interactions and viral RNA replication. This study reveals a novel role for nsP3 as a regulator of the cellular stress response.


Assuntos
Infecções por Alphavirus/virologia , Vírus Chikungunya/genética , Citoplasma/metabolismo , Proteínas não Estruturais Virais/genética , Infecções por Alphavirus/metabolismo , Motivos de Aminoácidos , Animais , Febre de Chikungunya , Chlorocebus aethiops , Sequência Conservada , Deleção de Genes , Modelos Genéticos , Ligação Proteica , Estrutura Terciária de Proteína , RNA Viral/metabolismo , Células Vero , Replicação Viral , Domínios de Homologia de src
7.
Nat Microbiol ; 6(10): 1219-1232, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34471255

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has claimed millions of lives and caused a global economic crisis. No effective antiviral drugs are currently available to treat infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The medical need imposed by the pandemic has spurred unprecedented research efforts to study coronavirus biology. Every virus depends on cellular host factors and pathways for successful replication. These proviral host factors represent attractive targets for antiviral therapy as they are genetically more stable than viral targets and may be shared among related viruses. The application of various 'omics' technologies has led to the rapid discovery of proviral host factors that are required for the completion of the SARS-CoV-2 life cycle. In this Review, we summarize insights into the proviral host factors that are required for SARS-CoV-2 infection that were mainly obtained using functional genetic and interactome screens. We discuss cellular processes that are important for the SARS-CoV-2 life cycle, as well as parallels with non-coronaviruses. Finally, we highlight host factors that could be targeted by clinically approved molecules and molecules in clinical trials as potential antiviral therapies for COVID-19.


Assuntos
COVID-19/metabolismo , SARS-CoV-2/fisiologia , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Peptídeo Hidrolases/metabolismo , RNA Viral/metabolismo , Receptores Virais/metabolismo , SARS-CoV-2/efeitos dos fármacos , Proteínas Virais/metabolismo , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Tratamento Farmacológico da COVID-19
8.
Nat Genet ; 53(4): 435-444, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33686287

RESUMO

The ongoing COVID-19 pandemic has caused a global economic and health crisis. To identify host factors essential for coronavirus infection, we performed genome-wide functional genetic screens with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human coronavirus 229E. These screens uncovered virus-specific as well as shared host factors, including TMEM41B and PI3K type 3. We discovered that SARS-CoV-2 requires the lysosomal protein TMEM106B to infect human cell lines and primary lung cells. TMEM106B overexpression enhanced SARS-CoV-2 infection as well as pseudovirus infection, suggesting a role in viral entry. Furthermore, single-cell RNA-sequencing of airway cells from patients with COVID-19 demonstrated that TMEM106B expression correlates with SARS-CoV-2 infection. The present study uncovered a collection of coronavirus host factors that may be exploited to develop drugs against SARS-CoV-2 infection or future zoonotic coronavirus outbreaks.


Assuntos
COVID-19/genética , Sistemas CRISPR-Cas , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Líquido da Lavagem Broncoalveolar/citologia , COVID-19/epidemiologia , COVID-19/virologia , Linhagem Celular Tumoral , Células Cultivadas , Coronavirus Humano 229E/genética , Epidemias , Células Epiteliais/virologia , Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Provírus/fisiologia , SARS-CoV-2/fisiologia , Internalização do Vírus
9.
mBio ; 10(4)2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409686

RESUMO

Encephalomyocarditis virus (EMCV) is an animal pathogen and an important model organism, whose receptor requirements are poorly understood. Here, we employed a genome-wide haploid genetic screen to identify novel EMCV host factors. In addition to the previously described picornavirus receptors sialic acid and glycosaminoglycans, this screen unveiled important new host factors for EMCV. These factors include components of the fibroblast growth factor (FGF) signaling pathway, such as the potential receptors FGFR1 and ADAM9, a cell-surface metalloproteinase. By employing various knockout cells, we confirmed the importance of the identified host factors for EMCV infection. The largest reduction in infection efficiency was observed in cells lacking ADAM9. Pharmacological inhibition of the metalloproteinase activity of ADAM9 did not affect virus infection. Moreover, reconstitution of inactive ADAM9 in knockout cells restored susceptibility to EMCV, pointing to a proteinase-independent role of ADAM9 in mediating EMCV infection. Using neutralization assays with ADAM9-specific antiserum and soluble receptor proteins, we provided evidence for a role of ADAM9 in EMCV entry. Finally, binding assays showed that ADAM9 facilitates attachment of EMCV to the cell surface. Together, our findings reveal a role for ADAM9 as a novel receptor or cofactor for EMCV.IMPORTANCE EMCV is an animal pathogen that causes acute viral infections, usually myocarditis or encephalitis. It is thought to circulate mainly among rodents, from which it is occasionally transmitted to other animal species, including humans. EMCV causes fatal outbreaks of myocarditis and encephalitis in pig farms and zoos, making it an important veterinary pathogen. Although EMCV has been widely used as a model to study mechanisms of viral disease in mice, little is known about its entry mechanism. Here, we employ a haploid genetic screen for EMCV host factors and identify an essential role for ADAM9 in EMCV entry.


Assuntos
Proteínas ADAM/metabolismo , Infecções por Cardiovirus/virologia , Vírus da Encefalomiocardite/fisiologia , Proteínas de Membrana/metabolismo , Internalização do Vírus , Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/genética , Animais , Infecções por Cardiovirus/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Vírus da Encefalomiocardite/metabolismo , Técnicas de Inativação de Genes , Genoma Humano/genética , Humanos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Camundongos , Ligação Viral , Replicação Viral
10.
Emerg Microbes Infect ; 8(1): 1076-1085, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31339457

RESUMO

Enterovirus A71 (EV-A71) is one of the main causative agents of hand-foot-and-mouth disease and is occasionally associated with severe neurological complications. EV-A71 pathophysiology is poorly understood due to the lack of small animal models that robustly support viral replication in relevant organs/tissues. Here, we show that adult severe combined immune-deficient (SCID) mice can serve as an EV-A71 infection model to study neurotropic determinants and viral tropism. Mice inoculated intraperitoneally with an EV-A71 clinical isolate had an initial infection of the lung compartment, followed by neuroinvasion and infection of (motor)neurons, resulting in slowly progressing paralysis of the limbs. We identified a substitution (V135I) in the capsid protein VP2 as a key requirement for neurotropism. This substitution was also present in a mouse-adapted variant, obtained by passaging the clinical isolate in the brain of one-day-old mice, and induced exclusive neuropathology and rapid paralysis, confirming its role in neurotropism. Finally, we showed that this residue enhances the capacity of EV-A71 to use mouse PSGL1 for viral entry. Our data reveal that EV-A71 initially disseminates to the lung and identify viral and host determinants that define the neurotropic character of EV-A71, pointing to a hitherto understudied role of PSGL1 in EV-A71 tropism and neuropathology.


Assuntos
Proteínas do Capsídeo/genética , Enterovirus Humano A/fisiologia , Infecções por Enterovirus/metabolismo , Glicoproteínas de Membrana/metabolismo , Neurônios/virologia , Animais , Proteínas do Capsídeo/metabolismo , Enterovirus Humano A/genética , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/genética , Infecções por Enterovirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Glicoproteínas de Membrana/genética , Camundongos , Camundongos SCID , Mutação de Sentido Incorreto , Neurônios/metabolismo , Tropismo Viral , Virulência , Internalização do Vírus
11.
Nat Commun ; 10(1): 3171, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320648

RESUMO

Enteroviruses are a major cause of human disease. Adipose-specific phospholipase A2 (PLA2G16) was recently identified as a pan-enterovirus host factor and potential drug target. In this study, we identify a possible mechanism of PLA2G16 evasion by employing a dual glycan receptor-binding enterovirus D68 (EV-D68) strain. We previously showed that this strain does not strictly require the canonical EV-D68 receptor sialic acid. Here, we employ a haploid screen to identify sulfated glycosaminoglycans (sGAGs) as its second glycan receptor. Remarkably, engagement of sGAGs enables this virus to bypass PLA2G16. Using cryo-EM analysis, we reveal that, in contrast to sialic acid, sGAGs stimulate genome release from virions via structural changes that enlarge the putative openings for genome egress. Together, we describe an enterovirus that can bypass PLA2G16 and identify additional virion destabilization as a potential mechanism to circumvent PLA2G16.


Assuntos
Enterovirus Humano D/crescimento & desenvolvimento , Glicosaminoglicanos/metabolismo , Fosfolipases A2 Independentes de Cálcio/metabolismo , Receptores Virais/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Internalização do Vírus , Desenvelopamento do Vírus/fisiologia , Linhagem Celular Tumoral , Microscopia Crioeletrônica , Enterovirus Humano D/genética , Infecções por Enterovirus/patologia , Genoma Viral/genética , Células HEK293 , Células HeLa , Humanos , Ácido N-Acetilneuramínico/metabolismo
12.
Nat Rev Microbiol ; 16(6): 368-381, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29626210

RESUMO

The genus Enterovirus (EV) of the family Picornaviridae includes poliovirus, coxsackieviruses, echoviruses, numbered enteroviruses and rhinoviruses. These diverse viruses cause a variety of diseases, including non-specific febrile illness, hand-foot-and-mouth disease, neonatal sepsis-like disease, encephalitis, paralysis and respiratory diseases. In recent years, several non-polio enteroviruses (NPEVs) have emerged as serious public health concerns. These include EV-A71, which has caused epidemics of hand-foot-and-mouth disease in Southeast Asia, and EV-D68, which recently caused a large outbreak of severe lower respiratory tract disease in North America. Infections with these viruses are associated with severe neurological complications. For decades, most research has focused on poliovirus, but in recent years, our knowledge of NPEVs has increased considerably. In this Review, we summarize recent insights from enterovirus research with a special emphasis on NPEVs. We discuss virion structures, host-receptor interactions, viral uncoating and the recent discovery of a universal enterovirus host factor that is involved in viral genome release. Moreover, we briefly explain the mechanisms of viral genome replication, virion assembly and virion release, and describe potential targets for antiviral therapy. We reflect on how these recent discoveries may help the development of antiviral therapies and vaccines.


Assuntos
Antivirais/farmacologia , Infecções por Enterovirus/prevenção & controle , Infecções por Enterovirus/virologia , Enterovirus/fisiologia , Replicação Viral/fisiologia , Animais , Antivirais/uso terapêutico , Enterovirus/genética , Infecções por Enterovirus/tratamento farmacológico , Infecções por Enterovirus/epidemiologia , Regulação Viral da Expressão Gênica , Saúde Global , Humanos , Replicação Viral/genética
13.
Nat Rev Microbiol ; 16(6): 391, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29725113

RESUMO

In the version of this Review originally published, co-author Hendrik Jan Thibaut's name was incorrectly indexed as "Jan Thibaut, H". It should have appeared as "Thibaut, HJ". This has now been corrected in all versions of the Review. The publisher apologizes to the authors and to readers for this error.

14.
Parasit Vectors ; 8: 464, 2015 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-26384002

RESUMO

BACKGROUND: Chikungunya virus (CHIKV) is an arthritogenic alphavirus (family Togaviridae), transmitted by Aedes species mosquitoes. CHIKV re-emerged in 2004 with multiple outbreaks worldwide and recently reached the Americas where it has infected over a million individuals in a rapidly expanding epidemic. While alphavirus replication is well understood in general, the specific function (s) of non-structural protein nsP3 remain elusive. CHIKV nsP3 modulates the mammalian stress response by preventing stress granule formation through sequestration of G3BP. In mosquitoes, nsP3 is a determinant of vector specificity, but its functional interaction with mosquito proteins is unclear. METHODS: In this research we studied the domains required for localization of CHIKV nsP3 in insect cells and demonstrated its molecular interaction with Rasputin (Rin), the mosquito homologue of G3BP. The biological involvement of Rin in CHIKV infection was investigated in live Ae. albopictus mosquitoes. RESULTS: In insect cells, nsP3 localized as cytoplasmic granules, which was dependent on the central domain and the C-terminal variable region but independent of the N-terminal macrodomain. Ae. albopictus Rin displayed a diffuse, cytoplasmic localization, but was effectively sequestered into nsP3-granules upon nsP3 co-expression. Site-directed mutagenesis showed that the Rin-nsP3 interaction involved the NTF2-like domain of Rin and two conserved TFGD repeats in the C-terminal variable domain of nsP3. Although in vitro silencing of Rin did not impact nsP3 localization or CHIKV replication in cell culture, Rin depletion in vivo significantly decreased the CHIKV infection rate and transmissibility in Ae.albopictus. CONCLUSIONS: We identified the nsP3 hypervariable C-terminal domain as a critical factor for granular localization and sequestration of mosquito Rin. Our study offers novel insight into a conserved virus-mosquito interaction at the molecular level, and reveals a strong proviral role for G3BP homologue Rin in live mosquitoes, making the nsP3-Rin interaction a putative target to interfere with the CHIKV transmission cycle.


Assuntos
Aedes/virologia , Vírus Chikungunya/fisiologia , Interações Hospedeiro-Patógeno , Proteínas de Insetos/metabolismo , Insetos Vetores/virologia , Mapeamento de Interação de Proteínas , Proteínas não Estruturais Virais/metabolismo , América , Animais , Dados de Sequência Molecular , Ligação Proteica , Análise de Sequência de DNA
15.
Nat Commun ; 6: 8865, 2015 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-26563423

RESUMO

Human enterovirus D68 (EV-D68) is a causative agent of childhood respiratory diseases and has now emerged as a global public health threat. Nevertheless, knowledge of the tissue tropism and pathogenesis of EV-D68 has been hindered by a lack of studies on the receptor-mediated EV-D68 entry into host cells. Here we demonstrate that cell surface sialic acid is essential for EV-D68 to bind to and infect susceptible cells. Crystal structures of EV-D68 in complex with sialylated glycan receptor analogues show that they bind into the 'canyon' on the virus surface. The sialic acid receptor induces a cascade of conformational changes in the virus to eject a fatty-acid-like molecule that regulates the stability of the virus. Thus, virus binding to a sialic acid receptor and to immunoglobulin-like receptors used by most other enteroviruses share a conserved mechanism for priming viral uncoating and facilitating cell entry.


Assuntos
Enterovirus Humano D/fisiologia , Infecções por Enterovirus/virologia , Ácido N-Acetilneuramínico/metabolismo , Internalização do Vírus , Enterovirus Humano D/genética , Humanos , Receptores de Superfície Celular/metabolismo , Receptores Virais/metabolismo
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