Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 78
Filtrar
1.
Cell ; 186(4): 850-863.e16, 2023 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-36803605

RESUMO

It is unknown whether pangolins, the most trafficked mammals, play a role in the zoonotic transmission of bat coronaviruses. We report the circulation of a novel MERS-like coronavirus in Malayan pangolins, named Manis javanica HKU4-related coronavirus (MjHKU4r-CoV). Among 86 animals, four tested positive by pan-CoV PCR, and seven tested seropositive (11 and 12.8%). Four nearly identical (99.9%) genome sequences were obtained, and one virus was isolated (MjHKU4r-CoV-1). This virus utilizes human dipeptidyl peptidase-4 (hDPP4) as a receptor and host proteases for cell infection, which is enhanced by a furin cleavage site that is absent in all known bat HKU4r-CoVs. The MjHKU4r-CoV-1 spike shows higher binding affinity for hDPP4, and MjHKU4r-CoV-1 has a wider host range than bat HKU4-CoV. MjHKU4r-CoV-1 is infectious and pathogenic in human airways and intestinal organs and in hDPP4-transgenic mice. Our study highlights the importance of pangolins as reservoir hosts of coronaviruses poised for human disease emergence.


Assuntos
Infecções por Coronavirus , Coronavirus , Dipeptidil Peptidase 4 , Pangolins , Animais , Humanos , Camundongos , Quirópteros , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/virologia , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Endopeptidases/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Peptídeo Hidrolases/metabolismo , Receptores Virais/metabolismo , Internalização do Vírus , Coronavirus/fisiologia
2.
Cell ; 182(1): 50-58.e8, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32516571

RESUMO

COVID-19 has spread worldwide since 2019 and is now a severe threat to public health. We previously identified the causative agent as a novel SARS-related coronavirus (SARS-CoV-2) that uses human angiotensin-converting enzyme 2 (hACE2) as the entry receptor. Here, we successfully developed a SARS-CoV-2 hACE2 transgenic mouse (HFH4-hACE2 in C3B6 mice) infection model. The infected mice generated typical interstitial pneumonia and pathology that were similar to those of COVID-19 patients. Viral quantification revealed the lungs as the major site of infection, although viral RNA could also be found in the eye, heart, and brain in some mice. Virus identical to SARS-CoV-2 in full-genome sequences was isolated from the infected lung and brain tissues. Last, we showed that pre-exposure to SARS-CoV-2 could protect mice from severe pneumonia. Our results show that the hACE2 mouse would be a valuable tool for testing potential vaccines and therapeutics.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Modelos Animais de Doenças , Camundongos Transgênicos , Pneumonia Viral/patologia , Enzima de Conversão de Angiotensina 2 , Animais , COVID-19 , Feminino , Humanos , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/virologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos/genética , Pandemias , Peptidil Dipeptidase A/genética , SARS-CoV-2 , Tropismo Viral , Redução de Peso
3.
Nature ; 582(7811): 289-293, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32272481

RESUMO

A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)1-4. Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-25,6. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of Mpro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of Mpro. Six of these compounds inhibited Mpro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 µM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.


Assuntos
Betacoronavirus/química , Cisteína Endopeptidases/química , Descoberta de Drogas/métodos , Modelos Moleculares , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Antivirais/química , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , COVID-19 , Células Cultivadas/virologia , Proteases 3C de Coronavírus , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/virologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Pandemias , Pneumonia Viral/enzimologia , Pneumonia Viral/virologia , Inibidores de Proteases/farmacologia , Estrutura Terciária de Proteína , SARS-CoV-2
4.
Nature ; 579(7798): 270-273, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32015507

RESUMO

Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1-4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5-7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2)-as SARS-CoV.


Assuntos
Betacoronavirus/classificação , Betacoronavirus/genética , Quirópteros/virologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Surtos de Doenças , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Enzima de Conversão de Angiotensina 2 , Animais , Anticorpos Antivirais/sangue , Betacoronavirus/metabolismo , Betacoronavirus/ultraestrutura , COVID-19 , Linhagem Celular , China/epidemiologia , Chlorocebus aethiops , Feminino , Genoma Viral/genética , Humanos , Masculino , Peptidil Dipeptidase A/metabolismo , Filogenia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/classificação , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , SARS-CoV-2 , Homologia de Sequência do Ácido Nucleico , Síndrome Respiratória Aguda Grave , Células Vero
5.
J Virol ; 97(9): e0079023, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37607058

RESUMO

Bats carry genetically diverse severe acute respiratory syndrome-related coronaviruses (SARSr-CoVs). Some of them utilize human angiotensin-converting enzyme 2 (hACE2) as a receptor and cannot efficiently replicate in wild-type mice. Our previous study demonstrated that the bat SARSr-CoV rRsSHC014S induces respiratory infection and lung damage in hACE2 transgenic mice but not wild-type mice. In this study, we generated a mouse-adapted strain of rRsSHC014S, which we named SMA1901, by serial passaging of wild-type virus in BALB/c mice. SMA1901 showed increased infectivity in mouse lungs and induced interstitial lung pneumonia in both young and aged mice after intranasal inoculation. Genome sequencing revealed mutations in not only the spike protein but the whole genome, which may be responsible for the enhanced pathogenicity of SMA1901 in wild-type BALB/c mice. SMA1901 induced age-related mortality similar to that observed in SARS and COVID-19. Drug testing using antibodies and antiviral molecules indicated that this mouse-adapted virus strain can be used to test prophylactic and therapeutic drug candidates against SARSr-CoVs. IMPORTANCE The genetic diversity of SARSr-CoVs in wildlife and their potential risk of cross-species infection highlights the importance of developing a powerful animal model to evaluate the antibodies and antiviral drugs. We acquired the mouse-adapted strain of a bat-origin coronavirus named SMA1901 by natural serial passaging of rRsSHC014S in BALB/c mice. The SMA1901 infection caused interstitial pneumonia and inflammatory immune responses in both young and aged BALB/c mice after intranasal inoculation. Our model exhibited age-related mortality similar to SARS and COVID-19. Therefore, our model will be of high value for investigating the pathogenesis of bat SARSr-CoVs and could serve as a prospective test platform for prophylactic and therapeutic candidates.


Assuntos
Quirópteros , Camundongos , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave , Animais , Camundongos/virologia , Quirópteros/virologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/classificação , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/efeitos dos fármacos , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/patogenicidade , Camundongos Endogâmicos BALB C , COVID-19/mortalidade , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/mortalidade , Inoculações Seriadas , Antivirais/farmacologia , Antivirais/uso terapêutico , Anticorpos Antivirais/farmacologia , Anticorpos Antivirais/uso terapêutico , Zoonoses Virais/tratamento farmacológico , Zoonoses Virais/transmissão , Zoonoses Virais/virologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/virologia , Envelhecimento , Avaliação Pré-Clínica de Medicamentos
6.
J Virol ; 97(2): e0171922, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36688655

RESUMO

Coronavirus disease 2019 (COVID-19), which is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the most severe emerging infectious disease in the current century. The discovery of SARS-CoV-2-related coronaviruses (SARSr-CoV-2) in bats and pangolins in South Asian countries indicates that SARS-CoV-2 likely originated from wildlife. To date, two SARSr-CoV-2 strains have been isolated from pangolins seized in Guangxi and Guangdong by the customs agency of China, respectively. However, it remains unclear whether these viruses cause disease in animal models and whether they pose a transmission risk to humans. In this study, we investigated the biological features of a SARSr-CoV-2 strain isolated from a smuggled Malayan pangolin (Manis javanica) captured by the Guangxi customs agency, termed MpCoV-GX, in terms of receptor usage, cell tropism, and pathogenicity in wild-type BALB/c mice, human angiotensin-converting enzyme 2 (ACE2)-transgenic mice, and human ACE2 knock-in mice. We found that MpCoV-GX can utilize ACE2 from humans, pangolins, civets, bats, pigs, and mice for cell entry and infect cell lines derived from humans, monkeys, bats, minks, and pigs. The virus could infect three mouse models but showed limited pathogenicity, with mild peribronchial and perivascular inflammatory cell infiltration observed in lungs. Our results suggest that this SARSr-CoV-2 virus from pangolins has the potential for interspecies infection, but its pathogenicity is mild in mice. Future surveillance among these wildlife hosts of SARSr-CoV-2 is needed to monitor variants that may have higher pathogenicity and higher spillover risk. IMPORTANCE SARS-CoV-2, which likely spilled over from wildlife, is the third highly pathogenic human coronavirus. Being highly transmissible, it is perpetuating a pandemic and continuously posing a severe threat to global public health. Several SARS-CoV-2-related coronaviruses (SARSr-CoV-2) in bats and pangolins have been identified since the SARS-CoV-2 outbreak. It is therefore important to assess their potential of crossing species barriers for better understanding of their risk of future emergence. In this work, we investigated the biological features and pathogenicity of a SARSr-CoV-2 strain isolated from a smuggled Malayan pangolin, named MpCoV-GX. We found that MpCoV-GX can utilize ACE2 from 7 species for cell entry and infect cell lines derived from a variety of mammalian species. MpCoV-GX can infect mice expressing human ACE2 without causing severe disease. These findings suggest the potential of cross-species transmission of MpCoV-GX, and highlight the need of further surveillance of SARSr-CoV-2 in pangolins and other potential animal hosts.


Assuntos
COVID-19 , Especificidade de Hospedeiro , Pangolins , Animais , Humanos , Camundongos , Enzima de Conversão de Angiotensina 2/genética , Linhagem Celular , China , COVID-19/transmissão , COVID-19/virologia , Pulmão/patologia , Pulmão/virologia , Camundongos Transgênicos , Pangolins/virologia , SARS-CoV-2/classificação , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , Suínos , Quirópteros
7.
J Virol ; 97(10): e0091623, 2023 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-37772826

RESUMO

IMPORTANCE: Gaining insight into the cell-entry mechanisms of swine acute diarrhea syndrome coronavirus (SADS-CoV) is critical for investigating potential cross-species infections. Here, we demonstrated that pretreatment of host cells with tunicamycin decreased SADS-CoV attachment efficiency, indicating that N-linked glycosylation of host cells was involved in SADS-CoV entry. Common N-linked sugars Neu5Gc and Neu5Ac did not interact with the SADS-CoV S1 protein, suggesting that these molecules were not involved in SADS-CoV entry. Additionally, various host proteases participated in SADS-CoV entry into diverse cells with different efficiencies. Our findings suggested that SADS-CoV may exploit multiple pathways to enter cells, providing insights into intervention strategies targeting the cell entry of this virus.


Assuntos
Alphacoronavirus , Infecções por Coronavirus , Endopeptidases , Glicoproteínas , Doenças dos Suínos , Suínos , Internalização do Vírus , Animais , Alphacoronavirus/fisiologia , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/virologia , Endopeptidases/metabolismo , Glicoproteínas/química , Glicoproteínas/metabolismo , Suínos/virologia , Doenças dos Suínos/enzimologia , Doenças dos Suínos/metabolismo , Doenças dos Suínos/virologia , Internalização do Vírus/efeitos dos fármacos , Tunicamicina/farmacologia , Glicosilação
8.
J Virol ; 96(15): e0095822, 2022 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-35852351

RESUMO

The spike protein on sarbecovirus virions contains two external, protruding domains: an N-terminal domain (NTD) with unclear function and a C-terminal domain (CTD) that binds the host receptor, allowing for viral entry and infection. While the CTD is well studied for therapeutic interventions, the role of the NTD is far less well understood for many coronaviruses. Here, we demonstrate that the spike NTD from SARS-CoV-2 and other sarbecoviruses binds to unidentified glycans in vitro similarly to other members of the Coronaviridae family. We also show that these spike NTD (S-NTD) proteins adhere to Calu3 cells, a human lung cell line, although the biological relevance of this is unclear. In contrast to what has been shown for Middle East respiratory syndrome coronavirus (MERS-CoV), which attaches sialic acids during cell entry, sialic acids present on Calu3 cells inhibited sarbecovirus infection. Therefore, while sarbecoviruses can interact with cell surface glycans similarly to other coronaviruses, their reliance on glycans for entry is different from that of other respiratory coronaviruses, suggesting sarbecoviruses and MERS-CoV have adapted to different cell types, tissues, or hosts during their divergent evolution. Our findings provide important clues for further exploring the biological functions of sarbecovirus glycan binding and adds to our growing understanding of the complex forces that shape coronavirus spike evolution. IMPORTANCE Spike N-terminal domains (S-NTD) of sarbecoviruses are highly diverse; however, their function remains largely understudied compared with the receptor-binding domains (RBD). Here, we show that sarbecovirus S-NTD can be phylogenetically clustered into five clades and exhibit various levels of glycan binding in vitro. We also show that, unlike some coronaviruses, including MERS-CoV, sialic acids present on the surface of Calu3, a human lung cell culture, inhibit SARS-CoV-2 and other sarbecoviruses. These results suggest that while glycan binding might be an ancestral trait conserved across different coronavirus families, the functional outcome during infection can vary, reflecting divergent viral evolution. Our results expand our knowledge on the biological functions of the S-NTD across diverse sarbecoviruses and provide insight on the evolutionary history of coronavirus spike.


Assuntos
Evolução Molecular , Coronavírus da Síndrome Respiratória do Oriente Médio , Polissacarídeos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , COVID-19/virologia , Linhagem Celular , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/química , Coronavírus da Síndrome Respiratória do Oriente Médio/classificação , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Polissacarídeos/metabolismo , Domínios Proteicos , Receptores Virais/metabolismo , SARS-CoV-2/química , SARS-CoV-2/classificação , SARS-CoV-2/metabolismo , Ácidos Siálicos/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo
9.
J Virol ; 96(8): e0016922, 2022 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-35343762

RESUMO

Severe acute respiratory syndrome coronavirus (SARS-CoV-1) and SARS-CoV-2 are highly pathogenic to humans and have caused pandemics in 2003 and 2019, respectively. Genetically diverse SARS-related coronaviruses (SARSr-CoVs) have been detected or isolated from bats, and some of these viruses have been demonstrated to utilize human angiotensin-converting enzyme 2 (ACE2) as a receptor and to have the potential to spill over to humans. A pan-sarbecovirus vaccine that provides protection against SARSr-CoV infection is urgently needed. In this study, we evaluated the protective efficacy of an inactivated SARS-CoV-2 vaccine against recombinant SARSr-CoVs carrying two different spike proteins (named rWIV1 and rRsSHC014S, respectively). Although serum neutralizing assays showed limited cross-reactivity between the three viruses, the inactivated SARS-CoV-2 vaccine provided full protection against SARS-CoV-2 and rWIV1 and partial protection against rRsSHC014S infection in human ACE2 transgenic mice. Passive transfer of SARS-CoV-2-vaccinated mouse sera provided low protection for rWIV1 but not for rRsSHC014S infection in human ACE2 mice. A specific cellular immune response induced by WIV1 membrane protein peptides was detected in the vaccinated animals, which may explain the cross-protection of the inactivated vaccine. This study shows the possibility of developing a pan-sarbecovirus vaccine against SARSr-CoVs for future preparedness. IMPORTANCE The genetic diversity of SARSr-CoVs in wildlife and their potential risk of cross-species infection highlight the necessity of developing wide-spectrum vaccines against infection of various SARSr-CoVs. In this study, we tested the protective efficacy of the SARS-CoV-2 inactivated vaccine (IAV) against two SARSr-CoVs with different spike proteins in human ACE2 transgenic mice. We demonstrate that the SARS-CoV-2 IAV provides full protection against rWIV1 and partial protection against rRsSHC014S. The T-cell response stimulated by the M protein may account for the cross protection against heterogeneous SARSr-CoVs. Our findings suggest the feasibility of the development of pan-sarbecovirus vaccines, which can be a strategy of preparedness for future outbreaks caused by novel SARSr-CoVs from wildlife.


Assuntos
Vacinas contra COVID-19 , Infecções por Coronavirus , Proteção Cruzada , Glicoproteína da Espícula de Coronavírus , Vacinas de Produtos Inativados , Enzima de Conversão de Angiotensina 2/genética , Animais , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Quirópteros , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Proteção Cruzada/imunologia , Humanos , Camundongos , Camundongos Transgênicos , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/metabolismo , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas de Produtos Inativados/imunologia , Zoonoses Virais/prevenção & controle
10.
J Virol ; 96(17): e0006522, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-35993737

RESUMO

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a recently emerging bat-borne coronavirus responsible for high mortality rates in piglets. In vitro studies have indicated that SADS-CoV has a wide tissue tropism in different hosts, including humans. However, whether this virus potentially threatens other animals remains unclear. Here, we report the experimental infection of wild-type BALB/c and C57BL/6J suckling mice with SADS-CoV. We found that mice less than 7 days old are susceptible to the virus, which caused notable multitissue infections and damage. The mortality rate was the highest in 2-day-old mice and decreased in older mice. Moreover, a preliminary neuroinflammatory response was observed in 7-day-old SADS-CoV-infected mice. Thus, our results indicate that SADS-CoV has potential pathogenicity in young hosts. IMPORTANCE SADS-CoV, which likely has originated from bat coronaviruses, is highly pathogenic to piglets and poses a threat to the swine industry. Little is known about its potential to disseminate to other animals. No efficient treatment is available, and the quarantine strategy is the only preventive measure. In this study, we demonstrated that SADS-CoV can efficiently replicate in suckling mice younger than 7 days. In contrast to infected piglets, in which intestinal tropism is shown, SADS-CoV caused infection and damage in all murine tissues evaluated in this study. In addition, neuroinflammatory responses were detected in some of the infected mice. Our work provides a preliminary cost-effective model for the screening of antiviral drugs against SADS-CoV infection.


Assuntos
Alphacoronavirus , Infecções por Coronavirus , Diarreia , Camundongos , Doenças dos Suínos , Alphacoronavirus/patogenicidade , Animais , Quirópteros/virologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/virologia , Diarreia/complicações , Diarreia/veterinária , Diarreia/virologia , Humanos , Camundongos/virologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias/complicações , Doenças Neuroinflamatórias/veterinária , Doenças Neuroinflamatórias/virologia , Suínos/virologia , Doenças dos Suínos/virologia
11.
J Virol ; 96(9): e0003822, 2022 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-35420442

RESUMO

Due to the limitation of human studies with respect to individual difference or the accessibility of fresh tissue samples, how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in pathological complications in lung, the main site of infection, is still incompletely understood. Therefore, physiologically relevant animal models under realistic SARS-CoV-2 infection conditions would be helpful to our understanding of dysregulated inflammation response in lung in the context of targeted therapeutics. Here, we characterized the single-cell landscape in lung and spleen upon SARS-CoV-2 infection in an acute severe disease mouse model that replicates human symptoms, including severe lung pathology and lymphopenia. We showed a reduction of lymphocyte populations and an increase of neutrophils in lung and then demonstrated the key role of neutrophil-mediated lung immunopathology in both mice and humans. Under severe conditions, neutrophils recruited by a chemokine-driven positive feedback produced elevated "fatal signature" proinflammatory genes and pathways related to neutrophil activation or releasing of granular content. In addition, we identified a new Cd177high cluster that is undergoing respiratory burst and Stfahigh cluster cells that may dampen antigen presentation upon infection. We also revealed the devastating effect of overactivated neutrophil by showing the highly enriched neutrophil extracellular traps in lung and a dampened B-cell function in either lung or spleen that may be attributed to arginine consumption by neutrophil. The current study helped our understanding of SARS-CoV-2-induced pneumonia and warranted the concept of neutrophil-targeting therapeutics in COVID-19 treatment. IMPORTANCE We demonstrated the single-cell landscape in lung and spleen upon SARS-CoV-2 infection in an acute severe disease mouse model that replicated human symptoms, including severe lung pathology and lymphopenia. Our comprehensive study revealed the key role of neutrophil-mediated lung immunopathology in SARS-CoV-2-induced severe pneumonia, which not only helped our understanding of COVID-19 but also warranted the concept of neutrophil targeting therapeutics in COVID-19 treatment.


Assuntos
COVID-19 , Pulmão , Neutrófilos , Animais , COVID-19/imunologia , Modelos Animais de Doenças , Humanos , Pulmão/patologia , Pulmão/virologia , Linfopenia/virologia , Camundongos , Neutrófilos/imunologia , SARS-CoV-2 , Baço/patologia , Baço/virologia
12.
J Exp Bot ; 74(1): 443-457, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36260345

RESUMO

Drought, which directly affects the yield of crops and trees, is a natural stress with a profound impact on the economy. Improving water use efficiency (WUE) and drought tolerance are relatively effective strategies to alleviate drought stress. OPEN STOMATA1 (OST1), at the core of abscisic acid (ABA) signaling, can improve WUE by regulating stomatal closure and photosynthesis. Methyl jasmonate (MeJA) and ABA crosstalk is considered to be involved in the response to drought stress, but the detailed molecular mechanism is insufficiently known. Here, Populus euphratica, which naturally grows in arid and semiarid regions, was selected as the species for studying MeJA and ABA crosstalk under drought. A yeast two-hybrid assay was performed using PeOST1 as bait and a nucleus-localized factor, JASMONATE ZIM-domain protein 2 (PeJAZ2), was found to participate in MeJA signaling by interacting with PeOST1. Overexpression of PeJAZ2 in poplar notably increased water deficit tolerance and WUE in both severe and mild drought stress by regulating ABA signaling rather than ABA synthesis. Furthermore, a PeJAZ2 overexpression line was shown to have greater ABA-induced stomatal closure and hydrogen peroxide (H2O2) production. Collectively, this evidence establishes a mechanism in which PeJAZ2 acts as a positive regulator in response to drought stress via ABA-induced stomatal closure caused by H2O2 production. Our study presents a new insight into the crosstalk of ABA and jasmonic acid signaling in regulating WUE and drought stress, providing a basis of the drought tolerance mechanism of P. euphratica.


Assuntos
Ácido Abscísico , Populus , Ácido Abscísico/metabolismo , Resistência à Seca , Populus/metabolismo , Peróxido de Hidrogênio/metabolismo , Secas , Água/metabolismo , Estômatos de Plantas/fisiologia
13.
Epidemiol Infect ; 150: e127, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35726529

RESUMO

The study aimed to explore the relationship between eosinophils and the prognosis of varicella in adults. We retrospectively reviewed the medical records of patients who were hospitalised in The Fifth People's Hospital of Suzhou with a diagnosis of adult varicella during the period between 1 January 2012 and 31 December 2020. Of the 359 patients, 228 (63.51%) had eosinopenia. The proportion of patients with mild type disease was significantly lower in the eosinopenia group than that in the non-eosinopenia group (50.44% vs. 65.65%, P = 0.006). The proportion of the patients with common type disease was significantly higher in the eosinopenia group than that in the non-eosinopenia group (39.47% vs. 28.24%, P = 0.039). The proportion of the patients with severe type disease was higher in the eosinopenia group, although the difference did not reach statistical significance (10.09% vs. 6.11%, P = 0.243). The rates of high fever (47.81% vs. 32.82%, P = 0.008; relative risk (RR) 1.296, 95% confidence interval (CI) 1.091-1.540), headache (43.42% vs. 22.14%, P < 0.001; RR 1.415, 95% CI 1.233-1.623), anorexia (53.51% vs. 35.88%, P = 0.001; RR 1.367, 95% CI 1.129-1.655) and complications (82.89% vs. 64.12%, P < 0.001; RR 2.106, 95% CI 1.460-3.038) were also significantly higher in the eosinopenia group. Among the complications, the liver injury and skin infection were more serious in the eosinopenia group. The disease course was significantly longer in the eosinopenia group than that in the non-eosinopenia group (9.43 ± 1.89 days vs. 8.73 ± 1.25 days, P < 0.001). The improvement rate of liver injury in the recovery period was lower in the eosinopenia group than that in the non-eosinopenia group (35.38% vs. 50%, P = 0.012). The study found that adult varicella patients with eosinopenia had a more serious condition, a higher morbidity of complications and a slower recovery. Blood eosinophils can be used as a new predictor of the severity of adult varicella.


Assuntos
Agranulocitose , Varicela , Adulto , Varicela/complicações , Varicela/epidemiologia , Eosinófilos , Humanos , Contagem de Leucócitos , Estudos Retrospectivos
15.
Sensors (Basel) ; 20(6)2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32178238

RESUMO

LiDAR sensors can provide dependable 3D spatial information at a low frequency (around 10 Hz) and have been widely applied in the field of autonomous driving and unmanned aerial vehicle (UAV). However, the camera with a higher frequency (around 20 Hz) has to be decreased so as to match with LiDAR in a multi-sensor system. In this paper, we propose a novel Pseudo-LiDAR interpolation network (PLIN) to increase the frequency of LiDAR sensor data. PLIN can generate temporally and spatially high-quality point cloud sequences to match the high frequency of cameras. To achieve this goal, we design a coarse interpolation stage guided by consecutive sparse depth maps and motion relationship. We also propose a refined interpolation stage guided by the realistic scene. Using this coarse-to-fine cascade structure, our method can progressively perceive multi-modal information and generate accurate intermediate point clouds. To the best of our knowledge, this is the first deep framework for Pseudo-LiDAR point cloud interpolation, which shows appealing applications in navigation systems equipped with LiDAR and cameras. Experimental results demonstrate that PLIN achieves promising performance on the KITTI dataset, significantly outperforming the traditional interpolation method and the state-of-the-art video interpolation technique.

16.
Sensors (Basel) ; 19(19)2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31590406

RESUMO

In this paper, we study the issue of out-of-sequence measurement (OOSM) in a multi-target scenario to improve tracking performance. The OOSM is very common in tracking systems, and it would result in performance degradation if we used it inappropriately. Thus, OOSM should be fully utilized as far as possible. To improve the performance of the tracking system and use OOSM sufficiently, firstly, the problem of OOSM is formulated. Then the classical B1 algorithm for OOSM problem of single target tracking is given. Next, the random finite set (RFS)-based Gaussian mixture probability hypothesis density (GM-PHD) is introduced. Consequently, we derived the equation for re-updating of posterior intensity with OOSM. Implementation of GM-PHD using OOSM is also given. Finally, several simulations are given, and results show that tracking performance of GM-PHD using OOSM is better than GM-PHD using in-sequence measurement (ISM), which can strongly demonstrate the effectiveness of our proposed algorithm.

17.
Water Sci Technol ; 77(7-8): 1891-1898, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29676746

RESUMO

Advanced treatment of biologically treated coking wastewater (BTCW) using persulfate (PS) oxidation with magnetic activated carbon composite (CuFe2O4:AC w/w ratio of 1:1.5, denoted as 1.5-MACC) as a green catalyst was evaluated at ambient temperature (30 °C). Effects of PS (K2S2O8) and 1.5-MACC doses on PS decomposition and total organic carbon (TOC) removal in BTCW were also studied during 360 min. The results showed that the 1.5-MACC/PS system has a much better performance on TOC removal in BTCW than only 1.5-MACC or PS system. PS decomposition and TOC removal follow first-order kinetics in the 1.5-MACC/PS system. The optimum condition of the 1.5-MACC/PS system to treat BTCW is with a K2S2O8 dose of 4 g L-1 and 1.5-MACC dose of 5 g L-1. Under this condition, TOC in the PS oxidation effluent is 20.4 mg L-1 with a removal efficiency of 85.4%. TOC removal is a synergistic effect of adsorption and oxidation. TOC oxidation is due to the generation of ·SO4- via the activation of PS by CuFe2O4 impregnated AC. The gas chromatography-mass spectrometry (GC-MS) analysis revealed that phenol compounds and esters were removed significantly by the 1.5-MACC/PS system. When 1.5-MACC was used for the fourth time in the 1.5-MACC/PS system, the removal ratio of TOC was still over 62.2% in 360 min reaction. Thus, the 1.5-MACC/PS system has a potential practical application in treatment of BTCW.


Assuntos
Cobre/química , Compostos Ferrosos/química , Compostos de Potássio/química , Sulfatos/química , Eliminação de Resíduos Líquidos/métodos , Águas Residuárias/química , Poluentes Químicos da Água/química , Adsorção , Catálise , Carvão Vegetal/química , Coque/análise , Cromatografia Gasosa-Espectrometria de Massas , Oxirredução
18.
Sensors (Basel) ; 17(10)2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28961206

RESUMO

In this paper, a novel infrared target co-detection model combining the self-correlation features of backgrounds and the commonality features of targets in the spatio-temporal domain is proposed to detect small targets in a sequence of infrared images with complex backgrounds. Firstly, a dense target extraction model based on nonlinear weights is proposed, which can better suppress background of images and enhance small targets than weights of singular values. Secondly, a sparse target extraction model based on entry-wise weighted robust principal component analysis is proposed. The entry-wise weight adaptively incorporates structural prior in terms of local weighted entropy, thus, it can extract real targets accurately and suppress background clutters efficiently. Finally, the commonality of targets in the spatio-temporal domain are used to construct target refinement model for false alarms suppression and target confirmation. Since real targets could appear in both of the dense and sparse reconstruction maps of a single frame, and form trajectories after tracklet association of consecutive frames, the location correlation of the dense and sparse reconstruction maps for a single frame and tracklet association of the location correlation maps for successive frames have strong ability to discriminate between small targets and background clutters. Experimental results demonstrate that the proposed small target co-detection method can not only suppress background clutters effectively, but also detect targets accurately even if with target-like interference.

19.
Sensors (Basel) ; 17(12)2017 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-29207541

RESUMO

Underwater wireless sensor networks (UWSNs) can provide a promising solution to underwater target tracking. Due to the limited computation and bandwidth resources, only a small part of nodes are selected to track the target at each interval. How to improve tracking accuracy with a small number of nodes is a key problem. In recent years, a node depth adjustment system has been developed and applied to issues of network deployment and routing protocol. As far as we know, all existing tracking schemes keep underwater nodes static or moving with water flow, and node depth adjustment has not been utilized for underwater target tracking yet. This paper studies node depth adjustment method for target tracking in UWSNs. Firstly, since a Fisher Information Matrix (FIM) can quantify the estimation accuracy, its relation to node depth is derived as a metric. Secondly, we formulate the node depth adjustment as an optimization problem to determine moving depth of activated node, under the constraint of moving range, the value of FIM is used as objective function, which is aimed to be minimized over moving distance of nodes. Thirdly, to efficiently solve the optimization problem, an improved Harmony Search (HS) algorithm is proposed, in which the generating probability is modified to improve searching speed and accuracy. Finally, simulation results are presented to verify performance of our scheme.

20.
Sensors (Basel) ; 17(11)2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-29112117

RESUMO

Target tracking is one of the broad applications of underwater wireless sensor networks (UWSNs). However, as a result of the temporal and spatial variability of acoustic channels, underwater acoustic communications suffer from an extremely limited bandwidth. In order to reduce network congestion, it is important to shorten the length of the data transmitted from local sensors to the fusion center by quantization. Although quantization can reduce bandwidth cost, it also brings about bad tracking performance as a result of information loss after quantization. To solve this problem, this paper proposes an optimal quantization-based target tracking scheme. It improves the tracking performance of low-bit quantized measurements by minimizing the additional covariance caused by quantization. The simulation demonstrates that our scheme performs much better than the conventional uniform quantization-based target tracking scheme and the increment of the data length affects our scheme only a little. Its tracking performance improves by only 4.4% from 2- to 3-bit, which means our scheme weakly depends on the number of data bits. Moreover, our scheme also weakly depends on the number of participate sensors, and it can work well in sparse sensor networks. In a 6 × 6 × 6 sensor network, compared with 4 × 4 × 4 sensor networks, the number of participant sensors increases by 334.92%, while the tracking accuracy using 1-bit quantized measurements improves by only 50.77%. Overall, our optimal quantization-based target tracking scheme can achieve the pursuit of data-efficiency, which fits the requirements of low-bandwidth UWSNs.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA