RESUMO
Acute Respiratory Distress Syndrome (ARDS) is an inflammatory disease that is associated with high mortality but no specific treatment. Our understanding of initial events that trigger ARDS pathogenesis is limited. We have developed a mouse model of inflammatory lung injury by influenza and methicillin-resistant Staphylococcus aureus (MRSA) coinfection plus daily antibiotic therapy. Using this pneumonic ARDS model, here we show that IFN-γ receptor signaling drives inflammatory cytokine storm and lung tissue damage. By single-cell RNA sequencing (scRNA-seq) analysis, we demonstrate that IFN-γ signaling induces a transcriptional shift in airway immune cells, particularly by upregulating macrophage and monocyte expression of genes associated with inflammatory diseases. Further evidence from conditional knockout mouse models reveals that IFN-γ receptor signaling in myeloid cells, particularly CD11c+ mononuclear phagocytes, directly promotes TNF-α hyperproduction and inflammatory lung damage. Collectively, the findings from this study, ranging from cell-intrinsic gene expression to overall disease outcome, demonstrate that influenza-induced IFN-γ triggers myeloid cell hyperresponsiveness to MRSA, thereby leading to excessive inflammatory response and lethal lung damage during coinfection.
Assuntos
Coinfecção , Influenza Humana , Lesão Pulmonar , Staphylococcus aureus Resistente à Meticilina , Síndrome do Desconforto Respiratório , Animais , Antibacterianos/farmacologia , Humanos , Interferon gama/genética , Lesão Pulmonar/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides , Transcriptoma , Fator de Necrose Tumoral alfa/genéticaRESUMO
The scientific community has been releasing whole genomic sequences of SARS-CoV-2 to facilitate the investigation of molecular features and evolutionary history. We retrieved 36 genomes of 18 prevalent countries of Asia, Europe and America for genomic diversity and mutational analysis. Besides, we studied mutations in the RBD regions of Spike (S) proteins to analyze the drug efficiency against these mutations. In this research, phylogenenetic analysis, evolutionary modeling, substitution pattern analysis, molecular docking, dynamics simulation, etc. were performed. The genomic sequences showed >99% similarity with the reference sequence of China.TN93 + G was predicted as a best nucleotide substitution model. It was revealed that effective transition from the co-existing SARS genome to the SARS-CoV-2 and a noticeable positive selection in the SARS-CoV-2 genomes occurred. Moreover, three mutations in RBD domain, Val/ Phe367, Val/ Leu 382 and Ala/ Val522, were discovered in the genomes from Netherland, Bangladesh and the USA, respectively. Molecular docking and dynamics study showed RBD with mutation Val/Leu382 had the lowest binding affinity with remdesivir. In conclusion, the SARS-CoV-2 genomes are similar, but multiple degrees of transitions and transversions occurred. The mutations cause a significant conformational change, which are needed to be investigated during drug and vaccine development.
Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/química , COVID-19/epidemiologia , Genoma Viral , Mutação , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacologia , Alanina/química , Alanina/farmacologia , Substituição de Aminoácidos , Antivirais/farmacologia , Bangladesh/epidemiologia , Sítios de Ligação , COVID-19/virologia , China/epidemiologia , Evolução Molecular , Expressão Gênica , Humanos , Funções Verossimilhança , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Países Baixos/epidemiologia , Filogenia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , SARS-CoV-2/classificação , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Estados Unidos/epidemiologia , Tratamento Farmacológico da COVID-19RESUMO
SARS-CoV-2, a new coronavirus strain responsible for COVID-19, has emerged in Wuhan City, China, and continuing its global pandemic nature. The availability of the complete gene sequences of the virus helps to know about the origin and molecular characteristics of this virus. In the present study, we performed bioinformatic analysis of the available gene sequence data of SARS-CoV-2 for the understanding of evolution and molecular characteristics and immunogenic resemblance of the circulating viruses. Phylogenetic analysis was performed for four types of representative viral proteins (spike, membrane, envelope and nucleoprotein) of SARS-CoV-2, HCoV-229E, HCoV-OC43, SARS-CoV, HCoV-NL63, HKU1, MERS-CoV, HKU4, HKU5 and BufCoV-HKU26. The findings demonstrated that SARS-CoV-2 exhibited convergent evolutionary relation with previously reported SARS-CoV. It was also depicted that SARS-CoV-2 proteins were highly similar and identical to SARS-CoV proteins, though proteins from other coronaviruses showed a lower level of resemblance. The cross-checked conservancy analysis of SARS-CoV-2 antigenic epitopes showed significant conservancy with antigenic epitopes derived from SARS-CoV. Descriptive epidemiological analysis on several epidemiological indices was performed on available epidemiological outbreak information from several open databases on COVID-19 (SARS-CoV-2). Satellite-derived imaging data have been employed to understand the role of temperature in the environmental persistence of the virus. Findings of the descriptive analysis were used to describe the global impact of newly emerged SARS-CoV-2, and the risk of an epidemic in Bangladesh.
Assuntos
Antígenos Virais/genética , Betacoronavirus/genética , Infecções por Coronavirus/epidemiologia , Genoma Viral , Pandemias , Pneumonia Viral/epidemiologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , Glicoproteína da Espícula de Coronavírus/química , Alphacoronavirus/classificação , Alphacoronavirus/genética , Alphacoronavirus/metabolismo , Sequência de Aminoácidos , Animais , Antígenos Virais/química , Antígenos Virais/metabolismo , Bangladesh/epidemiologia , Sequência de Bases , Betacoronavirus/classificação , Betacoronavirus/metabolismo , Sítios de Ligação , COVID-19 , Quirópteros/virologia , Biologia Computacional , Coronavirus Humano 229E/classificação , Coronavirus Humano 229E/genética , Coronavirus Humano 229E/metabolismo , Infecções por Coronavirus/virologia , Coronavirus Humano NL63/classificação , Coronavirus Humano NL63/genética , Coronavirus Humano NL63/metabolismo , Coronavirus Humano OC43/classificação , Coronavirus Humano OC43/genética , Coronavirus Humano OC43/metabolismo , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/classificação , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Modelos Moleculares , Mutação , Nucleoproteínas/química , Nucleoproteínas/genética , Nucleoproteínas/metabolismo , Filogenia , Pneumonia Viral/virologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/classificação , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/metabolismo , SARS-CoV-2 , Alinhamento de Sequência , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismoRESUMO
Coptidis Rhizoma is derived from the dried rhizome of Ranunculaceous plants and is a commonly used traditional Chinese medicine. Although Coptidis Rhizoma is commonly used for its many therapeutic effects, antiviral activity against respiratory syncytial virus (RSV) has not been reported in detail. In this study, we evaluated the antiviral activities of Coptidis Rhizoma extract (CRE) against RSV in human respiratory tract cell line (HEp2) and BALB/c mice. An effective dose of CRE significantly reduces the replication of RSV in HEp2 cells and reduces the RSV-induced cell death. This antiviral activity against RSV was through the induction of type I interferon-related signaling and the antiviral state in HEp2 cells. More importantly, oral administration of CRE exhibited prophylactic effects in BALB/c mice against RSV. In HPLC analysis, we found the presence of several compounds in the aqueous fraction and among them; we confirmed that palmatine was related to the antiviral properties and immunemodulation effect. Taken together, an extract of Coptidis Rhizoma and its components play roles as immunomodulators and could be a potential source as promising natural antivirals that can confer protection to RSV. These outcomes should encourage further allied studies in other natural products.
Assuntos
Antivirais/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sincicial Respiratório Humano/crescimento & desenvolvimento , Replicação Viral/efeitos dos fármacos , Animais , Alcaloides de Berberina/farmacologia , Linhagem Celular , Coptis chinensis , Humanos , Fatores Imunológicos/farmacologia , Interferon beta/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/farmacologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacosRESUMO
FAS-associated factor-1 (FAF1) is a component of the death-inducing signaling complex involved in Fas-mediated apoptosis. It regulates NF-κB activity, ubiquitination, and proteasomal degradation. Here, we found that FAF1 positively regulates the type I interferon pathway. FAF1gt/gt mice, which deficient in FAF1, and FAF1 knockdown immune cells were highly susceptible to RNA virus infection and showed low levels of inflammatory cytokines and type I interferon (IFN) production. FAF1 was bound competitively to NLRX1 and positively regulated type I IFN signaling by interfering with the interaction between NLRX1 and MAVS, thereby freeing MAVS to bind RIG-I, which switched on the MAVS-RIG-I-mediated antiviral signaling cascade. These results highlight a critical role of FAF1 in antiviral responses against RNA virus infection.
Assuntos
Proteínas de Transporte/imunologia , Interferon Tipo I/imunologia , Infecções por Vírus de RNA/imunologia , Vírus de RNA/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Proteínas Reguladoras de Apoptose , Proteínas de Transporte/genética , Feminino , Humanos , Interferon Tipo I/genética , Peptídeos e Proteínas de Sinalização Intracelular , Macrófagos/imunologia , Macrófagos/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Infecções por Vírus de RNA/genética , Infecções por Vírus de RNA/virologiaRESUMO
AIM: To develop emerging diagnostic technique for bovine tuberculosis and to identify its potential risk factors. MATERIALS & METHODS: Bacterial genomic DNA was isolated from bovine milk and human sputum samples and subjected to PCR using specific primer pairs. PCR results were validated using bacteriological cultures. RESULTS: PCR amplification of the targeted DNA fragment of Mycobacterium bovis was successful in 12.33% (37/300) of the bovine samples. Interestingly, 500-bp DNA fragment was also amplified in 6.67% (6/90) of the sputum indicating the possibility of zoonotic transmission. Rearing of livestock in household, unpasteurized milk consumption and smoking were identified as potential risk factors. CONCLUSION: Results of the study may add value to bovine tuberculosis eradication campaigns to achieve the One Health initiative.