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1.
Cell ; 187(8): 1936-1954.e24, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38490196

RESUMO

Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage. IFN-I gain of function increased neuronal engulfment by microglia in both mouse and zebrafish and restricted the accumulation of DNA-damaged neurons. Finally, IFN-I deficiency resulted in excess cortical excitatory neurons and tactile hypersensitivity. These data define a role for neuron-engulfing microglia during a critical window of brain development and reveal homeostatic functions of a canonical antiviral signaling pathway in the brain.


Assuntos
Encéfalo , Interferon Tipo I , Microglia , Animais , Camundongos , Interferon Tipo I/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Peixe-Zebra , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento
2.
Cell ; 186(1): 112-130.e20, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36580912

RESUMO

How SARS-CoV-2 penetrates the airway barrier of mucus and periciliary mucins to infect nasal epithelium remains unclear. Using primary nasal epithelial organoid cultures, we found that the virus attaches to motile cilia via the ACE2 receptor. SARS-CoV-2 traverses the mucus layer, using motile cilia as tracks to access the cell body. Depleting cilia blocks infection for SARS-CoV-2 and other respiratory viruses. SARS-CoV-2 progeny attach to airway microvilli 24 h post-infection and trigger formation of apically extended and highly branched microvilli that organize viral egress from the microvilli back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Phosphoproteomics and kinase inhibition reveal that microvillar remodeling is regulated by p21-activated kinases (PAK). Importantly, Omicron variants bind with higher affinity to motile cilia and show accelerated viral entry. Our work suggests that motile cilia, microvilli, and mucociliary-dependent mucus flow are critical for efficient virus replication in nasal epithelia.


Assuntos
COVID-19 , Sistema Respiratório , SARS-CoV-2 , Humanos , Cílios/fisiologia , Cílios/virologia , COVID-19/virologia , Sistema Respiratório/citologia , Sistema Respiratório/virologia , SARS-CoV-2/fisiologia , Microvilosidades/fisiologia , Microvilosidades/virologia , Internalização do Vírus , Células Epiteliais/fisiologia , Células Epiteliais/virologia
3.
Cell ; 184(25): 6037-6051.e14, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34852237

RESUMO

RNA viruses generate defective viral genomes (DVGs) that can interfere with replication of the parental wild-type virus. To examine their therapeutic potential, we created a DVG by deleting the capsid-coding region of poliovirus. Strikingly, intraperitoneal or intranasal administration of this genome, which we termed eTIP1, elicits an antiviral response, inhibits replication, and protects mice from several RNA viruses, including enteroviruses, influenza, and SARS-CoV-2. While eTIP1 replication following intranasal administration is limited to the nasal cavity, its antiviral action extends non-cell-autonomously to the lungs. eTIP1 broad-spectrum antiviral effects are mediated by both local and distal type I interferon responses. Importantly, while a single eTIP1 dose protects animals from SARS-CoV-2 infection, it also stimulates production of SARS-CoV-2 neutralizing antibodies that afford long-lasting protection from SARS-CoV-2 reinfection. Thus, eTIP1 is a safe and effective broad-spectrum antiviral generating short- and long-term protection against SARS-CoV-2 and other respiratory infections in animal models.


Assuntos
Proteínas do Capsídeo/genética , Vírus Defeituosos Interferentes/metabolismo , Replicação Viral/efeitos dos fármacos , Administração Intranasal , Animais , Antivirais/farmacologia , Anticorpos Amplamente Neutralizantes/imunologia , Anticorpos Amplamente Neutralizantes/farmacologia , COVID-19 , Proteínas do Capsídeo/metabolismo , Linhagem Celular , Vírus Defeituosos Interferentes/patogenicidade , Modelos Animais de Doenças , Genoma Viral/genética , Humanos , Influenza Humana , Interferons/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Poliovirus/genética , Poliovirus/metabolismo , Infecções Respiratórias/virologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade
4.
Cell ; 184(13): 3426-3437.e8, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-33991487

RESUMO

We identified an emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant by viral whole-genome sequencing of 2,172 nasal/nasopharyngeal swab samples from 44 counties in California, a state in the western United States. Named B.1.427/B.1.429 to denote its two lineages, the variant emerged in May 2020 and increased from 0% to >50% of sequenced cases from September 2020 to January 2021, showing 18.6%-24% increased transmissibility relative to wild-type circulating strains. The variant carries three mutations in the spike protein, including an L452R substitution. We found 2-fold increased B.1.427/B.1.429 viral shedding in vivo and increased L452R pseudovirus infection of cell cultures and lung organoids, albeit decreased relative to pseudoviruses carrying the N501Y mutation common to variants B.1.1.7, B.1.351, and P.1. Antibody neutralization assays revealed 4.0- to 6.7-fold and 2.0-fold decreases in neutralizing titers from convalescent patients and vaccine recipients, respectively. The increased prevalence of a more transmissible variant in California exhibiting decreased antibody neutralization warrants further investigation.


Assuntos
Anticorpos Neutralizantes/imunologia , COVID-19/imunologia , COVID-19/transmissão , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Humanos , Mutação/genética , Sequenciamento Completo do Genoma/métodos
5.
PLoS Pathog ; 20(2): e1011535, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38335237

RESUMO

A better mechanistic understanding of virus-host dependencies can help reveal vulnerabilities and identify opportunities for therapeutic intervention. Of particular interest are essential interactions that enable production of viral proteins, as those could target an early step in the virus lifecycle. Here, we use subcellular proteomics, ribosome profiling analyses and reporter assays to detect changes in protein synthesis dynamics during SARS-CoV-2 (CoV2) infection. We identify specific translation factors and molecular chaperones that are used by CoV2 to promote the synthesis and maturation of its own proteins. These can be targeted to inhibit infection, without major toxicity to the host. We also find that CoV2 non-structural protein 1 (Nsp1) cooperates with initiation factors EIF1 and 1A to selectively enhance translation of viral RNA. When EIF1/1A are depleted, more ribosomes initiate translation from a conserved upstream CUG start codon found in all genomic and subgenomic viral RNAs. This results in higher translation of an upstream open reading frame (uORF1) and lower translation of the main ORF, altering the stoichiometry of viral proteins and attenuating infection. Replacing the upstream CUG with AUG strongly inhibits translation of the main ORF independently of Nsp1, EIF1, or EIF1A. Taken together, our work describes multiple dependencies of CoV2 on host biosynthetic networks and proposes a model for dosage control of viral proteins through Nsp1-mediated control of translation start site selection.


Assuntos
COVID-19 , RNA Viral , Humanos , RNA Viral/genética , SARS-CoV-2/genética , COVID-19/genética , Fatores de Iniciação de Peptídeos , Proteínas Virais
6.
PLoS Pathog ; 17(9): e1009898, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34478458

RESUMO

The respiratory disease COVID-19 is caused by the coronavirus SARS-CoV-2. Here we report the discovery of ethacridine as a potent drug against SARS-CoV-2 (EC50 ~ 0.08 µM). Ethacridine was identified via high-throughput screening of an FDA-approved drug library in living cells using a fluorescence assay. Plaque assays, RT-PCR and immunofluorescence imaging at various stages of viral infection demonstrate that the main mode of action of ethacridine is through inactivation of viral particles, preventing their binding to the host cells. Consistently, ethacridine is effective in various cell types, including primary human nasal epithelial cells that are cultured in an air-liquid interface. Taken together, our work identifies a promising, potent, and new use of the old drug via a distinct mode of action for inhibiting SARS-CoV-2.


Assuntos
Antivirais/farmacologia , Etacridina/farmacologia , Inibidores de Proteases/farmacologia , Ativação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Chlorocebus aethiops , Proteases 3C de Coronavírus/antagonistas & inibidores , Genes Reporter , Proteínas de Fluorescência Verde/genética , Humanos , Células Vero , Vírion/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
7.
Proc Natl Acad Sci U S A ; 117(30): 17937-17948, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32651271

RESUMO

Species-specific limits to lifespan (lifespan setpoint) determine the life expectancy of any given organism. Whether limiting lifespan provides an evolutionary benefit or is the result of an inevitable decline in fitness remains controversial. The identification of mutations extending lifespan suggests that aging is under genetic control, but the evolutionary driving forces limiting lifespan have not been defined. By examining the impact of lifespan on pathogen spread in a population, we propose that epidemics drive lifespan setpoints' evolution. Shorter lifespan limits infection spread and accelerates pathogen clearance when compared to populations with longer-lived individuals. Limiting longevity is particularly beneficial in the context of zoonotic transmissions, where pathogens must undergo adaptation to a new host. Strikingly, in populations exposed to pathogens, shorter-living variants outcompete individuals with longer lifespans. We submit that infection outbreaks can contribute to control the evolution of species' lifespan setpoints.


Assuntos
Adaptação Psicológica , Evolução Biológica , Expectativa de Vida , Longevidade , Modelos Teóricos , Envelhecimento , Algoritmos , Animais , Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/etiologia , Doenças Transmissíveis/mortalidade , Doenças Transmissíveis/transmissão , Aptidão Genética , Interações Hospedeiro-Patógeno , Zoonoses
8.
Biochemistry (Mosc) ; 87(12): 1413-1445, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36717438

RESUMO

Aging is an evolutionary paradox. Several hypotheses have been proposed to explain it, but none fully explains all the biochemical and ecologic data accumulated over decades of research. We suggest that senescence is a primitive immune strategy which acts to protect an individual's kin from chronic infections. Older organisms are exposed to pathogens for a longer period of time and have a higher likelihood of acquiring infectious diseases. Accordingly, the parasitic load in aged individuals is higher than in younger ones. Given that the probability of pathogen transmission is higher within the kin, the inclusive fitness cost of infection might exceed the benefit of living longer. In this case, programmed lifespan termination might be an evolutionarily stable strategy. Here, we discuss the classical evolutionary hypotheses of aging and compare them with the pathogen control hypothesis, discuss the consistency of these hypotheses with existing empirical data, and present a revised conceptual framework to understand the evolution of aging.


Assuntos
Envelhecimento , Evolução Biológica , Humanos , Idoso , Longevidade , Adaptação Fisiológica
9.
Development ; 145(4)2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29437781

RESUMO

Oxygen concentrations vary between tissues of multicellular organisms and change under certain physiological or pathological conditions. Multiple methods have been developed for measuring oxygenation of biological samples in vitro and in vivo However, most require complex equipment, are laborious and have significant limitations. Here we report that oxygen concentration determines the choice between two maturation pathways of DsRed FT (Timer). At high oxygen levels, this DsRed derivate matures predominantly into a red fluorescent isoform. By contrast, a green fluorescent isoform is favored by low oxygen levels. Ratiometric analysis of green and red fluorescence after a pulse of Timer expression in Drosophila larvae provides a record of the history of tissue oxygenation during a subsequent chase period, for the whole animal with single-cell precision. Tissue spreads revealed fine differences in oxygen exposure among different cells of the same organ. We expect that the simplicity and robustness of our approach will greatly impact hypoxia research, especially in small animal models.


Assuntos
Drosophila melanogaster/metabolismo , Corantes Fluorescentes/química , Proteínas Luminescentes/química , Proteínas Luminescentes/genética , Oxigênio/análise , Animais , Animais Geneticamente Modificados , Drosophila melanogaster/genética , Microscopia de Fluorescência/métodos , Isoformas de Proteínas/genética
10.
Biophys J ; 109(2): 380-9, 2015 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-26200874

RESUMO

Spectral diversity of fluorescent proteins, crucial for multiparameter imaging, is based mainly on chemical diversity of their chromophores. Recently we have reported, to our knowledge, a new green fluorescent protein WasCFP-the first fluorescent protein with a tryptophan-based chromophore in the anionic state. However, only a small portion of WasCFP molecules exists in the anionic state at physiological conditions. In this study we report on an improved variant of WasCFP, named NowGFP, with the anionic form dominating at 37°C and neutral pH. It is 30% brighter than enhanced green fluorescent protein (EGFP) and exhibits a fluorescence lifetime of 5.1 ns. We demonstrated that signals of NowGFP and EGFP can be clearly distinguished by fluorescence lifetime in various models, including mammalian cells, mouse tumor xenograft, and Drosophila larvae. NowGFP thus provides an additional channel for multiparameter fluorescence lifetime imaging microscopy of green fluorescent proteins.


Assuntos
Proteínas de Fluorescência Verde/química , Animais , Animais Geneticamente Modificados , Ânions/química , Drosophila , Escherichia coli , Fluorescência , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Microscopia Confocal , Mutação , Processos Fotoquímicos , Temperatura , Triptofano/química , Triptofano/metabolismo
11.
J Cell Sci ; 126(Pt 20): 4782-93, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23943877

RESUMO

Centromeres are specified epigenetically in animal cells. Therefore, faithful chromosome inheritance requires accurate maintenance of epigenetic centromere marks during progression through the cell cycle. Clarification of the mechanisms that control centromere protein behavior during the cell cycle should profit from the relatively simple protein composition of Drosophila centromeres. Thus we have analyzed the dynamics of the three key players Cid/Cenp-A, Cenp-C and Cal1 in S2R+ cells using quantitative microscopy and fluorescence recovery after photobleaching, in combination with novel fluorescent cell cycle markers. As revealed by the observed protein abundances and mobilities, centromeres proceed through at least five distinct states during the cell cycle, distinguished in part by unexpected Cid behavior. In addition to the predominant Cid loading onto centromeres during G1, a considerable but transient increase was detected during early mitosis. A low level of Cid loading was detected in late S and G2, starting at the reported time of centromere DNA replication. Our results reveal the complexities of Drosophila centromere protein dynamics and its intricate coordination with cell cycle progression.


Assuntos
Centrômero/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/citologia , Drosophila/metabolismo , Animais , Técnicas de Cultura de Células , Ciclo Celular/fisiologia , Divisão Celular/fisiologia , Proteínas de Ligação a DNA/genética , Drosophila/genética , Proteínas de Drosophila/genética , Plasmídeos
12.
bioRxiv ; 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37873388

RESUMO

To evaluate the properties of insect virus internal ribosomal entry sites (IRESs) for protein expression in Drosophila, we have introduced Cricket Paralysis virus (CrPV) and Drosophila C virus (DCV) IRESs into UAS/SV40-polyA vector. We found that introduction of IRESs induce premature polyadenylation, resulting in both truncation of the mRNA, and an increase in mRNA levels of approximately 40-fold. The increase in mRNA levels was accompanied by increased resistance to nonsense-mediated mRNA decay (NMD)-mediated degradation. Our results suggest that premature polyadenylation increases mRNA stability in the SV40 polyadenylation site-containing constructs, suggesting a novel method for robust overexpression of transgenes in Drosophila.

13.
bioRxiv ; 2023 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-37502856

RESUMO

Cells exhibit stress responses to various environmental changes. Among these responses, the integrated stress response (ISR) plays a pivotal role as a crucial stress signaling pathway. While extensive ISR research has been conducted on cultured cells, our understanding of its implications in multicellular organisms remains limited, largely due to the constraints of current techniques that hinder our ability to track and manipulate the ISR in vivo. To overcome these limitations, we have successfully developed an internal ribosome entry site (IRES)-based fluorescent reporter system. This innovative reporter enables us to label Drosophila cells, within the context of a living organism, that exhibit eIF2 phosphorylation-dependent translational shutoff - a characteristic feature of the ISR and viral infections. Through this methodology, we have unveiled tissue- and cell-specific regulation of stress response in Drosophila flies and have even been able to detect stressed tissues in vivo during virus and bacterial infections. To further validate the specificity of our reporter, we have engineered ISR-null eIF2αS50A mutant flies for stress response analysis. Our results shed light on the tremendous potential of this technique for investigating a broad range of developmental, stress, and infection-related experimental conditions. Combining the reporter tool with ISR-null mutants establishes Drosophila as an exceptionally powerful model for studying the ISR in the context of multicellular organisms.

14.
bioRxiv ; 2023 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-37461541

RESUMO

A better mechanistic understanding of virus-host interactions can help reveal vulnerabilities and identify opportunities for therapeutic interventions. Of particular interest are essential interactions that enable production of viral proteins, as those could target an early step in the virus lifecycle. Here, we use subcellular proteomics, ribosome profiling analyses and reporter assays to detect changes in polysome composition and protein synthesis during SARS-CoV-2 (CoV2) infection. We identify specific translation factors and molecular chaperones whose inhibition impairs infectious particle production without major toxicity to the host. We find that CoV2 non-structural protein Nsp1 selectively enhances virus translation through functional interactions with initiation factor EIF1A. When EIF1A is depleted, more ribosomes initiate translation from an upstream CUG start codon, inhibiting translation of non-structural genes and reducing viral titers. Together, our work describes multiple dependencies of CoV2 on host biosynthetic networks and identifies druggable targets for potential antiviral development.

15.
bioRxiv ; 2023 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-35233577

RESUMO

Microglia are brain resident phagocytes that can engulf synaptic components and extracellular matrix as well as whole neurons. However, whether there are unique molecular mechanisms that regulate these distinct phagocytic states is unknown. Here we define a molecularly distinct microglial subset whose function is to engulf neurons in the developing brain. We transcriptomically identified a cluster of Type I interferon (IFN-I) responsive microglia that expanded 20-fold in the postnatal day 5 somatosensory cortex after partial whisker deprivation, a stressor that accelerates neural circuit remodeling. In situ, IFN-I responsive microglia were highly phagocytic and actively engulfed whole neurons. Conditional deletion of IFN-I signaling (Ifnar1fl/fl) in microglia but not neurons resulted in dysmorphic microglia with stalled phagocytosis and an accumulation of neurons with double strand DNA breaks, a marker of cell stress. Conversely, exogenous IFN-I was sufficient to drive neuronal engulfment by microglia and restrict the accumulation of damaged neurons. IFN-I deficient mice had excess excitatory neurons in the developing somatosensory cortex as well as tactile hypersensitivity to whisker stimulation. These data define a molecular mechanism through which microglia engulf neurons during a critical window of brain development. More broadly, they reveal key homeostatic roles of a canonical antiviral signaling pathway in brain development.

16.
Nat Microbiol ; 8(1): 121-134, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36604514

RESUMO

The coronavirus SARS-CoV-2 causes the severe disease COVID-19. SARS-CoV-2 infection is initiated by interaction of the viral spike protein and host receptor angiotensin-converting enzyme 2 (ACE2). We report an improved bright and reversible fluorogenic reporter, named SURF (split UnaG-based reversible and fluorogenic protein-protein interaction reporter), that we apply to monitor real-time interactions between spike and ACE2 in living cells. SURF has a large dynamic range with a dark-to-bright fluorescence signal that requires no exogenous cofactors. Utilizing this reporter, we carried out a high-throughput screening of small-molecule libraries. We identified three natural compounds that block replication of SARS-CoV-2 in both Vero cells and human primary nasal and bronchial epithelial cells. Cell biological and biochemical experiments validated all three compounds and showed that they block the early stages of viral infection. Two of the inhibitors, bruceine A and gamabufotalin, were also found to block replication of the Delta and Omicron variants of SARS-CoV-2. Both bruceine A and gamabufotalin exhibited potent antiviral activity in K18-hACE2 and wild-type C57BL6/J mice, as evidenced by reduced viral titres in the lung and brain, and protection from alveolar and peribronchial inflammation in the lung, thereby limiting disease progression. We propose that our fluorescent assay can be applied to identify antiviral compounds with potential as therapeutic treatment for COVID-19 and other respiratory diseases.


Assuntos
COVID-19 , SARS-CoV-2 , Chlorocebus aethiops , Camundongos , Humanos , Animais , SARS-CoV-2/metabolismo , Células Vero , Enzima de Conversão de Angiotensina 2 , Peptidil Dipeptidase A/metabolismo , Antivirais/farmacologia
17.
Trends Ecol Evol ; 37(12): 1046-1057, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36096982

RESUMO

Aging is often attributed to the detrimental side effects of beneficial traits but not a programmed adaptive process. Alternatively, the pathogen control hypothesis posits that defense against infectious diseases may provide a strong selection force for restriction of lifespan. Aging might have evolved to remove older individuals who carry chronic diseases that may transmit to their younger kin. Thus, selection for shorter lifespans may benefit kin's fitness. The pathogen control hypothesis addresses arguments typically raised against adaptive aging concepts: it explains the benefit of shorter lifespan and the absence of mutant variants that do not age. We discuss the consistency and explanatory power of this hypothesis and compare it with classic hypotheses of aging.


Assuntos
Evolução Biológica , Doenças Transmissíveis , Humanos , Envelhecimento , Longevidade
18.
Cell Metab ; 33(8): 1565-1576.e5, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34081912

RESUMO

Emerging evidence points toward an intricate relationship between the pandemic of coronavirus disease 2019 (COVID-19) and diabetes. While preexisting diabetes is associated with severe COVID-19, it is unclear whether COVID-19 severity is a cause or consequence of diabetes. To mechanistically link COVID-19 to diabetes, we tested whether insulin-producing pancreatic ß cells can be infected by SARS-CoV-2 and cause ß cell depletion. We found that the SARS-CoV-2 receptor, ACE2, and related entry factors (TMPRSS2, NRP1, and TRFC) are expressed in ß cells, with selectively high expression of NRP1. We discovered that SARS-CoV-2 infects human pancreatic ß cells in patients who succumbed to COVID-19 and selectively infects human islet ß cells in vitro. We demonstrated that SARS-CoV-2 infection attenuates pancreatic insulin levels and secretion and induces ß cell apoptosis, each rescued by NRP1 inhibition. Phosphoproteomic pathway analysis of infected islets indicates apoptotic ß cell signaling, similar to that observed in type 1 diabetes (T1D). In summary, our study shows SARS-CoV-2 can directly induce ß cell killing.


Assuntos
COVID-19/virologia , Diabetes Mellitus/virologia , Células Secretoras de Insulina/virologia , Neuropilina-1/metabolismo , Receptores Virais/metabolismo , SARS-CoV-2/patogenicidade , Internalização do Vírus , Células A549 , Adulto , Idoso , Idoso de 80 Anos ou mais , Enzima de Conversão de Angiotensina 2/metabolismo , Antígenos CD/metabolismo , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , COVID-19/complicações , COVID-19/diagnóstico , Estudos de Casos e Controles , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/metabolismo , Feminino , Interações Hospedeiro-Patógeno , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores da Transferrina/metabolismo , SARS-CoV-2/metabolismo , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo
19.
medRxiv ; 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33758899

RESUMO

We identified a novel SARS-CoV-2 variant by viral whole-genome sequencing of 2,172 nasal/nasopharyngeal swab samples from 44 counties in California. Named B.1.427/B.1.429 to denote its 2 lineages, the variant emerged around May 2020 and increased from 0% to >50% of sequenced cases from September 1, 2020 to January 29, 2021, exhibiting an 18.6-24% increase in transmissibility relative to wild-type circulating strains. The variant carries 3 mutations in the spike protein, including an L452R substitution. Our analyses revealed 2-fold increased B.1.427/B.1.429 viral shedding in vivo and increased L452R pseudovirus infection of cell cultures and lung organoids, albeit decreased relative to pseudoviruses carrying the N501Y mutation found in the B.1.1.7, B.1.351, and P.1 variants. Antibody neutralization assays showed 4.0 to 6.7-fold and 2.0-fold decreases in neutralizing titers from convalescent patients and vaccine recipients, respectively. The increased prevalence of a more transmissible variant in California associated with decreased antibody neutralization warrants further investigation.

20.
Cell Rep Med ; 2(10): 100421, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34604819

RESUMO

Understanding viral tropism is an essential step toward reducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, decreasing mortality from coronavirus disease 2019 (COVID-19) and limiting opportunities for mutant strains to arise. Currently, little is known about the extent to which distinct tissue sites in the human head and neck region and proximal respiratory tract selectively permit SARS-CoV-2 infection and replication. In this translational study, we discover key variabilities in expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), essential SARS-CoV-2 entry factors, among the mucosal tissues of the human proximal airways. We show that SARS-CoV-2 infection is present in all examined head and neck tissues, with a notable tropism for the nasal cavity and tracheal mucosa. Finally, we uncover an association between smoking and higher SARS-CoV-2 viral infection in the human proximal airway, which may explain the increased susceptibility of smokers to developing severe COVID-19. This is at least partially explained by differences in interferon (IFN)-ß1 levels between smokers and non-smokers.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , COVID-19/transmissão , Mucosa Respiratória/metabolismo , Serina Endopeptidases/genética , Fumantes , Tropismo Viral , Idoso , Idoso de 80 Anos ou mais , COVID-19/genética , COVID-19/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Cavidade Nasal/metabolismo , SARS-CoV-2/fisiologia , Traqueia/metabolismo
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