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1.
Food Chem ; 404(Pt A): 134593, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36444017

RESUMO

High-throughput sequencing techniques can provide important information for understanding the interaction between exogenous microbial agents and fruit microbial communities, and explain how it controls postharvest fungal diseases. In this study, we found that Wickerhamomyces anomalus could control the postharvest disease of kiwifruit. Meanwhile, high-throughput sequencing technology results showed that the composition and structure changes of the fungal community in microbial flora were significantly greater than those of bacteria after W. anomalus treated. W. anomalus could colonize inside the fruit and regulate the community composition of bacteria to reduce the abundance of pathogens and eventually maintain the healthy state of the fruit. The dominant genus in the microbiota of kiwifruit after application of W. anomalus showed an increased ability to interact. Some fungi or bacteria are positively associated with yeast in the epiphytic and endophytic sample communities, guiding the synthesis of compound biocontrol strains for kiwifruit postharvest diseases.


Assuntos
Actinidia , Contaminação de Alimentos , Frutas , Microbiota , Saccharomycetales , Actinidia/microbiologia , Frutas/microbiologia , Armazenamento de Alimentos , Contaminação de Alimentos/prevenção & controle , Fungos/patogenicidade
2.
Sci Rep ; 12(1): 20518, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36443356

RESUMO

Lagovirus europaeus GI.1 belongs to Lagovirus in the Caliciviridae family. GI.1 causes an acute, septic, and highly lethal disease in rabbits. Lagovirus europaeus GI.2, a new variant of GI.1, has caused explosive mortality in rabbits of all ages in Sichuan Province, China. To explore the differences in pathogenicity of rabbits infected with GI.1/GI.2, we investigated the virulence and disease progression of a naturally occurring GI.1/GI.2 in 4-week-old, 13-week-old, and 25-week-old New Zealand White laboratory rabbits after GI.1/GI.2 infection. Objective measures of disease progression were recorded using continuous body-temperature monitoring. We observed the kittens were infected with GI.2 during the most urgent course of the disease, and GI.1 was not lethal to kittens. We found that the target organ of both GI.1 and GI.2 was the liver, but the disease course of the two viruses was differed. Our study enriches the research on the pathogenicity of GI.1 and GI.2 under the same conditions.


Assuntos
Lagomorpha , Lagovirus , Animais , Coelhos , China , Progressão da Doença , Lagovirus/genética , Lagovirus/patogenicidade , Virulência , Infecções por Caliciviridae/epidemiologia
3.
J Mol Biol ; 434(23): 167871, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36404438

RESUMO

Porphyromonas gingivalis is a gram-negative oral anaerobic pathogen and is one of the key causative agents of periodontitis. P. gingivalis utilises a range of virulence factors, including the cysteine protease RgpB, to drive pathogenesis and these are exported and attached to the cell surface via the type IX secretion system (T9SS). All cargo proteins possess a conserved C-terminal signal domain (CTD) which is recognised by the T9SS, and the outer membrane ß-barrel protein PorV (PG0027/LptO) can interact with cargo proteins as they are exported to the bacterial surface. Using a combination of solution nuclear magnetic resonance (NMR) spectroscopy, biochemical analyses, machine-learning-based modelling and molecular dynamics (MD) simulations, we present a structural model of a PorV:RgpB-CTD complex from P. gingivalis. This is the first structural insight into CTD recognition by the T9SS and shows how the conserved motifs in the CTD are the primary sites that mediate binding. In PorV, interactions with extracellular surface loops are important for binding the CTD, and together these appear to cradle and lock RgpB-CTD in place. This work provides insight into cargo recognition by PorV but may also have important implications for understanding other aspects of type-IX dependent secretion.


Assuntos
Proteínas de Bactérias , Sistemas de Secreção Bacterianos , Proteínas de Membrana , Simulação de Dinâmica Molecular , Porphyromonas gingivalis , Proteínas de Bactérias/química , Proteínas de Membrana/química , Porphyromonas gingivalis/metabolismo , Porphyromonas gingivalis/patogenicidade , Fatores de Virulência/química , Sistemas de Secreção Bacterianos/química , Domínios Proteicos
4.
Nature ; 611(7937): 780-786, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36385534

RESUMO

Enteric pathogens are exposed to a dynamic polymicrobial environment in the gastrointestinal tract1. This microbial community has been shown to be important during infection, but there are few examples illustrating how microbial interactions can influence the virulence of invading pathogens2. Here we show that expansion of a group of antibiotic-resistant, opportunistic pathogens in the gut-the enterococci-enhances the fitness and pathogenesis of Clostridioides difficile. Through a parallel process of nutrient restriction and cross-feeding, enterococci shape the metabolic environment in the gut and reprogramme C. difficile metabolism. Enterococci provide fermentable amino acids, including leucine and ornithine, which increase C. difficile fitness in the antibiotic-perturbed gut. Parallel depletion of arginine by enterococci through arginine catabolism provides a metabolic cue for C. difficile that facilitates increased virulence. We find evidence of microbial interaction between these two pathogenic organisms in multiple mouse models of infection and patients infected with C. difficile. These findings provide mechanistic insights into the role of pathogenic microbiota in the susceptibility to and the severity of C. difficile infection.


Assuntos
Clostridioides difficile , Enterococcus , Interações Microbianas , Animais , Humanos , Camundongos , Antibacterianos/farmacologia , Arginina/deficiência , Arginina/metabolismo , Clostridioides difficile/metabolismo , Clostridioides difficile/patogenicidade , Clostridioides difficile/fisiologia , Modelos Animais de Doenças , Farmacorresistência Bacteriana , Enterococcus/efeitos dos fármacos , Enterococcus/metabolismo , Enterococcus/patogenicidade , Enterococcus/fisiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Intestinos/metabolismo , Intestinos/microbiologia , Leucina/metabolismo , Ornitina/metabolismo , Virulência , Suscetibilidade a Doenças
5.
Science ; 378(6617): 242-245, 2022 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-36264794
6.
FASEB J ; 36(11): e22599, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36250902

RESUMO

Emerging evidence suggest that C3aR plays important roles in homeostasis, host defense and disease. Although it is known that C3aR is protective in several models of acute bacterial infections, the role for C3aR in chronic infection is largely unknown. Here we show that C3aR is protective in experimental chronic pyelonephritis. Global C3aR deficient (C3ar-/- ) mice had higher renal bacterial load, more pronounced renal histological lesions, increased renal apoptotic cell accumulation, tissue inflammation and extracellular matrix deposition following renal infection with uropathogenic E. coli (UPEC) strain IH11128, compared to WT control mice. Myeloid C3aR deficient (Lyz2-C3ar-/- ) mice exhibited a similar disease phenotype to global C3ar-/- mice. Pharmacological treatment with a C3aR agonist reduced disease severity in experimental chronic pyelonephritis. Furthermore, macrophages of C3ar-/- mice exhibited impaired ability to phagocytose UPEC. Our data clearly demonstrate a protective role for C3aR against experimental chronic pyelonephritis, macrophage C3aR plays a major role in the protection, and C3aR is necessary for phagocytosis of UPEC by macrophages. Our observation that C3aR agonist curtailed the pathology suggests a therapeutic potential for activation of C3aR in chronic infection.


Assuntos
Infecções por Escherichia coli , Pielonefrite , Receptores de Complemento , Animais , Camundongos , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/patologia , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/patologia , Rim/microbiologia , Rim/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Pielonefrite/imunologia , Pielonefrite/microbiologia , Pielonefrite/patologia , Pielonefrite/prevenção & controle , Escherichia coli Uropatogênica/patogenicidade , Receptores de Complemento/agonistas , Receptores de Complemento/deficiência , Receptores de Complemento/genética , Receptores de Complemento/imunologia , Matriz Extracelular/metabolismo
7.
Antimicrob Agents Chemother ; 66(11): e0078722, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36200773

RESUMO

OXA-48 is the most common carbapenemase in Enterobacterales in Germany and many other European countries. Depending on the genomic location of blaOXA-48, OXA-48-producing isolates vary in phenotype and intra- and interspecies transferability of blaOXA-48. In most bacterial isolates, blaOXA-48 is located on one of seven variants of Tn1999 (Tn1999.1 to Tn1999.6 and invTn1999.2). Here, a novel Tn1999 variant, Tn1999.7, is described, which was identified in 11 clinical isolates from 2016 to 2020. Tn1999.7 differs from Tn1999.1 by the insertion of the 8,349-bp Tn3 family transposon Tn7442 between the lysR gene and blaOXA-48 open reading frame. Tn7442 carries genes coding for a restriction endonuclease and a DNA methyltransferase as cargo, forming a type III restriction modification system. Tn1999.7 was carried on an ~71-kb IncL plasmid in 9/11 isolates. In one isolate, Tn1999.7 was situated on an ~76-kb plasmid, harboring an additional insertion sequence in the plasmid backbone. In one isolate, the plasmid size is only ~63 kb due to a deletion adjacent to Tn7442 that extends into the plasmid backbone. Mean conjugation rates of the Tn1999.7-harboring plasmids in J53 ranged from 4.47 × 10-5 to 2.03 × 10-2, similar to conjugation rates of other pOXA-48-type IncL plasmids. The stability of plasmids with Tn1999.7 was significantly higher than that of a Tn1999.2-harboring plasmid in vitro. This increase in stability could be related to the insertion of a restriction-modification system, which can promote postsegregational killing. The increased plasmid stability associated with Tn1999.7 could contribute to the further spread of OXA-48.


Assuntos
Proteínas de Bactérias , Elementos de DNA Transponíveis , Plasmídeos , beta-Lactamases , Proteínas de Bactérias/genética , beta-Lactamases/genética , beta-Lactamases/metabolismo , Elementos de DNA Transponíveis/genética , Europa (Continente) , Alemanha , Plasmídeos/genética , Enterobacteriaceae/genética , Enterobacteriaceae/patogenicidade , Variação Genética
8.
Environ Pollut ; 314: 120294, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36181932

RESUMO

Per- and Poly-fluoroalkyl substances (PFAS) are major persistent environmental contaminants. Epidemiological studies have linked PFAS exposures to altered immunity and increased occurrence of infections in children. However, the mechanisms leading to immune susceptibility to bacterial infections remains unclear. To elucidate the mechanism, transcriptional alteration in the Caenorhabditis elegans model caused by a PFAS contaminated environmental water and two reconstituted PFAS solutions were evaluated using RNA-sequencing. PFAS affected the expression of several genes involved in C. elegans immune surveillance to Gram-positive bacteria (cpr-2, tag-38, spp-1, spp-5, clec-7, clec-172). The combined exposure to PFAS and Staphylococcus aureus significantly reduced C. elegans survival and increased intestinal membrane permeability. Furthermore, the growth of S. aureus in the presence of PFAS increased the expression of virulence genes, specifically, the virulence gene regulator saeR and α-hemolysin, hla, which resulted in increased hemolytic activity. The present study demonstrated that PFAS exposure not only increased C. elegans susceptibility to pathogens by reducing host immunity and increasing intestinal membrane permeability, but also increased bacteria virulence. This presents a broader implication for humans and other animals, where environmental contaminants simultaneously reduce host resilience, while, increasing microbial pathogenicity.


Assuntos
Caenorhabditis elegans , Fluorcarbonetos , Staphylococcus aureus , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/imunologia , Caenorhabditis elegans/microbiologia , Fluorcarbonetos/toxicidade , Proteínas Hemolisinas , Imunidade , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade , Virulência/genética , Poluentes Ambientais/toxicidade
9.
Harmful Algae ; 118: 102288, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36195431

RESUMO

Chytrid parasites are increasingly recognized as ubiquitous and potent control agents of phytoplankton, including bloom-forming toxigenic cyanobacteria. In order to explore the fate of the cyanobacterial toxin microcystins (MCs) and assess potential upregulation of their production under parasite attack, a laboratory experiment was conducted to evaluate short- and long-term variation in extracellular and intracellular MC in the cyanobacteria Planktothrix agardhii and P. rubescens, both under chytrid infection and in the presence of lysates of previously infected cyanobacteria. MCs release under parasite infection was limited and not different to uninfected cyanobacteria, with extracellular toxin shares never exceeding 10%, substantially below those caused by mechanical lysis induced by a cold-shock. Intracellular MC contents in P. rubescens under infection were not significantly different from uninfected controls, whereas infected P. agardhii showed a 1.5-fold increase in intracellular MC concentrations, but this was detected within the first 48 hours after parasite inoculation and not later, indicating no substantial MC upregulation in cells being infected. The presence of lysates of previously infected cyanobacteria did not elicit higher intracellular MC contents in exposed cyanobacteria, speaking against a putative upregulation of toxin production induced via quorum sensing in response to parasite attack. These results indicate that chytrid epidemics can constitute a bloom decay mechanism that is not accompanied by massive release of toxins into the medium.


Assuntos
Quitridiomicetos , Cianobactérias , Quitridiomicetos/patogenicidade , Toxinas de Cianobactérias , Microcistinas , Fitoplâncton/microbiologia
10.
Nature ; 610(7931): 381-388, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36198800

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and caused the devastating global pandemic of coronavirus disease 2019 (COVID-19), in part because of its ability to effectively suppress host cell responses1-3. In rare cases, viral proteins dampen antiviral responses by mimicking critical regions of human histone proteins4-8, particularly those containing post-translational modifications required for transcriptional regulation9-11. Recent work has demonstrated that SARS-CoV-2 markedly disrupts host cell epigenetic regulation12-14. However, how SARS-CoV-2 controls the host cell epigenome and whether it uses histone mimicry to do so remain unclear. Here we show that the SARS-CoV-2 protein encoded by ORF8 (ORF8) functions as a histone mimic of the ARKS motifs in histone H3 to disrupt host cell epigenetic regulation. ORF8 is associated with chromatin, disrupts regulation of critical histone post-translational modifications and promotes chromatin compaction. Deletion of either the ORF8 gene or the histone mimic site attenuates the ability of SARS-CoV-2 to disrupt host cell chromatin, affects the transcriptional response to infection and attenuates viral genome copy number. These findings demonstrate a new function of ORF8 and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Further, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19.


Assuntos
COVID-19 , Epigênese Genética , Histonas , Interações entre Hospedeiro e Microrganismos , Mimetismo Molecular , SARS-CoV-2 , Proteínas Virais , COVID-19/genética , COVID-19/metabolismo , COVID-19/virologia , Cromatina/genética , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , Epigenoma/genética , Histonas/química , Histonas/metabolismo , Humanos , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Proteínas Virais/química , Proteínas Virais/genética , Proteínas Virais/metabolismo
11.
Nature ; 611(7935): 312-319, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36261521

RESUMO

Infectious diseases are among the strongest selective pressures driving human evolution1,2. This includes the single greatest mortality event in recorded history, the first outbreak of the second pandemic of plague, commonly called the Black Death, which was caused by the bacterium Yersinia pestis3. This pandemic devastated Afro-Eurasia, killing up to 30-50% of the population4. To identify loci that may have been under selection during the Black Death, we characterized genetic variation around immune-related genes from 206 ancient DNA extracts, stemming from two different European populations before, during and after the Black Death. Immune loci are strongly enriched for highly differentiated sites relative to a set of non-immune loci, suggesting positive selection. We identify 245 variants that are highly differentiated within the London dataset, four of which were replicated in an independent cohort from Denmark, and represent the strongest candidates for positive selection. The selected allele for one of these variants, rs2549794, is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages. Finally, we show that protective variants overlap with alleles that are today associated with increased susceptibility to autoimmune diseases, providing empirical evidence for the role played by past pandemics in shaping present-day susceptibility to disease.


Assuntos
DNA Antigo , Predisposição Genética para Doença , Imunidade , Peste , Seleção Genética , Yersinia pestis , Humanos , Aminopeptidases/genética , Aminopeptidases/imunologia , Peste/genética , Peste/imunologia , Peste/microbiologia , Peste/mortalidade , Yersinia pestis/imunologia , Yersinia pestis/patogenicidade , Seleção Genética/imunologia , Europa (Continente)/epidemiologia , Europa (Continente)/etnologia , Imunidade/genética , Conjuntos de Dados como Assunto , Londres/epidemiologia , Dinamarca/epidemiologia
12.
Proc Natl Acad Sci U S A ; 119(40): e2201473119, 2022 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-36161886

RESUMO

Antimicrobial resistance (AMR) in soils represents a serious risk to human health through the food chain and human-nature contact. However, the active antibiotic-resistant bacteria (ARB) residing in soils that primarily drive AMR dissemination are poorly explored. Here, single-cell Raman-D2O coupled with targeted metagenomics is developed as a culture-independent approach to phenotypically and genotypically profiling active ARB against clinical antibiotics in a wide range of soils. This method quantifies the prevalence (contamination degree) and activity (spread potential) of soil ARB and reveals a clear elevation with increasing anthropogenic activities such as farming and the creation of pollution, thereby constituting a factor that is critical for the assessment of AMR risks. Further targeted sorting and metagenomic sequencing of the most active soil ARB uncover several uncultured genera and a pathogenic strain. Furthermore, the underlying resistance genes, virulence factor genes, and associated mobile genetic elements (including plasmids, insertion sequences, and prophages) are fully deciphered at the single-cell level. This study advances our understanding of the soil active AMR repertoire by linking the resistant phenome to the genome. It will aid in the risk assessment of environmental AMR and guide the combat under the One Health framework.


Assuntos
Antibacterianos , Bactérias , Farmacorresistência Bacteriana , Metagenômica , Microbiologia do Solo , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/patogenicidade , Elementos de DNA Transponíveis , Genes Bacterianos , Humanos , Análise de Célula Única , Solo , Fatores de Virulência/genética
13.
Proc Natl Acad Sci U S A ; 119(40): e2206990119, 2022 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-36161913

RESUMO

Rapid detection of pathogenic bacteria within a few minutes is the key to control infectious disease. However, rapid detection of pathogenic bacteria in clinical samples is quite a challenging task due to the complex matrix, as well as the low abundance of bacteria in real samples. Herein, we employ a label-free single-particle imaging approach to address this challenge. By tracking the scattering intensity variation of single particles in free solution, the morphological heterogeneity can be well identified with particle size smaller than the diffraction limit, facilitating the morphological identification of single bacteria from a complex matrix in a label-free manner. Furthermore, the manipulation of convection in free solution enables the rapid screening of low-abundance bacteria in a small field of view, which significantly improves the sensitivity of single-particle detection. As a proof of concept demonstration, we are able to differentiate the group B streptococci (GBS)-positive samples within 10 min from vaginal swabs without using any biological reagents. This is the most rapid and low-cost method to the best of our knowledge. We believe that such a single-particle imaging approach will find wider applications in clinical diagnosis and disease control due to its high sensitivity, rapidity, simplicity, and low cost.


Assuntos
Bactérias , Doenças Transmissíveis , Análise de Célula Única , Bactérias/isolamento & purificação , Bactérias/patogenicidade , Doenças Transmissíveis/diagnóstico por imagem , Feminino , Humanos , Tamanho da Partícula , Análise de Célula Única/métodos , Esfregaço Vaginal
14.
Respir Res ; 23(1): 241, 2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36096803

RESUMO

BACKGROUND: Liver kinase B1 (Lkb1, gene name Stk11) functions as a tumor suppressor in cancer. Myeloid cell Lkb1 potentiates lung inflammation induced by the Gram-negative bacterial cell wall component lipopolysaccharide and in host defense during Gram-negative pneumonia. Here, we sought to investigate the role of myeloid Lkb1 in lung inflammation elicited by the Gram-positive bacterial cell wall component lipoteichoic acid (LTA) and during pneumonia caused by the Gram-positive respiratory pathogen Streptococcus pneumoniae (Spneu). METHODS: Alveolar and bone marrow derived macrophages (AMs, BMDMs) harvested from myeloid-specific Lkb1 deficient (Stk11-ΔM) and littermate control mice were stimulated with LTA or Spneu in vitro. Stk11-ΔM and control mice were challenged via the airways with LTA or infected with Spneu in vivo. RESULTS: Lkb1 deficient AMs and BMDMs produced less tumor necrosis factor (TNF)α upon activation by LTA or Spneu. During LTA-induced lung inflammation, Stk11-ΔM mice had reduced numbers of AMs in the lungs, as well as diminished cytokine release and neutrophil recruitment into the airways. During pneumonia induced by either encapsulated or non-encapsulated Spneu, Stk11-ΔM and control mice had comparable bacterial loads and inflammatory responses in the lung, with the exception of lower TNFα levels in Stk11-ΔM mice after infection with the non-encapsulated strain. CONCLUSION: Myeloid Lkb1 contributes to LTA-induced lung inflammation, but is not important for host defense during pneumococcal pneumonia.


Assuntos
Pneumonia Bacteriana , Pneumonia Pneumocócica , Streptococcus pneumoniae , Proteínas Quinases Ativadas por AMP , Animais , Lipopolissacarídeos/imunologia , Fígado , Camundongos , Pneumonia Bacteriana/induzido quimicamente , Streptococcus pneumoniae/patogenicidade , Ácidos Teicoicos , Fator de Necrose Tumoral alfa
15.
Front Public Health ; 10: 952916, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091499

RESUMO

With the COVID-19 pandemic continuing, more contagious SARS-CoV-2 variants, including Omicron, have been emerging. The mutations, especially those that occurred on the spike (S) protein receptor-binding domain (RBD), are of significant concern due to their potential capacity to increase viral infectivity, virulence, and breakthrough antibodies' protection. However, the molecular mechanism involved in the pathophysiological change of SARS-CoV-2 mutations remains poorly understood. Here, we summarized 21 RBD mutations and their human angiotensin-converting enzyme 2 (hACE2) and/or neutralizing antibodies' binding characteristics. We found that most RBD mutations, which could increase surface positive charge or polarity, enhanced their hACE2 binding affinity and immune evasion. Based on the dependence of electrostatic interaction of the epitope residue of virus and docking protein (like virus receptors or antibodies) for its invasion, we postulated that the charge and/or polarity changes of novel mutations on the RBD domain of S protein could affect its affinity for the hACE2 and antibodies. Thus, we modeled mutant S trimers and RBD-hACE2 complexes and calculated their electrotactic distribution to study surface charge changes. Meanwhile, we emphasized that heparan sulfate proteoglycans (HSPGs) might play an important role in the hACE2-mediated entry of SARS-CoV-2 into cells. Those hypotheses provide some hints on how SARS-CoV-2 mutations enhance viral fitness and immune evasion, which may indicate potential ways for drug design, next-generation vaccine development, and antibody therapies.


Assuntos
COVID-19 , Proteoglicanas de Heparan Sulfato , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , COVID-19/genética , Proteoglicanas de Heparan Sulfato/genética , Humanos , Mutação , Pandemias , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/genética
16.
Science ; 377(6612): 1252-1255, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-36108009
17.
Nature ; 609(7927): 582-589, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36071157

RESUMO

Increased levels of proteases, such as trypsin, in the distal intestine have been implicated in intestinal pathological conditions1-3. However, the players and mechanisms that underlie protease regulation in the intestinal lumen have remained unclear. Here we show that Paraprevotella strains isolated from the faecal microbiome of healthy human donors are potent trypsin-degrading commensals. Mechanistically, Paraprevotella recruit trypsin to the bacterial surface through type IX secretion system-dependent polysaccharide-anchoring proteins to promote trypsin autolysis. Paraprevotella colonization protects IgA from trypsin degradation and enhances the effectiveness of oral vaccines against Citrobacter rodentium. Moreover, Paraprevotella colonization inhibits lethal infection with murine hepatitis virus-2, a mouse coronavirus that is dependent on trypsin and trypsin-like proteases for entry into host cells4,5. Consistently, carriage of putative genes involved in trypsin degradation in the gut microbiome was associated with reduced severity of diarrhoea in patients with SARS-CoV-2 infection. Thus, trypsin-degrading commensal colonization may contribute to the maintenance of intestinal homeostasis and protection from pathogen infection.


Assuntos
Microbioma Gastrointestinal , Intestino Grosso , Simbiose , Tripsina , Administração Oral , Animais , Sistemas de Secreção Bacterianos , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/imunologia , Bacteroidetes/isolamento & purificação , Bacteroidetes/metabolismo , COVID-19/complicações , Citrobacter rodentium/imunologia , Diarreia/complicações , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Humanos , Imunoglobulina A/metabolismo , Intestino Grosso/metabolismo , Intestino Grosso/microbiologia , Camundongos , Vírus da Hepatite Murina/metabolismo , Vírus da Hepatite Murina/patogenicidade , Proteólise , SARS-CoV-2/patogenicidade , Tripsina/metabolismo , Internalização do Vírus
18.
Fish Shellfish Immunol ; 130: 132-140, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36084889

RESUMO

Non-coding RNAs (ncRNAs) have been implicated in a variety of biological processes. However, most ncRNAs are of unknown function and are as-yet unannotated. The immune-related functions of ncRNAs in the pearl oyster Pinctada fucata martensii were explored based on transcriptomic differences in the expression levels of long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) in the hemocytes of P.f. martensii after challenge by the pathogenic bacterium Vibrio parahaemolyticus. Across the challenged and control pearl oysters, 144 miRNAs and 14,571 lncRNAs were identified. In total, 13,375 ncRNAs were differentially expressed between the challenged and control pearl oysters; in the challenged pearl oysters as compared to the controls, 15 miRNAs and 5147 lncRNAs were upregulated, while 51 miRNAs and 8162 lncRNAs were downregulated. The sequencing results were validated using quantitative real-time polymerase chain reaction (qRT-PCR) analysis. GO and KEGG pathway analysis showed that genes targeted by the differentially expressed ncRNAs were associated with the vascular endothelial growth factor (VEGF) signaling pathway and the nuclear factor kappa-B (NF-κB) signaling pathway. An lncRNA-mRNA-miRNA network that was developed based on the transcriptomic results of this study suggested that lncRNAs may compete with miRNAs for mRNA binding sites. This study may provide a useful framework for the detection of additional novel ncRNAs, as well as new insights into the pathogenic mechanisms underlying the response of P.f. martensii to V. parahaemolyticus.


Assuntos
MicroRNAs , Pinctada , RNA Longo não Codificante , RNA Mensageiro , Vibrio parahaemolyticus , Animais , Imunidade , MicroRNAs/genética , NF-kappa B/metabolismo , Pinctada/genética , Pinctada/imunologia , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Vibrio parahaemolyticus/patogenicidade
20.
PLoS One ; 17(9): e0274005, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36054213

RESUMO

Listeria monocytogenes is a ubiquitous opportunistic foodborne pathogen capable of survival in various adverse environmental conditions. Pathogenesis of L. monocytogenes is tightly controlled by a complex regulatory network of transcriptional regulators that are necessary for survival and adaptations to harsh environmental conditions both inside and outside host cells. Among these regulatory pathways are members of the DeoR-family transcriptional regulators that are known to play a regulatory role in sugar metabolism. In this study, we deciphered the role of FruR, a DeoR family protein, which is a fructose operon transcriptional repressor protein, in L. monocytogenes pathogenesis and growth. Following intravenous (IV) inoculation in mice, a mutant strain with deletion of fruR exhibited a significant reduction in bacterial burden in liver and spleen tissues compared to the parent strain. Further, the ΔfruR strain had a defect in cell-to-cell spread in L2 fibroblast monolayers. Constitutive activation of PrfA, a pleiotropic activator of L. monocytogenes virulence factors, did not restore virulence to the ΔfruR strain, suggesting that the attenuation was not a result of impaired PrfA activation. Transcriptome analysis revealed that FruR functions as a positive regulator for genes encoding enzymes involved in the pentose phosphate pathway (PPP) and as a repressor for genes encoding enzymes in the glycolysis pathway. These results suggested that FruR may function to facilitate NADPH regeneration, which is necessary for full protection from oxidative stress. Interestingly, deletion of fruR increased sensitivity of L. monocytogenes to H2O2, confirming a role for FruR in survival of L. monocytogenes during oxidative stress. Using anti-mouse neutrophil/monocyte monoclonal antibody RB6-8C5 (RB6) in an in vivo infection model, we found that FruR has a specific function in protecting L. monocytogenes from neutrophil/monocyte-mediated killing. Overall, this work clarifies the role of FruR in controlling L. monocytogenes carbon flow between glycolysis and PPP for NADPH homeostasis, which provides a new mechanism allowing metabolic adaptation of L. monocytogenes to oxidative stress.


Assuntos
Listeria monocytogenes , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Peróxido de Hidrogênio/metabolismo , Listeria monocytogenes/genética , Listeria monocytogenes/patogenicidade , Camundongos , Fatores de Terminação de Peptídeos/metabolismo , Regulon , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Virulência
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