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1.
Int J Mol Sci ; 22(11)2021 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-34072418

RESUMEN

Staphylococcus aureus is one of the most prevalent pathogens associated with several types of biofilm-based infections, including infections of chronic wounds. Mature staphylococcal biofilm is extremely hard to eradicate from a wound and displays a high tendency to induce recurring infections. Therefore, in the present study, we aimed to investigate in vitro the interaction between S. aureus biofilm and fibroblast cells searching for metabolites that could be considered as potential biomarkers of critical colonization and infection. Utilizing advanced microscopy and microbiological methods to examine biofilm formation and the staphylococcal infection process, we were able to distinguish 4 phases of biofilm development. The analysis of staphylococcal biofilm influence on the viability of fibroblasts allowed us to pinpoint the moment of critical colonization-12 h post contamination. Based on the obtained model we performed a metabolomics analysis by 1H NMR spectroscopy to provide new insights into the pathophysiology of infection. We identified a set of metabolites related to the switch to anaerobic metabolism that was characteristic for staphylococcal biofilm co-cultured with fibroblast cells. The data presented in this study may be thus considered a noteworthy but preliminary step in the direction of developing a new, NMR-based tool for rapid diagnosing of infection in a chronic wound.


Asunto(s)
Biopelículas/crecimiento & desarrollo , Técnicas de Cocultivo , Fibroblastos/metabolismo , Fibroblastos/microbiología , Staphylococcus aureus/crecimiento & desarrollo , Staphylococcus aureus/metabolismo , Supervivencia Celular , Fibroblastos/ultraestructura , Técnica del Anticuerpo Fluorescente , Interacciones Huésped-Patógeno , Cinética , Espectroscopía de Resonancia Magnética , Metaboloma , Metabolómica/métodos , Staphylococcus aureus/ultraestructura
2.
Int J Mol Sci ; 22(11)2021 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-34072443

RESUMEN

As an important zoonotic pathogen, Streptococcus suis (S. suis) infection has been reported to be a causative agent for variety of diseases in humans and animals, especially Streptococcal toxic shock-like syndrome (STSLS), which is commonly seen in cases of severe S. suis infection. STSLS is often accompanied by excessive production of inflammatory cytokines, which is the main cause of death. This calls for development of new strategies to avert the damage caused by STSLS. In this study, we found for the first time that Baicalein, combined with ampicillin, effectively improved severe S. suis infection. Further experiments demonstrated that baicalein significantly inhibited the hemolytic activity of SLY by directly binding to SLY and destroying its secondary structure. Cell-based assays revealed that Baicalein did not exert toxic effects and conferred protection in S. suis-infected cells. Interestingly, compared with ampicillin alone, Baicalein combined with ampicillin resulted in a higher survival rate in mice severely infected with S. suis. At the same time, we found that baicalein can be combined with meropenem against MRSA. In conclusion, these results indicate that baicalein has a good application prospect.


Asunto(s)
Antibacterianos/farmacología , Flavanonas/farmacología , Infecciones Estreptocócicas/microbiología , Streptococcus suis/efectos de los fármacos , Animales , Antibacterianos/química , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Farmacorresistencia Bacteriana/efectos de los fármacos , Quimioterapia Combinada , Flavanonas/química , Hemólisis/efectos de los fármacos , Interacciones Huésped-Patógeno , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Infecciones Estreptocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/metabolismo , Infecciones Estreptocócicas/patología , Relación Estructura-Actividad
3.
Commun Biol ; 4(1): 715, 2021 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-34112887

RESUMEN

While SARS-CoV-2 is causing modern human history's most serious health crisis and upending our way of life, clinical and basic research on the virus is advancing rapidly, leading to fascinating discoveries. Two studies have revealed how the viral virulence factor, nonstructural protein 1 (Nsp1), binds human ribosomes to inhibit host cell translation. Here, we examine the main conclusions on the molecular activity of Nsp1 and its role in suppressing innate immune responses. We discuss different scenarios potentially explaining how the viral RNA can bypass its own translation blockage and speculate on the suitability of Nsp1 as a therapeutic target.


Asunto(s)
Interacciones Huésped-Patógeno/fisiología , Ribosomas/virología , SARS-CoV-2/patogenicidad , Proteínas no Estructurales Virales/metabolismo , Regiones no Traducidas 5' , Regulación Viral de la Expresión Génica , Humanos , Inmunidad Innata , Biosíntesis de Proteínas , ARN Mensajero/metabolismo , Ribosomas/metabolismo , SARS-CoV-2/genética , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/genética
4.
Viruses ; 13(6)2021 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-34064125

RESUMEN

To initiate infection, a virus enters a host cell typically via receptor-dependent endocytosis. It then penetrates a subcellular membrane, reaching a destination that supports transcription, translation, and replication of the viral genome. These steps lead to assembly and morphogenesis of the new viral progeny. The mature virus finally exits the host cell to begin the next infection cycle. Strikingly, viruses hijack host molecular chaperones to accomplish these distinct entry steps. Here we highlight how DNA viruses, including polyomavirus and the human papillomavirus, exploit soluble and membrane-associated chaperones to enter a cell, penetrating and escaping an intracellular membrane en route for infection. We also describe the mechanism by which RNA viruses-including flavivirus and coronavirus-co-opt cytosolic and organelle-selective chaperones to promote viral endocytosis, protein biosynthesis, replication, and assembly. These examples underscore the importance of host chaperones during virus infection, potentially revealing novel antiviral strategies to combat virus-induced diseases.


Asunto(s)
Virus ADN/fisiología , Chaperonas Moleculares/metabolismo , Virus ARN/fisiología , Citosol/metabolismo , Virus ADN/metabolismo , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/virología , Endosomas/metabolismo , Endosomas/virología , Interacciones Huésped-Patógeno , Membranas Intracelulares/metabolismo , Virus ARN/metabolismo , Internalización del Virus , Replicación Viral
5.
Cells ; 10(5)2021 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-34065953

RESUMEN

Macrophages play a key role in induction of inflammatory responses. These inflammatory responses are mostly considered to be instigated by activation of pattern recognition receptors (PRRs) or cytokine receptors. However, recently it has become clear that also antibodies and pentraxins, which can both activate Fc receptors (FcRs), induce very powerful inflammatory responses by macrophages that can even be an order of magnitude greater than PRRs. While the physiological function of this antibody-dependent inflammation (ADI) is to counteract infections, undesired activation or over-activation of this mechanism will lead to pathology, as observed in a variety of disorders, including viral infections such as COVID-19, chronic inflammatory disorders such as Crohn's disease, and autoimmune diseases such as rheumatoid arthritis. In this review we discuss how physiological ADI provides host defense by inducing pathogen-specific immunity, and how erroneous activation of this mechanism leads to pathology. Moreover, we will provide an overview of the currently known signaling and metabolic pathways that underlie ADI, and how these can be targeted to counteract pathological inflammation.


Asunto(s)
Anticuerpos/metabolismo , Proteína C-Reactiva/metabolismo , Inflamación/inmunología , Componente Amiloide P Sérico/metabolismo , Anticuerpos/inmunología , Proteína C-Reactiva/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Innata , Inflamación/metabolismo , Inflamación/microbiología , Macrófagos/inmunología , Macrófagos/metabolismo , Redes y Vías Metabólicas/inmunología , Receptores Fc/metabolismo , Componente Amiloide P Sérico/inmunología , Transducción de Señal/inmunología
6.
Int J Mol Sci ; 22(10)2021 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-34070159

RESUMEN

Pathogens are one of the main selective pressures that ancestral humans had to adapt to. Components of the immune response system have been preferential targets of natural selection in response to such pathogen-driven pressure. In turn, there is compelling evidence showing that positively selected immune gene variants conferring increased resistance to past or present infectious agents are today associated with increased risk for autoimmune or inflammatory disorders but decreased risk of cancer, the other side of the same coin. CD5 and CD6 are lymphocytic scavenger receptors at the interphase of the innate and adaptive immune responses since they are involved in both: (i) microbial-associated pattern recognition; and (ii) modulation of intracellular signals mediated by the clonotypic antigen-specific receptor present in T and B cells (TCR and BCR, respectively). Here, we review available information on CD5 and CD6 as targets of natural selection as well as on the role of CD5 and CD6 variation in autoimmunity and cancer.


Asunto(s)
Antígenos CD/genética , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos CD5/genética , Enfermedades del Sistema Inmune/genética , Polimorfismo Genético , Selección Genética , Animales , Autoinmunidad/genética , Linfocitos B/inmunología , Evolución Molecular , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Ratones , Neoplasias/genética , Neoplasias/inmunología , Receptores Depuradores/genética , Linfocitos T/inmunología
7.
Int J Med Sci ; 18(12): 2561-2569, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34104087

RESUMEN

SARS-CoV-2 infection poses a global challenge to human health. Upon viral infection, host cells initiate the innate antiviral response, which primarily involves type I interferons (I-IFNs), to enable rapid elimination of the invading virus. Previous studies revealed that SARS-CoV-2 infection limits the expression of I-IFNs in vitro and in vivo, but the underlying mechanism remains incompletely elucidated. In the present study, we performed data mining and longitudinal data analysis using SARS-CoV-2-infected normal human bronchial epithelial (NHBE) cells and ferrets, and the results confirmed the strong inhibitory effect of SARS-CoV-2 on the induction of I-IFNs. Moreover, we identified genes that are negatively correlated with IFNB1 expression in vitro and in vivo based on Pearson correlation analysis. We found that SARS-CoV-2 activates numerous intrinsic pathways, such as the circadian rhythm, phosphatidylinositol signaling system, peroxisome, and TNF signaling pathways, to inhibit I-IFNs. These intrinsic inhibitory pathways jointly facilitate the successful immune evasion of SARS-CoV-2. Our study elucidates the underlying mechanism by which SARS-CoV-2 evades the host innate antiviral response in vitro and in vivo, providing theoretical evidence for targeting these immune evasion-associated pathways to combat SARS-CoV-2 infection.


Asunto(s)
COVID-19/inmunología , Interacciones Huésped-Patógeno/inmunología , Interferón gamma/metabolismo , SARS-CoV-2/inmunología , Animales , Bronquios/citología , COVID-19/virología , Línea Celular , Conjuntos de Datos como Asunto , Modelos Animales de Enfermedad , Células Epiteliales , Hurones , Regulación de la Expresión Génica/inmunología , Interacciones Huésped-Patógeno/genética , Humanos , Inmunidad Innata , Interferón gamma/inmunología , RNA-Seq , Mucosa Respiratoria/citología , Transducción de Señal/genética , Transducción de Señal/inmunología
8.
Molecules ; 26(10)2021 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-34068970

RESUMEN

Due to the complicated pathogenic pathways of coronavirus disease 2019 (COVID-19), related medicinal therapies have remained a clinical challenge. COVID-19 highlights the urgent need to develop mechanistic pathogenic pathways and effective agents for preventing/treating future epidemics. As a result, the destructive pathways of COVID-19 are in the line with clinical symptoms induced by severe acute coronary syndrome (SARS), including lung failure and pneumonia. Accordingly, revealing the exact signaling pathways, including inflammation, oxidative stress, apoptosis, and autophagy, as well as relative representative mediators such as tumor necrosis factor-α (TNF-α), nuclear factor erythroid 2-related factor 2 (Nrf2), Bax/caspases, and Beclin/LC3, respectively, will pave the road for combating COVID-19. Prevailing host factors and multiple steps of SARS-CoV-2 attachment/entry, replication, and assembly/release would be hopeful strategies against COVID-19. This is a comprehensive review of the destructive signaling pathways and host-pathogen interaction of SARS-CoV-2, as well as related therapeutic targets and treatment strategies, including potential natural products-based candidates.


Asunto(s)
Antivirales/uso terapéutico , Productos Biológicos/uso terapéutico , COVID-19/tratamiento farmacológico , COVID-19/metabolismo , Interacciones Huésped-Patógeno/efectos de los fármacos , SARS-CoV-2/fisiología , Transducción de Señal/efectos de los fármacos , Humanos
9.
Genes (Basel) ; 12(6)2021 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-34071309

RESUMEN

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection provides a critical host-immunological challenge. AIM: We explore the effect of host-genetic variation in interferon-lambda-3 rs12979860, Tolloid Like-1 (TLL1) rs17047200 and Discoidin domain receptor 1(DDR1) rs4618569 on host response to respiratory viral infections and disease severity that may probe the mechanistic approach of allelic variation in virus-induced inflammatory responses. METHODS: 141 COVID-19 positive patients and 100 healthy controls were tested for interferon-lambda-3 rs12979860, TLL1 rs17047200 and DDR1 rs4618569 polymorphism by TaqMan probe-based genotyping. Different genotypes were assessed regarding the COVID-19 severity and prognosis. RESULTS: There were statistically significant differences between the studied cases and control group with regard to the presence of comorbidities, total leucocytic count, lymphocytic count, CRP, serum LDH, ferritin and D-dimer (p < 0.01). The CC genotype of rs12979860 cytokine, the AA genotype of TLL1 rs17047200 and the AA genotype of the rs4618569 variant of DDR1 showed a higher incidence of COVID-19 compared to the others. There were significant differences between the rs4618569 variant of DDR and the outcome of the disease, with the highest mortality in AG genotype 29 (60.4%) in comparison to 16 (33.3%) and 3 (6.2%) in the AA and GG genotypes, respectively (p = 0.007*), suggesting that the A allele is associated with a poor outcome in the disease. CONCLUSION: Among people who carry C and A alleles of SNPs IFN-λ rs12979860 and TLL1 rs17047200, respectively, the AG genotype of the DDR1 rs4618569 variant is correlated with a COVID-19 poor outcome. In those patients, the use of anti-IFN-λ 3, TLL1 and DDR1 therapy may be promising for personalized translational clinical practice.


Asunto(s)
COVID-19/genética , COVID-19/virología , Receptor con Dominio Discoidina 1/genética , Predisposición Genética a la Enfermedad , Interferones/genética , Polimorfismo de Nucleótido Simple , SARS-CoV-2/fisiología , Metaloproteinasas Similares a Tolloid/genética , Alelos , Biomarcadores , COVID-19/diagnóstico , COVID-19/inmunología , Estudios de Casos y Controles , Comorbilidad , Citocinas/metabolismo , Femenino , Genotipo , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Innata , Masculino , Pronóstico , Índice de Severidad de la Enfermedad , Carga Viral
10.
Genes (Basel) ; 12(6)2021 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-34072181

RESUMEN

The genomic diversity of SARS-CoV-2 has been a focus during the ongoing COVID-19 pandemic. Here, we analyzed the distribution and character of emerging mutations in a data set comprising more than 95,000 virus genomes covering eight major SARS-CoV-2 lineages in the GISAID database, including genotypes arising during COVID-19 therapy. Globally, the C>U transitions and G>U transversions were the most represented mutations, accounting for the majority of single-nucleotide variations. Mutational spectra were not influenced by the time the virus had been circulating in its host or medical treatment. At the amino acid level, we observed about a 2-fold excess of substitutions in favor of hydrophobic amino acids over the reverse. However, most mutations constituting variants of interests of the S-protein (spike) lead to hydrophilic amino acids, counteracting the global trend. The C>U and G>U substitutions altered codons towards increased amino acid hydrophobicity values in more than 80% of cases. The bias is explained by the existing differences in the codon composition for amino acids bearing contrasting biochemical properties. Mutation asymmetries apparently influence the biochemical features of SARS CoV-2 proteins, which may impact protein-protein interactions, fusion of viral and cellular membranes, and virion assembly.


Asunto(s)
COVID-19/virología , Genoma Viral , Interacciones Hidrofóbicas e Hidrofílicas , Mutación , SARS-CoV-2/genética , Proteínas Virales/química , Proteínas Virales/genética , Desaminasas APOBEC , Alelos , Sustitución de Aminoácidos , Aminoácidos/química , Aminoácidos/genética , Evolución Molecular , Variación Genética , Genotipo , Interacciones Huésped-Patógeno , Humanos , Filogenia , Polimorfismo de Nucleótido Simple , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética
11.
Genes (Basel) ; 12(6)2021 05 24.
Artículo en Inglés | MEDLINE | ID: mdl-34073716

RESUMEN

The current SARS-CoV-2 pandemic is still threatening humankind. Despite first successes in vaccine development and approval, no antiviral treatment is available for COVID-19 patients. The success is further tarnished by the emergence and spreading of mutation variants of SARS-CoV-2, for which some vaccines have lower efficacy. This highlights the urgent need for antiviral therapies even more. This article describes how the genome-scale metabolic model (GEM) of the host-virus interaction of human alveolar macrophages and SARS-CoV-2 was refined by incorporating the latest information about the virus's structural proteins and the mutant variants B.1.1.7, B.1.351, B.1.28, B.1.427/B.1.429, and B.1.617. We confirmed the initially identified guanylate kinase as a potential antiviral target with this refined model and identified further potential targets from the purine and pyrimidine metabolism. The model was further extended by incorporating the virus' lipid requirements. This opened new perspectives for potential antiviral targets in the altered lipid metabolism. Especially the phosphatidylcholine biosynthesis seems to play a pivotal role in viral replication. The guanylate kinase is even a robust target in all investigated mutation variants currently spreading worldwide. These new insights can guide laboratory experiments for the validation of identified potential antiviral targets. Only the combination of vaccines and antiviral therapies will effectively defeat this ongoing pandemic.


Asunto(s)
COVID-19/metabolismo , COVID-19/virología , Metabolismo Energético , Genoma Viral , Guanilato-Quinasas/metabolismo , Interacciones Huésped-Patógeno , Mutación , SARS-CoV-2/genética , Antivirales/farmacología , Antivirales/uso terapéutico , COVID-19/tratamiento farmacológico , COVID-19/genética , Técnicas de Silenciamiento del Gen , Humanos , Metabolismo de los Lípidos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/virología , SARS-CoV-2/efectos de los fármacos , Carga Viral , Replicación Viral
12.
MAbs ; 13(1): 1919285, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34074219

RESUMEN

The newly emerging variants of SARS-CoV-2 from South Africa (B.1.351/501Y.V2) and Brazil (P.1/501Y.V3) have led to a higher infection rate and reinfection of COVID-19 patients. We found that the mutations K417N, E484K, and N501Y within the receptor-binding domains (RBDs) of the virus could confer ~2-fold higher binding affinity to the human receptor, angiotensin converting enzyme 2 (ACE2), compared to the wildtype RBD. The mutated version of RBD also completely abolishes the binding of bamlanivimab, a therapeutic antibody, in vitro. Detailed analysis shows that the ~10-fold gain of binding affinity between ACE2 and Y501-RBD, which also exits in the high contagious variant B.1.1.7/501Y.V1 from the United Kingdom, is compromised by additional introduction of the K417/N/T mutation. Mutation of E484K leads to the loss of bamlanivimab binding to RBD, although this mutation does not affect the binding between RBD and ACE2.


Asunto(s)
Anticuerpos Monoclonales Humanizados/metabolismo , Antivirales/metabolismo , COVID-19/virología , Mutación , SARS-CoV-2/metabolismo , Enzima Convertidora de Angiotensina 2/metabolismo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , Sitios de Unión , COVID-19/diagnóstico , COVID-19/tratamiento farmacológico , Interacciones Huésped-Patógeno , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Receptores Virales/metabolismo , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/genética
13.
Nat Commun ; 12(1): 3392, 2021 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-34099666

RESUMEN

Cells infected with pathogens can contribute to clearing infections by releasing signals that instruct neighbouring cells to mount a pro-inflammatory cytokine response, or by other mechanisms that reduce bystander cells' susceptibility to infection. Here, we show the opposite effect: epithelial cells infected with Salmonella Typhimurium secrete host factors that facilitate the infection of bystander cells. We find that the endoplasmic reticulum stress response is activated in both infected and bystander cells, and this leads to activation of JNK pathway, downregulation of transcription factor E2F1, and consequent reprogramming of microRNA expression in a time-dependent manner. These changes are not elicited by infection with other bacterial pathogens, such as Shigella flexneri or Listeria monocytogenes. Remarkably, the protein HMGB1 present in the secretome of Salmonella-infected cells is responsible for the activation of the IRE1 branch of the endoplasmic reticulum stress response in non-infected, neighbouring cells. Furthermore, E2F1 downregulation and the associated microRNA alterations promote Salmonella replication within infected cells and prime bystander cells for more efficient infection.


Asunto(s)
Efecto Espectador/genética , Factor de Transcripción E2F1/metabolismo , MicroARNs/metabolismo , Infecciones por Salmonella/inmunología , Salmonella typhimurium/inmunología , Animales , Efecto Espectador/inmunología , Modelos Animales de Enfermedad , Regulación hacia Abajo/inmunología , Factor de Transcripción E2F1/genética , Estrés del Retículo Endoplásmico/inmunología , Endorribonucleasas/metabolismo , Proteína HMGB1/metabolismo , Células HeLa , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Listeria monocytogenes/inmunología , Sistema de Señalización de MAP Quinasas/genética , Sistema de Señalización de MAP Quinasas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , RNA-Seq , Infecciones por Salmonella/genética , Infecciones por Salmonella/microbiología , Salmonella typhimurium/patogenicidad , Shigella flexneri/inmunología , Porcinos
14.
FASEB J ; 35(7): e21713, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34105201

RESUMEN

Syrian golden hamsters (Mesocricetus auratus) infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) manifests lung pathology. In this study, efforts were made to check the infectivity of a local SARS-CoV-2 isolate in a self-limiting and non-lethal hamster model and evaluate the differential expression of lung proteins during acute infection and convalescence. The findings of this study confirm the infectivity of this isolate in vivo. Analysis of clinical parameters and tissue samples show the pathophysiological manifestation of SARS-CoV-2 infection similar to that reported earlier in COVID-19 patients and hamsters infected with other isolates. However, diffuse alveolar damage (DAD), a common histopathological feature of human COVID-19 was only occasionally noticed. The lung-associated pathological changes were very prominent on the 4th day post-infection (dpi), mostly resolved by 14 dpi. Here, we carried out the quantitative proteomic analysis of the lung tissues from SARS-CoV-2-infected hamsters on day 4 and day 14 post-infection. This resulted in the identification of 1585 proteins of which 68 proteins were significantly altered between both the infected groups. Pathway analysis revealed complement and coagulation cascade, platelet activation, ferroptosis, and focal adhesion as the top enriched pathways. In addition, we also identified altered expression of two pulmonary surfactant-associated proteins (Sftpd and Sftpb), known for their protective role in lung function. Together, these findings will aid in understanding the mechanism(s) involved in SARS-CoV-2 pathogenesis and progression of the disease.


Asunto(s)
COVID-19/metabolismo , COVID-19/patología , Interacciones Huésped-Patógeno , Pulmón/metabolismo , Pulmón/virología , Proteómica , SARS-CoV-2/patogenicidad , Animales , COVID-19/virología , Cricetinae , Modelos Animales de Enfermedad , Femenino , Pulmón/patología , Masculino , Proteoma/análisis , Proteoma/biosíntesis , Reproducibilidad de los Resultados , Carga Viral
15.
Microb Pathog ; 157: 105011, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34062227

RESUMEN

BACKGROUND: Several studies have linked chronic typhoid infection with gallbladder carcinoma without completely understood mechanism. This study was performed in order to understand role of Salmonella in gallbladder cancer etiology. METHODS: Known Salmonella host-pathogen interactions were screened from database in addition to known gallbladder carcinoma targets. Host-pathogen interaction map of S. enterica was prepared and screened for interactions with gallbladder carcinoma targets. Further functional overrepresentation analysis was performed to understand the role of human targets involved in Salmonella host-pathogen interactions in gallbladder carcinoma. RESULTS: Salmonella interact with several human proteins involved in gallbladder carcinoma. MAPK and RAC1 are the most important human proteins based on node degree value among all GBC associated interactors identified in current data search. Functional over-representation analysis reveals that Salmonella can induce adenocarcinoma which constitutes 85% of gallbladder cancer. CONCLUSION: Though, the role of MAPK/ERK and PI3K/AKT/mTOR pathway is already suggested for Salmonella mediated gallbladder cancer, but current data based approach indicate several new insight for exploration of the role of Salmonella in gallbladder cancer etiology. The results indicate about several other processes including CREB/SP-1 and BSG(CD147) signaling, that must be given consideration for understanding the role of Salmonella in gallbladder cancer.


Asunto(s)
Neoplasias de la Vesícula Biliar , Salmonella enterica , Interacciones Huésped-Patógeno , Humanos , Fosfatidilinositol 3-Quinasas , Salmonella
16.
Int J Mol Sci ; 22(11)2021 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-34071094

RESUMEN

Three main approaches are used to combat severe viral respiratory infections. The first is preemptive vaccination that blocks infection. Weakened or dead viral particles, as well as genetic constructs carrying viral proteins or information about them, are used as an antigen. However, the viral genome is very evolutionary labile and changes continuously. Second, chemical agents are used during infection and inhibit the function of a number of viral proteins. However, these drugs lose their effectiveness because the virus can rapidly acquire resistance to them. The third is the search for points in the host metabolism the effect on which would suppress the replication of the virus but would not have a significant effect on the metabolism of the host. Here, we consider the possibility of using the copper metabolic system as a target to reduce the severity of influenza infection. This is facilitated by the fact that, in mammals, copper status can be rapidly reduced by silver nanoparticles and restored after their cancellation.


Asunto(s)
Cobre/metabolismo , Virus de la Influenza A/fisiología , Gripe Humana/metabolismo , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , Ceruloplasmina/fisiología , Proteínas Transportadoras de Cobre/metabolismo , ATPasas Transportadoras de Cobre/fisiología , Farmacorresistencia Viral , Interacciones Huésped-Patógeno , Humanos , Vacunas contra la Influenza , Gripe Humana/tratamiento farmacológico , Gripe Humana/prevención & control , Gripe Humana/virología , Mamíferos/metabolismo , Nanopartículas del Metal/uso terapéutico , Chaperonas Moleculares/metabolismo , Proteínas PrPC/fisiología , ARN Viral/fisiología , Plata/uso terapéutico , Superóxido Dismutasa-1/fisiología , Proteínas Virales/fisiología , Replicación Viral
18.
Nat Commun ; 12(1): 2855, 2021 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-34001896

RESUMEN

Ebola virus (EBOV) causes neurological symptoms yet its effects on the central nervous system (CNS) are not well-described. Here, we longitudinally assess the acute effects of EBOV on the brain, using quantitative MR-relaxometry, 18F-Fluorodeoxyglucose PET and immunohistochemistry in a monkey model. We report blood-brain barrier disruption, likely related to high cytokine levels and endothelial viral infection, with extravasation of fluid, Gadolinium-based contrast material and albumin into the extracellular space. Increased glucose metabolism is also present compared to the baseline, especially in the deep gray matter and brainstem. This regional hypermetabolism corresponds with mild neuroinflammation, sporadic neuronal infection and apoptosis, as well as increased GLUT3 expression, consistent with increased neuronal metabolic demands. Neuroimaging changes are associated with markers of disease progression including viral load and cytokine/chemokine levels. Our results provide insight into the pathophysiology of CNS involvement with EBOV and may help assess vaccine/treatment efficacy in real time.


Asunto(s)
Encéfalo/diagnóstico por imagen , Modelos Animales de Enfermedad , Fluorodesoxiglucosa F18 , Fiebre Hemorrágica Ebola/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Animales , Barrera Hematoencefálica/diagnóstico por imagen , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/virología , Encéfalo/metabolismo , Encéfalo/virología , Citocinas/metabolismo , Ebolavirus/fisiología , Haplorrinos , Fiebre Hemorrágica Ebola/virología , Interacciones Huésped-Patógeno , Humanos
19.
Mol Med ; 27(1): 49, 2021 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-34022793

RESUMEN

A SARS-like coronavirus 2 (SARS-CoV-2) has caused a pandemic Coronavirus Disease 2019 (COVID-19) that killed more than 3.3 million people worldwide. Like the SARS-CoV, SARS-CoV-2 also employs a receptor-binding motif (RBM) of its spike protein to bind a host receptor, the angiotensin-converting enzyme 2 (ACE2), to gain entry. Currently, several mRNA or adenoviral vaccines encoding for the spike protein of SARS-CoV-2 are being used to boost antibodies capable of inhibiting spike-ACE2 interaction and viral entry. However, recent evidence has also suggested an anti-inflammatory effect of spike-reactive antibodies, suggesting that some SARS-CoV-2 spike-based vaccines may elicit protective antibodies capable of inhibiting GM-CSF production and COVID-19 progression.


Asunto(s)
Enzima Convertidora de Angiotensina 2/metabolismo , Anticuerpos Neutralizantes/metabolismo , Vacunas contra la COVID-19/uso terapéutico , COVID-19/prevención & control , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Glicoproteína de la Espiga del Coronavirus/metabolismo , Anticuerpos Neutralizantes/inmunología , COVID-19/metabolismo , COVID-19/virología , Vacunas contra la COVID-19/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Unión Proteica/efectos de los fármacos , SARS-CoV-2/inmunología , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiología , Glicoproteína de la Espiga del Coronavirus/inmunología , Internalización del Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacos
20.
Sci Rep ; 11(1): 9378, 2021 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-33931664

RESUMEN

The Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus needs a fast recognition of effective drugs to save lives. In the COVID-19 situation, finding targets for drug repurposing can be an effective way to present new fast treatments. We have designed a two-step solution to address this approach. In the first step, we identify essential proteins from virus targets or their associated modules in human cells as possible drug target candidates. For this purpose, we apply two different algorithms to detect some candidate sets of proteins with a minimum size that drive a significant disruption in the COVID-19 related biological networks. We evaluate the resulted candidate proteins sets with three groups of drugs namely Covid-Drug, Clinical-Drug, and All-Drug. The obtained candidate proteins sets approve 16 drugs out of 18 in the Covid-Drug, 273 drugs out of 328 in the Clinical-Drug, and a large number of drugs in the All-Drug. In the second step, we study COVID-19 associated proteins sets and recognize proteins that are essential to disease pathology. This analysis is performed using DAVID to show and compare essential proteins that are contributed between the COVID-19 comorbidities. Our results for shared proteins show significant enrichment for cardiovascular-related, hypertension, diabetes type 2, kidney-related and lung-related diseases.


Asunto(s)
COVID-19/tratamiento farmacológico , Reposicionamiento de Medicamentos , Mapas de Interacción de Proteínas , Antivirales/uso terapéutico , COVID-19/metabolismo , Sistemas de Liberación de Medicamentos , Interacciones Huésped-Patógeno , Humanos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/fisiología , Transducción de Señal/efectos de los fármacos
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