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2.
J Clin Invest ; 131(13)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196300

RESUMO

BACKGROUNDSARS-CoV-2 plasma viremia has been associated with severe disease and death in COVID-19 in small-scale cohort studies. The mechanisms behind this association remain elusive.METHODSWe evaluated the relationship between SARS-CoV-2 viremia, disease outcome, and inflammatory and proteomic profiles in a cohort of COVID-19 emergency department participants. SARS-CoV-2 viral load was measured using a quantitative reverse transcription PCR-based platform. Proteomic data were generated with Proximity Extension Assay using the Olink platform.RESULTSThis study included 300 participants with nucleic acid test-confirmed COVID-19. Plasma SARS-CoV-2 viremia levels at the time of presentation predicted adverse disease outcomes, with an adjusted OR of 10.6 (95% CI 4.4-25.5, P < 0.001) for severe disease (mechanical ventilation and/or 28-day mortality) and 3.9 (95% CI 1.5-10.1, P = 0.006) for 28-day mortality. Proteomic analyses revealed prominent proteomic pathways associated with SARS-CoV-2 viremia, including upregulation of SARS-CoV-2 entry factors (ACE2, CTSL, FURIN), heightened markers of tissue damage to the lungs, gastrointestinal tract, and endothelium/vasculature, and alterations in coagulation pathways.CONCLUSIONThese results highlight the cascade of vascular and tissue damage associated with SARS-CoV-2 plasma viremia that underlies its ability to predict COVID-19 disease outcomes.FUNDINGMark and Lisa Schwartz; the National Institutes of Health (U19AI082630); the American Lung Association; the Executive Committee on Research at Massachusetts General Hospital; the Chan Zuckerberg Initiative; Arthur, Sandra, and Sarah Irving for the David P. Ryan, MD, Endowed Chair in Cancer Research; an EMBO Long-Term Fellowship (ALTF 486-2018); a Cancer Research Institute/Bristol Myers Squibb Fellowship (CRI2993); the Harvard Catalyst/Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH awards UL1TR001102 and UL1TR002541-01); and by the Harvard University Center for AIDS Research (National Institute of Allergy and Infectious Diseases, 5P30AI060354).


Assuntos
COVID-19/sangue , COVID-19/virologia , SARS-CoV-2 , Viremia/sangue , Viremia/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Coortes , Feminino , Interações entre Hospedeiro e Microrganismos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Pandemias , Prognóstico , Proteoma/metabolismo , Proteômica , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Internalização do Vírus
3.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200325

RESUMO

The SARS-CoV-2 infection determines the COVID-19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokine release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. Among survivors, the presence of the so-called persistent post-COVID-19 syndrome (PPCS) is a common finding. In COVID-19 survivors, PPCS presents one or more symptoms: fatigue, dyspnea, memory loss, sleep disorders, and difficulty concentrating. In this study, a cohort of 117 COVID-19 survivors (post-COVID-19) and 144 non-infected volunteers (COVID-19-free) was analyzed using pyrosequencing of defined CpG islands previously identified as suitable for biological age determination. The results show a consistent biological age increase in the post-COVID-19 population, determining a DeltaAge acceleration of 10.45 ± 7.29 years (+5.25 years above the range of normality) compared with 3.68 ± 8.17 years for the COVID-19-free population (p < 0.0001). A significant telomere shortening parallels this finding in the post-COVID-19 cohort compared with COVID-19-free subjects (p < 0.0001). Additionally, ACE2 expression was decreased in post-COVID-19 patients, compared with the COVID-19-free population, while DPP-4 did not change. In light of these observations, we hypothesize that some epigenetic alterations are associated with the post-COVID-19 condition, particularly in younger patients (< 60 years).


Assuntos
Envelhecimento/genética , COVID-19/genética , COVID-19/fisiopatologia , Ilhas de CpG , Encurtamento do Telômero , Telômero/metabolismo , Adulto , Idoso , Enzima de Conversão de Angiotensina 2/sangue , Biomarcadores , COVID-19/complicações , COVID-19/etiologia , Metilação de DNA , Dipeptidil Peptidase 4/sangue , Epigenômica , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Interações entre Hospedeiro e Microrganismos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sobreviventes
4.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201415

RESUMO

The SARS-CoV-2 virus utilizes angiotensin converting enzyme (ACE-2) for cell entry and infection. This enzyme has important functions in the renin-angiotensin aldosterone system to preserve cardiovascular function. In addition to the heart, it is expressed in many tissues including the lung, intestines, brain, and kidney, however, its functions in these organs are mostly unknown. ACE-2 has membrane-bound and soluble forms. Its expression levels are altered in disease states and by a variety of medications. Currently, it is not clear how altered ACE-2 levels influence ACE-2 virulence and relevant complications. In addition, membrane-bound and soluble forms are thought to have different effects. Most work on this topic in the literature is on the SARS-CoV virus that has a high genetic resemblance to SARS-Co-V-2 and also uses ACE-2 enzyme to enter the cell, but with much lower affinity. More recent studies on SARS-CoV-2 are mainly clinical studies aiming at relating the effect of medications that are thought to influence ACE-2 levels, with COVID-19 outcomes for patients under these medications. This review paper aims to summarize what is known about the relationship between ACE-2 levels and SARS-CoV/SARS-CoV-2 virulence under altered ACE-2 expression states.


Assuntos
Enzima de Conversão de Angiotensina 2/fisiologia , COVID-19/fisiopatologia , COVID-19/virologia , SARS-CoV-2/patogenicidade , Enzima de Conversão de Angiotensina 2/química , Inibidores da Enzima Conversora de Angiotensina , Interações entre Hospedeiro e Microrganismos , Humanos , Pulmão/metabolismo , Virulência
5.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201797

RESUMO

The coronavirus disease 2019 (COVID-19) caused by infection of the severe respiratory syndrome coronavirus-2 (SARS-CoV-2) significantly impacted human society. Recently, the synthetic pure glucocorticoid dexamethasone was identified as an effective compound for treatment of severe COVID-19. However, glucocorticoids are generally harmful for infectious diseases, such as bacterial sepsis and severe influenza pneumonia, which can develop respiratory failure and systemic inflammation similar to COVID-19. This apparent inconsistency suggests the presence of pathologic mechanism(s) unique to COVID-19 that renders this steroid effective. We review plausible mechanisms and advance the hypothesis that SARS-CoV-2 infection is accompanied by infected cell-specific glucocorticoid insensitivity as reported for some other viruses. This alteration in local glucocorticoid actions interferes with undesired glucocorticoid to facilitate viral replication but does not affect desired anti-inflammatory properties in non-infected organs/tissues. We postulate that the virus coincidentally causes glucocorticoid insensitivity in the process of modulating host cell activities for promoting its replication in infected cells. We explore this tenet focusing on SARS-CoV-2-encoding proteins and potential molecular mechanisms supporting this hypothetical glucocorticoid insensitivity unique to COVID-19 but not characteristic of other life-threatening viral diseases, probably due to a difference in specific virally-encoded molecules and host cell activities modulated by them.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Dexametasona/farmacologia , Sistema Hipotálamo-Hipofisário/fisiologia , Inflamação/tratamento farmacológico , Interações entre Hospedeiro e Microrganismos , Humanos , Imunidade Inata , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Replicação Viral/efeitos dos fármacos
7.
Sci Signal ; 14(690)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230209

RESUMO

Inorganic polyphosphates (polyPs) are linear polymers composed of repeated phosphate (PO4 3-) units linked together by multiple high-energy phosphoanhydride bonds. In addition to being a source of energy, polyPs have cytoprotective and antiviral activities. Here, we investigated the antiviral activities of long-chain polyPs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In molecular docking analyses, polyPs interacted with several conserved amino acid residues in angiotensin-converting enzyme 2 (ACE2), the host receptor that facilitates virus entry, and in viral RNA-dependent RNA polymerase (RdRp). ELISA and limited proteolysis assays using nano- LC-MS/MS mapped polyP120 binding to ACE2, and site-directed mutagenesis confirmed interactions between ACE2 and SARS-CoV-2 RdRp and identified the specific amino acid residues involved. PolyP120 enhanced the proteasomal degradation of both ACE2 and RdRp, thus impairing replication of the British B.1.1.7 SARS-CoV-2 variant. We thus tested polyPs for functional interactions with the virus in SARS-CoV-2-infected Vero E6 and Caco2 cells and in primary human nasal epithelial cells. Delivery of a nebulized form of polyP120 reduced the amounts of viral positive-sense genomic and subgenomic RNAs, of RNA transcripts encoding proinflammatory cytokines, and of viral structural proteins, thereby presenting SARS-CoV-2 infection in cells in vitro.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Polifosfatos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Administração por Inalação , Sequência de Aminoácidos , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antivirais/administração & dosagem , Antivirais/química , COVID-19/metabolismo , COVID-19/virologia , Células CACO-2 , Chlorocebus aethiops , RNA-Polimerase RNA-Dependente de Coronavírus/química , RNA-Polimerase RNA-Dependente de Coronavírus/genética , RNA-Polimerase RNA-Dependente de Coronavírus/metabolismo , Citocinas/metabolismo , Células HEK293 , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Técnicas In Vitro , Modelos Biológicos , Simulação de Acoplamento Molecular , Nebulizadores e Vaporizadores , Polifosfatos/administração & dosagem , Polifosfatos/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Domínios e Motivos de Interação entre Proteínas , Proteólise/efeitos dos fármacos , RNA Viral/genética , RNA Viral/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Homologia de Sequência de Aminoácidos , Transdução de Sinais/efeitos dos fármacos , Células Vero , Replicação Viral/efeitos dos fármacos
8.
Nat Commun ; 12(1): 3691, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140527

RESUMO

The HIV-1 accessory proteins Vif, Vpu, and Nef can promote infection by overcoming the inhibitory effects of the host cell restriction factors APOBEC3G, Tetherin, and SERINC5, respectively. However, how the HIV-1 accessory protein Vpr enhances infection in macrophages but not in CD4+ T cells remains elusive. Here, we report that Vpr counteracts lysosomal-associated transmembrane protein 5 (LAPTM5), a potent inhibitor of HIV-1 particle infectivity, to enhance HIV-1 infection in macrophages. LAPTM5 transports HIV-1 envelope glycoproteins to lysosomes for degradation, thereby inhibiting virion infectivity. Vpr counteracts the restrictive effects of LAPTM5 by triggering its degradation via DCAF1. In the absence of Vpr, the silencing of LAPTM5 precisely phenocopied the effect of Vpr on HIV-1 infection. In contrast, Vpr did not enhance HIV-1 infection in the absence of LAPTM5. Moreover, LAPTM5 was highly expressed in macrophages but not in CD4+ T lymphocytes. Re-expressing LAPTM5 reconstituted the Vpr-dependent promotion of HIV-1 infection in primary CD4+ T cells, as observed in macrophages. Herein, we demonstrate the molecular mechanism used by Vpr to overcome LAPTM5 restriction in macrophages, providing a potential strategy for anti-HIV/AIDS therapeutics.


Assuntos
Infecções por HIV/metabolismo , HIV-1/metabolismo , Interações entre Hospedeiro e Microrganismos , Macrófagos/metabolismo , Macrófagos/virologia , Proteínas de Membrana/metabolismo , Produtos do Gene vpr do Vírus da Imunodeficiência Humana/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Inativação Gênica , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , HIV-1/patogenicidade , HIV-2/metabolismo , HIV-2/patogenicidade , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Lisossomos/metabolismo , Proteínas de Membrana/genética , Estabilidade Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Vírus da Imunodeficiência Símia/metabolismo , Vírus da Imunodeficiência Símia/patogenicidade , Ubiquitina-Proteína Ligases/metabolismo , Regulação para Cima , Vírion/metabolismo
10.
Cells ; 10(6)2021 05 23.
Artigo em Inglês | MEDLINE | ID: covidwho-1243956

RESUMO

The recent SARS-CoV-2 pandemic has refocused attention to the betacoronaviruses, only eight years after the emergence of another zoonotic betacoronavirus, the Middle East respiratory syndrome coronavirus (MERS-CoV). While the wild source of SARS-CoV-2 may be disputed, for MERS-CoV, dromedaries are considered as source of zoonotic human infections. Testing 100 immune-response genes in 121 dromedaries from United Arab Emirates (UAE) for potential association with present MERS-CoV infection, we identified candidate genes with important functions in the adaptive, MHC-class I (HLA-A-24-like) and II (HLA-DPB1-like), and innate immune response (PTPN4, MAGOHB), and in cilia coating the respiratory tract (DNAH7). Some of these genes previously have been associated with viral replication in SARS-CoV-1/-2 in humans, others have an important role in the movement of bronchial cilia. These results suggest similar host genetic pathways associated with these betacoronaviruses, although further work is required to better understand the MERS-CoV disease dynamics in both dromedaries and humans.


Assuntos
Imunidade Adaptativa/genética , Camelus/virologia , Doenças Transmissíveis Emergentes/imunologia , Infecções por Coronavirus/imunologia , Imunidade Inata/genética , Zoonoses/imunologia , Animais , Anticorpos Antivirais , Brônquios/citologia , Brônquios/fisiologia , COVID-19/genética , COVID-19/imunologia , COVID-19/virologia , Camelus/genética , Camelus/imunologia , Cílios/fisiologia , Doenças Transmissíveis Emergentes/genética , Doenças Transmissíveis Emergentes/transmissão , Doenças Transmissíveis Emergentes/virologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Reservatórios de Doenças/virologia , Feminino , Predisposição Genética para Doença , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Masculino , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Mucosa Respiratória/citologia , Mucosa Respiratória/fisiologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Emirados Árabes Unidos , Replicação Viral/genética , Replicação Viral/imunologia , Zoonoses/genética , Zoonoses/transmissão , Zoonoses/virologia
11.
Viruses ; 13(5)2021 05 17.
Artigo em Inglês | MEDLINE | ID: covidwho-1234830

RESUMO

COVID-19 is a highly infectious respiratory disease caused by the novel coronavirus SARS-CoV-2. It has become a global pandemic and its frequent mutations may pose new challenges for vaccine design. During viral infection, the Spike RBD of SARS-CoV-2 binds the human host cell receptor ACE2, enabling the virus to enter the host cell. Both the Spike and ACE2 are densely glycosylated, and it is unclear how distinctive glycan types may modulate the interaction of RBD and ACE2. Detailed understanding of these determinants is key for the development of novel therapeutic strategies. To this end, we perform extensive all-atom simulations of the (i) RBD-ACE2 complex without glycans, (ii) RBD-ACE2 with oligomannose MAN9 glycans in ACE2, and (iii) RBD-ACE2 with complex FA2 glycans in ACE2. These simulations identify the key residues at the RBD-ACE2 interface that form contacts with higher probabilities, thus providing a quantitative evaluation that complements recent structural studies. Notably, we find that this RBD-ACE2 contact signature is not altered by the presence of different glycoforms, suggesting that RBD-ACE2 interaction is robust. Applying our simulated results, we illustrate how the recently prevalent N501Y mutation may alter specific interactions with host ACE2 that facilitate the virus-host binding. Furthermore, our simulations reveal how the glycan on Asn90 of ACE2 can play a distinct role in the binding and unbinding of RBD. Finally, an energetics analysis shows that MAN9 glycans on ACE2 decrease RBD-ACE2 affinity, while FA2 glycans lead to enhanced binding of the complex. Together, our results provide a more comprehensive picture of the detailed interplay between virus and human receptor, which is much needed for the discovery of effective treatments that aim at modulating the physical-chemical properties of this virus.


Assuntos
Enzima de Conversão de Angiotensina 2/química , COVID-19/virologia , Polissacarídeos/química , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/química , Sequência de Aminoácidos , Sítios de Ligação , Glicosilação , Interações entre Hospedeiro e Microrganismos , Humanos , Simulação de Dinâmica Molecular , Mutação , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Ligação Viral
12.
Viruses ; 13(5)2021 05 04.
Artigo em Inglês | MEDLINE | ID: covidwho-1248052

RESUMO

Mucins and mucin-like molecules are highly glycosylated, high-molecular-weight cell surface proteins that possess a semi-rigid and highly extended extracellular domain. P-selectin glycoprotein ligand-1 (PSGL-1), a mucin-like glycoprotein, has recently been found to restrict HIV-1 infectivity through virion incorporation that sterically hinders virus particle attachment to target cells. Here, we report the identification of a family of antiviral cellular proteins, named the Surface-Hinged, Rigidly-Extended Killer (SHREK) family of virion inactivators (PSGL-1, CD43, TIM-1, CD34, PODXL1, PODXL2, CD164, MUC1, MUC4, and TMEM123) that share similar structural characteristics with PSGL-1. We demonstrate that SHREK proteins block HIV-1 infectivity by inhibiting virus particle attachment to target cells. In addition, we demonstrate that SHREK proteins are broad-spectrum host antiviral factors that block the infection of diverse viruses such as influenza A. Furthermore, we demonstrate that a subset of SHREKs also blocks the infectivity of a hybrid alphavirus-SARS-CoV-2 (Ha-CoV-2) pseudovirus. These results suggest that SHREK proteins may be a part of host innate immunity against enveloped viruses.


Assuntos
COVID-19/imunologia , Infecções por HIV/imunologia , Glicoproteínas de Membrana/metabolismo , Ligação Viral , Animais , COVID-19/virologia , Cães , Células HEK293 , HIV-1/imunologia , Células HeLa , Interações entre Hospedeiro e Microrganismos , Humanos , Imunidade Inata , Células Madin Darby de Rim Canino , Mucinas/farmacologia , SARS-CoV-2/imunologia
13.
Cells ; 10(6)2021 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-34070971

RESUMO

The recent SARS-CoV-2 pandemic has refocused attention to the betacoronaviruses, only eight years after the emergence of another zoonotic betacoronavirus, the Middle East respiratory syndrome coronavirus (MERS-CoV). While the wild source of SARS-CoV-2 may be disputed, for MERS-CoV, dromedaries are considered as source of zoonotic human infections. Testing 100 immune-response genes in 121 dromedaries from United Arab Emirates (UAE) for potential association with present MERS-CoV infection, we identified candidate genes with important functions in the adaptive, MHC-class I (HLA-A-24-like) and II (HLA-DPB1-like), and innate immune response (PTPN4, MAGOHB), and in cilia coating the respiratory tract (DNAH7). Some of these genes previously have been associated with viral replication in SARS-CoV-1/-2 in humans, others have an important role in the movement of bronchial cilia. These results suggest similar host genetic pathways associated with these betacoronaviruses, although further work is required to better understand the MERS-CoV disease dynamics in both dromedaries and humans.


Assuntos
Imunidade Adaptativa/genética , Camelus/virologia , Doenças Transmissíveis Emergentes/imunologia , Infecções por Coronavirus/imunologia , Imunidade Inata/genética , Zoonoses/imunologia , Animais , Anticorpos Antivirais , Brônquios/citologia , Brônquios/fisiologia , COVID-19/genética , COVID-19/imunologia , COVID-19/virologia , Camelus/genética , Camelus/imunologia , Cílios/fisiologia , Doenças Transmissíveis Emergentes/genética , Doenças Transmissíveis Emergentes/transmissão , Doenças Transmissíveis Emergentes/virologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Reservatórios de Doenças/virologia , Feminino , Predisposição Genética para Doença , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Masculino , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Mucosa Respiratória/citologia , Mucosa Respiratória/fisiologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Emirados Árabes Unidos , Replicação Viral/genética , Replicação Viral/imunologia , Zoonoses/genética , Zoonoses/transmissão , Zoonoses/virologia
14.
J Insect Sci ; 21(3)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34146106

RESUMO

Facultative endosymbionts can affect the growth, physiology, and behavior of their arthropod hosts. There are several endosymbionts in the invasive whitefly Bemisia tabaci Mediterranean (MED, Q biotype) that influence host fitness by altering stylet probing behavior. We investigated the probing behavior of B. tabaci MED infected with the facultative endosymbiont Candidatus Cardinium hertigii (Cardinium (Sphingobacteriales: Flexibacteraceae)). We generated genetically similar Cardinium-infected (C*+) and uninfected (C-) clonal sublines and analyzed the probing behavior of newly emerged adult on cotton (Malvales: Malvaceae), Gossypium hirsutum L., using electropenetrography (EPG). The C- subline demonstrated a longer duration of E2 (2.81-fold) and more events of E2 (2.22-fold) than the C*+ subline, indicating a greater level of sustained ingestion of plant phloem. These findings provide insight into the fitness costs (fitness of a particular genotype is lower than the average fitness of the population) of the Cardinium-infected B. tabaci.


Assuntos
Comportamento , Hemípteros , Interações entre Hospedeiro e Microrganismos/fisiologia , Simbiose , Animais , Bactérias , Infecções Bacterianas , Hemípteros/microbiologia , Hemípteros/fisiologia
15.
Viruses ; 13(5)2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064525

RESUMO

Mucins and mucin-like molecules are highly glycosylated, high-molecular-weight cell surface proteins that possess a semi-rigid and highly extended extracellular domain. P-selectin glycoprotein ligand-1 (PSGL-1), a mucin-like glycoprotein, has recently been found to restrict HIV-1 infectivity through virion incorporation that sterically hinders virus particle attachment to target cells. Here, we report the identification of a family of antiviral cellular proteins, named the Surface-Hinged, Rigidly-Extended Killer (SHREK) family of virion inactivators (PSGL-1, CD43, TIM-1, CD34, PODXL1, PODXL2, CD164, MUC1, MUC4, and TMEM123) that share similar structural characteristics with PSGL-1. We demonstrate that SHREK proteins block HIV-1 infectivity by inhibiting virus particle attachment to target cells. In addition, we demonstrate that SHREK proteins are broad-spectrum host antiviral factors that block the infection of diverse viruses such as influenza A. Furthermore, we demonstrate that a subset of SHREKs also blocks the infectivity of a hybrid alphavirus-SARS-CoV-2 (Ha-CoV-2) pseudovirus. These results suggest that SHREK proteins may be a part of host innate immunity against enveloped viruses.


Assuntos
COVID-19/imunologia , Infecções por HIV/imunologia , Glicoproteínas de Membrana/metabolismo , Ligação Viral , Animais , COVID-19/virologia , Cães , Células HEK293 , HIV-1/imunologia , Células HeLa , Interações entre Hospedeiro e Microrganismos , Humanos , Imunidade Inata , Células Madin Darby de Rim Canino , Mucinas/farmacologia , SARS-CoV-2/imunologia
16.
Viruses ; 13(5)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067878

RESUMO

COVID-19 is a highly infectious respiratory disease caused by the novel coronavirus SARS-CoV-2. It has become a global pandemic and its frequent mutations may pose new challenges for vaccine design. During viral infection, the Spike RBD of SARS-CoV-2 binds the human host cell receptor ACE2, enabling the virus to enter the host cell. Both the Spike and ACE2 are densely glycosylated, and it is unclear how distinctive glycan types may modulate the interaction of RBD and ACE2. Detailed understanding of these determinants is key for the development of novel therapeutic strategies. To this end, we perform extensive all-atom simulations of the (i) RBD-ACE2 complex without glycans, (ii) RBD-ACE2 with oligomannose MAN9 glycans in ACE2, and (iii) RBD-ACE2 with complex FA2 glycans in ACE2. These simulations identify the key residues at the RBD-ACE2 interface that form contacts with higher probabilities, thus providing a quantitative evaluation that complements recent structural studies. Notably, we find that this RBD-ACE2 contact signature is not altered by the presence of different glycoforms, suggesting that RBD-ACE2 interaction is robust. Applying our simulated results, we illustrate how the recently prevalent N501Y mutation may alter specific interactions with host ACE2 that facilitate the virus-host binding. Furthermore, our simulations reveal how the glycan on Asn90 of ACE2 can play a distinct role in the binding and unbinding of RBD. Finally, an energetics analysis shows that MAN9 glycans on ACE2 decrease RBD-ACE2 affinity, while FA2 glycans lead to enhanced binding of the complex. Together, our results provide a more comprehensive picture of the detailed interplay between virus and human receptor, which is much needed for the discovery of effective treatments that aim at modulating the physical-chemical properties of this virus.


Assuntos
Enzima de Conversão de Angiotensina 2/química , COVID-19/virologia , Polissacarídeos/química , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/química , Sequência de Aminoácidos , Sítios de Ligação , Glicosilação , Interações entre Hospedeiro e Microrganismos , Humanos , Simulação de Dinâmica Molecular , Mutação , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Ligação Viral
17.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070174

RESUMO

This review focuses on the molecular chaperone ClpB that belongs to the Hsp100/Clp subfamily of the AAA+ ATPases and its biological function in selected bacterial pathogens, causing a variety of human infectious diseases, including zoonoses. It has been established that ClpB disaggregates and reactivates aggregated cellular proteins. It has been postulated that ClpB's protein disaggregation activity supports the survival of pathogenic bacteria under host-induced stresses (e.g., high temperature and oxidative stress), which allows them to rapidly adapt to the human host and establish infection. Interestingly, ClpB may also perform other functions in pathogenic bacteria, which are required for their virulence. Since ClpB is not found in human cells, this chaperone emerges as an attractive target for novel antimicrobial therapies in combating bacterial infections.


Assuntos
Endopeptidase Clp/fisiologia , Interações entre Hospedeiro e Microrganismos/fisiologia , ATPases Associadas a Diversas Atividades Celulares/fisiologia , Animais , Bactérias/patogenicidade , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/etiologia , Fenômenos Fisiológicos Bacterianos , Proteínas de Bactérias/fisiologia , Zoonoses Bacterianas/etiologia , Endopeptidase Clp/química , Proteínas de Choque Térmico/fisiologia , Humanos , Modelos Moleculares , Conformação Proteica , Virulência/fisiologia
18.
Nat Commun ; 12(1): 3282, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078900

RESUMO

Bacterial processes necessary for adaption to stressful host environments are potential targets for new antimicrobials. Here, we report large-scale transcriptomic analyses of 32 human bacterial pathogens grown under 11 stress conditions mimicking human host environments. The potential relevance of the in vitro stress conditions and responses is supported by comparisons with available in vivo transcriptomes of clinically important pathogens. Calculation of a probability score enables comparative cross-microbial analyses of the stress responses, revealing common and unique regulatory responses to different stresses, as well as overlapping processes participating in different stress responses. We identify conserved and species-specific 'universal stress responders', that is, genes showing altered expression in multiple stress conditions. Non-coding RNAs are involved in a substantial proportion of the responses. The data are collected in a freely available, interactive online resource (PATHOgenex).


Assuntos
Regulação Bacteriana da Expressão Gênica , Bactérias Gram-Negativas/genética , Bactérias Gram-Positivas/genética , RNA Bacteriano/genética , Estresse Fisiológico/genética , Transcriptoma , Adaptação Fisiológica/genética , Atlas como Assunto , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Genes Bacterianos , Bactérias Gram-Negativas/classificação , Bactérias Gram-Negativas/metabolismo , Bactérias Gram-Negativas/patogenicidade , Bactérias Gram-Positivas/classificação , Bactérias Gram-Positivas/metabolismo , Bactérias Gram-Positivas/patogenicidade , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Internet , Microbiota/genética , Filogenia , RNA Bacteriano/metabolismo
20.
Res Vet Sci ; 137: 217-225, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34023545

RESUMO

HoBi-like pestivirus, an emerging species within the Pestivirus genus, is an important pathogen associated with a variety of clinical manifestations of ruminants, especially cattle. HoBi-like pestiviruses were identified in several countries and from different hosts, and raised concerns with regard to their acute and persistent infections, which is implicated in economic losses for cattle farmers. However, the transmission path, codon usage bias, and host adaptation of the virus has not been studied. Hence, we performed the analysis the spatio-temporal transmission based on the available 5'-UTR sequences of HoBi-like pestivirus, and then conducted codon analysis of the complete coding sequence of the virus. The results show the virus appeared in 1952 (95% HPD: 1905-1985) and may have originated in India. In addition, Italy is the hub for the spread of the virus. Moreover, six potential recombination events and two complex recombination events were discovered. Analysis of codon usage patterns revealed that the effective number of codon (ENC) values with an average of 50.85, and the codon usage bias is greatly affected by natural selection, which is different from the previous BVDV-1, 2. Finally, codon adaptation index (CAI) analysis shows that pigs may be the potential origin species of the HoBi-like pestivirus. These findings will contribute to more effective control of the spread of the virus, extend the knowledge about the genetic and evolutionary features of HoBi-like viruses and provide some information for vaccine research.


Assuntos
Doenças Transmissíveis Emergentes/virologia , Evolução Molecular , Pestivirus/genética , Regiões 5' não Traduzidas , Animais , Uso do Códon , Conjuntos de Dados como Assunto , Vírus da Diarreia Viral Bovina Tipo 1/genética , Interações entre Hospedeiro e Microrganismos , Índia , Itália , Fases de Leitura Aberta , Filogenia , Filogeografia , Recombinação Genética
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