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1.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445114

RESUMO

The strong decoration of tRNAs with post-transcriptional modifications provides an unprecedented adaptability of this class of non-coding RNAs leading to the regulation of bacterial growth and pathogenicity. Accumulating data indicate that tRNA post-transcriptional modifications possess a central role in both the formation of bacterial cell wall and the modulation of transcription and translation fidelity, but also in the expression of virulence factors. Evolutionary conserved modifications in tRNA nucleosides ensure the proper folding and stability redounding to a totally functional molecule. However, environmental factors including stress conditions can cause various alterations in tRNA modifications, disturbing the pathogen homeostasis. Post-transcriptional modifications adjacent to the anticodon stem-loop, for instance, have been tightly linked to bacterial infectivity. Currently, advances in high throughput methodologies have facilitated the identification and functional investigation of such tRNA modifications offering a broader pool of putative alternative molecular targets and therapeutic avenues against bacterial infections. Herein, we focus on tRNA epitranscriptome shaping regarding modifications with a key role in bacterial infectivity including opportunistic pathogens of the human microbiome.


Assuntos
Bactérias/genética , Bactérias/patogenicidade , Transcriptoma/genética , Anticódon/genética , Humanos , Nucleosídeos/genética , Biossíntese de Proteínas/genética , Processamento Pós-Transcricional do RNA/genética , RNA de Transferência/genética , Virulência/genética
2.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445780

RESUMO

The bacterial pathogen Salmonella enterica, which causes enteritis, has a broad host range and extensive environmental longevity. In water and soil, Salmonella interacts with protozoa and multiplies inside their phagosomes. Although this relationship resembles that between Salmonella and mammalian phagocytes, the interaction mechanisms and bacterial genes involved are unclear. Here, we characterized global gene expression patterns of S. enterica serovar Typhimurium within Acanthamoeba castellanii at the early stage of infection by Cappable-Seq. Gene expression features of S. Typhimurium within A. castellanii were presented with downregulation of glycolysis-related, and upregulation of glyoxylate cycle-related genes. Expression of Salmonella Pathogenicity Island-1 (SPI-1), chemotaxis system, and flagellar apparatus genes was upregulated. Furthermore, expression of genes mediating oxidative stress response and iron uptake was upregulated within A. castellanii as well as within mammalian phagocytes. Hence, global S. Typhimurium gene expression patterns within A. castellanii help better understand the molecular mechanisms of Salmonella adaptation to an amoeba cell and intracellular persistence in protozoa inhabiting water and soil ecosystems.


Assuntos
Acanthamoeba castellanii/microbiologia , Salmonella typhimurium/genética , Virulência/genética , Animais , Proteínas de Bactérias/genética , Ecossistema , Regulação Bacteriana da Expressão Gênica/genética , Ilhas Genômicas/genética , Mamíferos/microbiologia
3.
Microb Pathog ; 159: 105145, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34411653

RESUMO

Pasteurella multocida (P. multocida) is a Gram-negative bacterium which causes diseases in poultry, livestock, and humans, resulting in huge economic losses. P. multocida serovar A CQ6 (PmCQ6) is a naturally occurring attenuated strain with a thin capsule. Thus, we aimed to explore why this strain is less virulent and produces less capsule compared with P. multocida serovar A strain CQ2 (PmCQ2). Analysis of capsular polysaccharide synthesis genes in PmCQ6 revealed that, compared with PmCQ2, there was only a single point mutation in the initiation codon sequence of the hyaC gene. To test whether this point mutation caused capsular deficiency and reduced virulence, we rescued this hyaC mutation and observed a restoration of capsule production and higher virulence. Transcriptome analysis showed that the hyaC point mutation led to a downregulation of capsule synthesis and/or iron utilization related-genes. Taken together, the results indicate that the start codon mutation of hyaC is an important factor affecting the capsule synthesis and virulence of PmCQ6.


Assuntos
Infecções por Pasteurella , Pasteurella multocida , Uridina Difosfato Glucose Desidrogenase/genética , Humanos , Infecções por Pasteurella/veterinária , Pasteurella multocida/enzimologia , Pasteurella multocida/genética , Mutação Puntual , Sorogrupo , Virulência/genética
4.
mBio ; 12(4): e0141521, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34425707

RESUMO

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) possesses a discriminative polybasic cleavage motif in its spike protein that is recognized by the host furin protease. Proteolytic cleavage activates the spike protein, thereby affecting both the cellular entry pathway and cell tropism of SARS-CoV-2. Here, we investigated the impact of the furin cleavage site on viral growth and pathogenesis using a hamster animal model infected with SARS-CoV-2 variants bearing mutations at the furin cleavage site (S gene mutants). In the airway tissues of hamsters, the S gene mutants exhibited low growth properties. In contrast to parental pathogenic SARS-CoV-2, hamsters infected with the S gene mutants showed no body weight loss and only a mild inflammatory response, thereby indicating the attenuated variant nature of S gene mutants. This transient infection was sufficient for inducing protective neutralizing antibodies that cross-react with different SARS-CoV-2 lineages. Consequently, hamsters inoculated with S gene mutants showed resistance to subsequent infection with both the parental strain and the currently emerging SARS-CoV-2 variants belonging to lineages B.1.1.7 and P.1. Taken together, our findings revealed that the loss of the furin cleavage site causes attenuation in the airway tissues of hamsters and highlighted the potential benefits of S gene mutants as potential immunogens. IMPORTANCE SARS-CoV-2 uses its spike protein to enter target cells. The spike protein is cleaved by a host protease, and this event facilitates viral entry and broadens cell tropism. In this study, we employed SARS-CoV-2 mutants lacking the S protein cleavage site and characterized their growth and pathogenicity using hamsters, a laboratory animal model for SARS-CoV-2 infection. These mutants exerted low pathogenicity but induced sufficient levels of neutralizing antibodies in hamsters, which protected hamsters from rechallenge with pathogenic clinical SARS-CoV-2 strains. These virus mutants may be used as protective immunogens against SARS-CoV-2 infection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/patologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética , Animais , Linhagem Celular , Chlorocebus aethiops , Reações Cruzadas/imunologia , Furina/metabolismo , Humanos , SARS-CoV-2/genética , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Vacinas Atenuadas/imunologia , Células Vero , Virulência/genética
5.
Science ; 373(6556)2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34385369

RESUMO

Capturing the heterogeneous phenotypes of microbial populations at relevant spatiotemporal scales is highly challenging. Here, we present par-seqFISH (parallel sequential fluorescence in situ hybridization), a transcriptome-imaging approach that records gene expression and spatial context within microscale assemblies at a single-cell and molecule resolution. We applied this approach to the opportunistic pathogen Pseudomonas aeruginosa, analyzing about 600,000 individuals across dozens of conditions in planktonic and biofilm cultures. We identified numerous metabolic- and virulence-related transcriptional states that emerged dynamically during planktonic growth, as well as highly spatially resolved metabolic heterogeneity in sessile populations. Our data reveal that distinct physiological states can coexist within the same biofilm just several micrometers away, underscoring the importance of the microenvironment. Our results illustrate the complex dynamics of microbial populations and present a new way of studying them at high resolution.


Assuntos
Pseudomonas aeruginosa/genética , Transcriptoma , Biofilmes/crescimento & desenvolvimento , Proteínas de Fímbrias/genética , Flagelina/genética , Perfilação da Expressão Gênica , Regulação Bacteriana da Expressão Gênica , Hibridização in Situ Fluorescente , Fenótipo , Plâncton/genética , Plâncton/crescimento & desenvolvimento , Plâncton/metabolismo , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/patogenicidade , Piocinas/biossíntese , RNA Bacteriano/genética , RNA Bacteriano/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Célula Única , Análise Espaço-Temporal , Virulência/genética
6.
Zhonghua Yi Xue Za Zhi ; 101(31): 2478-2484, 2021 Aug 17.
Artigo em Chinês | MEDLINE | ID: mdl-34399563

RESUMO

Objective: To characterize the antibiotic resistance and virulence in a carbapenem-resistant Klebsiella pneumoniae (CRKP). Methods: A CRKP (designated K. pneumoniae C35) was isolated from a stool sample. The minimal inhibitory concentrations of antimicrobial agents were determined using the broth microdilution method. Whole-genome sequencing and genome analysis were performed to identify the antibiotic resistance and virulence genes. The genetic relationship among K. pneumoniae C35 and other CRKP isolates from our hospital was analyzed by single nucleotide polymorphism (SNP) typing of core genomes. Conjugation experiments were carried out by filter mating to evaluate the transferability and efficiency of resistance genes. The virulence phenotype was determined by Galleria mellonella infection model. Results: K. pneumoniae C35 exhibited resistance to the majority of tested antibiotics, especially carbapenems, sulbactam, and polymyxins. SNP typing showed that K. pneumoniae C35 shared a high degree of sequence homology with several CRKP isolates from different wards. This ST11 CRKP carried 13 resistance genes, including blaKPC-2, blaCTX-M-199, mcr-1, and tet(A) variant. blaKPC-2 gene was located on an IncFⅡ plasmid with>69 800 bp in size, blaCTX-M-199 and mcr-1 genes were located on an IncI2 plasmid (>64 800 bp), and tet(A) variant was located on an unknown Inc-type plasmid (83 628bp). All these three plasmids were conjugative. K. pneumoniae C35 was found to harbor rmpA, rmpA2, and iucABCD aerobactin-related genes, and was considered to be classic carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP). The virulence potential of this strain was confirmed in a Galleria mellonella infection model. The survival rate of the larvae injected with strain C35 at 48 h after infection was significantly lower than that of negative control strain (16.7% vs 80.0%). Conclusion: Multiple conjugative plasmids are identified in a faecal CR-hvKP. The IncI2 plasmid co-carrying both blaCTX-M-199 and mcr-1 genes is firstly identified in CR-hvKP. The emergence of such strain should be alerted and active surveillance is warranted.


Assuntos
Infecções por Klebsiella , Klebsiella pneumoniae , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Proteínas de Bactérias/genética , Carbapenêmicos/farmacologia , Resistência Microbiana a Medicamentos , Humanos , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/genética , Tipagem de Sequências Multilocus , Plasmídeos/genética , Virulência/genética , beta-Lactamases
7.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 50(3): 345-351, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34402255

RESUMO

To investigate the relationship of biofilm-forming ability of (PA) with swimming motility, twitching motility and virulence gene distribution. A total of 192 clinical isolates of PA were collected consecutively. Microtiter plate method was used to evaluate the ability to form biofilm. The swimming and twitching motilities were detected by plate method. Polymerase chain reaction (PCR) was used to detect virulence genes. Of the 192 PA clinical isolates, 186 (96.9%) showed biofilm-forming ability. Among them, 36 isolates showed weak biofilm-forming ability, 84 exhibited moderate biofilm-forming ability and 66 showed strong biofilm-forming ability. The diameters of the swimming ring for PA with none biofilm-forming ability, weak biofilm-forming ability, moderate biofilm-forming ability, strong biofilm-forming ability were (9.12±6.76), (18.42±7.51), (19.10±4.77) and respectively. The diameters of the twitching ring for PA in above groups were (8.38±1.50), (17.21±7.42), (18.49±5.62) and respectively. The swimming motility and twitching motility of none biofilm-forming ability group were weaker than biofilm-forming ability groups (all <0.05). Among 192 PA strains, 163 were positive (84.9%), 40 were positive (20.8%), 183 were positive (95.3%), and 189 were positive (98.4%). The positive rate of PA virulence gene , and were different in strains with different biofilm-forming abilities (<0.05). The rate of in the strong biofilm-forming ability group was lower than that in the moderate biofilm-forming ability group (=9.293, <0.01) and the weak biofilm-forming ability group (=9.997, <0.01). The rate of in the strong biofilm-forming ability group was higher than that in the weak biofilm-forming ability group (=10.803, <0.01). Most clinical isolates of PA can form biofilm. Swimming and twitching motilities are related to the formation of biofilm, but not significantly related to strength of biofilm-forming ability. The virulence genes of type Ⅲ secretion system for PA may be related to the biofilm-forming ability.


Assuntos
Biofilmes , Natação , Humanos , Virulência/genética
8.
Clin Lab ; 67(8)2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34383413

RESUMO

BACKGROUND: To investigate the distribution of virulence genes exoS and exoU of Pseudomonas aeruginosa type III secretion system and their antimicrobial resistance characteristics in Xinjiang Province. METHODS: A total of 228 isolates of Pseudomonas aeruginosa were collected from January 2017 to April 2017 in our hospital. The VITEK2-compac system was used for strain identification and antimicrobial susceptibility test. The disk diffusion method was used for antimicrobial susceptibility supplementation. PCR method was used for detection of exoS and exoU virulence gene. RESULTS: Among 228 isolates of Pseudomonas aeruginosa, 178 (78.07%) were positive for exoS gene, 91 (39.91%) were positive for exoU gene, and 21.49% of the isolates carried both genes (exoU+/exoS+). A total of 30 MDR strains were detected, accounting for 13.16%. The antimicrobial resistance of the exoU+ group was 76.67%, which was significantly higher than that of the exoU-group (23.33%). The difference was statistically significant (p < 0.001). The detection rate of fluoroquinolone-insensitive strains in exoU+ group was as high as 57.45%, which was significantly higher than 42.55% in exoU-group and the difference was statistically significant (p < 0.05). The 30-day mortality rate of the exoU+ group was 8.79%, which was higher than that of the exoU-group (4.38%), and the difference was statistically significant (p < 0.05). CONCLUSIONS: The expression of exoU gene is associated with multidrug resistance, fluoroquinolone resistance, and prognosis. We should enhance the detection of drug resistance and study the pathogenesis and regulation mecha-nism of T3SS, in order to provide new ideas for the design of reasonable treatment strategies and the development of new therapeutic drugs.


Assuntos
Infecções por Pseudomonas , Pseudomonas aeruginosa , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Proteínas de Bactérias/genética , Genótipo , Humanos , Infecções por Pseudomonas/diagnóstico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/genética , Sistemas de Secreção Tipo III/genética , Virulência/genética , Fatores de Virulência/genética
9.
Food Res Int ; 147: 110461, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34399461

RESUMO

Salmonella enterica and Shiga toxin-producing (or verotoxin-producing) Escherichia coli are major foodborne pathogens, posing substantial food safety risks. Due to the negative effects of chemical treatment against foodborne pathogens, the application of enzyme-based techniques is currently receiving great attention. Here, we evaluated the inhibitory properties of Flavourzyme, a commercial peptidase, against these two foodborne pathogens. We noticed 4.0 and 5.5 log inhibition of biofilm formation by S. Typhimurium and E. coli, respectively, while treated with sub-minimum inhibitory concentrations of Flavourzyme for 24 h. For both bacteria, the enzyme exhibited quorum-quenching activity, preventing autoinducer-2 production completely by E. coli. In addition, Flavourzyme significantly suppressed the relative expression levels of biofilm-forming, quorum sensing, and virulence regulatory genes as measured by qRT-PCR. Based on our results, we suggest the use of Flavourzyme as a preventive agent against foodborne pathogens that possibly acts by inhibiting bacterial self-defense mechanisms following disruption of cellular proteins. This finding may shed light on how enzymes can be applied as a novel weapon to control foodborne illnesses to ensure food safety and public health.


Assuntos
Salmonella typhimurium , Escherichia coli Shiga Toxigênica , Biofilmes , Endopeptidases , Percepção de Quorum , Salmonella typhimurium/genética , Escherichia coli Shiga Toxigênica/genética , Virulência/genética
10.
Postepy Biochem ; 67(2): 172-176, 2021 06 30.
Artigo em Polonês | MEDLINE | ID: mdl-34378888

RESUMO

The research concerned the determination of the frequency of occurrence of selected virulence genes (cadF, flaA, iam) and genes responsible for the formation of the CDT cytotoxin (cdtA, cdtB, cdtC) in Campylobacter spp. The research object consisted of 100 faecal samples collected from stallions showing no symptoms of campylobacteriosis. The presence of bacteria of the genus Campylobacter spp. Was found in 25 individuals (25%). The molecular biology techniques used in the research allowed us to distinguish the following species from the positive samples: C. jejuni (68%); C. coli (28%) and C. lari (4%). In total, the following genes were found within the marked species: cadF (n=10); flaA (n=5); iam (n=3); cdtA (n=1); cdtB (n=10) and cdtC (n=2). In none of the obtained isolates, the simultaneous presence of genes responsible for the synthesis of CDT toxin was found.


Assuntos
Infecções por Campylobacter , Campylobacter , Animais , Campylobacter/genética , Infecções por Campylobacter/veterinária , Cavalos , Masculino , Virulência/genética
12.
J Med Microbiol ; 70(7)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34309502

RESUMO

Introduction. Shiga toxin-producing Escherichia coli (STEC) can cause severe disease and large outbreaks. In England, the incidence and clinical significance of STEC serogroups other than O157 (non-O157) is unknown due to a testing bias for detection of STEC O157. Since 2013, the implementation of PCR to detect all STEC serogroups by an increasing number of diagnostic laboratories has led to an increase in the detection of non-O157 STEC.Hypothesis/Gap statement. Due to a bias in testing methodologies to select for STEC serogroup O157 in frontline diagnostic laboratories in most countries, very little surveillance data have been previously generated on non-O157 STEC.Aim. Five years (2014-2018) of STEC national surveillance data were extracted and descriptive analysis undertaken to assess disease severity of non-O157 STEC strains.Methods. Data from 1 January 2014 to 31 December 2018 were extracted from the National Enhanced Surveillance System for STEC and analysed.Results. The implementation of Gastrointestinal Polymerase Chain Reaction (GI-PCR) has resulted in a four-fold increase in the detection of non-O157 STEC cases between 2014 and 2018. There were 2579 cases infected with 97 different non-O157 serogroups. The gender distribution was similar amongst STEC O157 and non-O157 STEC cases with 57 and 56 % of cases being female respectively, but a significantly higher proportion of cases (P <0.001) under 5 years of age was observed among STEC O157 (22 %) cases compared to non-O157 STEC (14 %). The most common non-O157 serogroups were O26 (16 %), O146 (11 %), O91 (10 %), O128 (7 %), O103 (5 %) and O117 (3 %). Overall, rates of bloody diarrhoea were highest in O26 (44 %) and O103 (48 %) cases and lowest in STEC O117 cases (17 %). Strains harbouring Shiga toxin stx1a caused the highest proportion of diarrhoea (93 %) and caused the same level of bloody diarrhoea as stx2a (39 %). However, stx2a caused the highest proportion of vomiting (46 %), hospitalisation (49 %) and considerably more HUS (29 %) than other stx profiles.Conclusion. The implementation of PCR targeting stx at diagnostic laboratories has shown that non-O157 STEC, most notably STEC O26, are an emerging risk to public health.


Assuntos
Infecções por Escherichia coli/epidemiologia , Infecções por Escherichia coli/microbiologia , Escherichia coli Shiga Toxigênica/isolamento & purificação , Adolescente , Adulto , Distribuição por Idade , Criança , Pré-Escolar , Inglaterra/epidemiologia , Feminino , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Reação em Cadeia da Polimerase , Sorogrupo , Distribuição por Sexo , Toxina Shiga I/genética , Toxina Shiga II/genética , Escherichia coli Shiga Toxigênica/classificação , Escherichia coli Shiga Toxigênica/genética , Escherichia coli Shiga Toxigênica/patogenicidade , Virulência/genética , Adulto Jovem
13.
Nat Commun ; 12(1): 4649, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330925

RESUMO

The bacterium Vibrio cholerae can colonize the human intestine and cause cholera, but spends much of its life cycle in seawater. The pathogen must adapt to substantial environmental changes when moving between seawater and the human intestine, including different availability of carbon sources such as fructose. Here, we use in vitro experiments as well as mouse intestinal colonization assays to study the mechanisms used by pandemic V. cholerae to adapt to these environmental changes. We show that a LacI-type regulator (FruI) and a fructose/H+ symporter (FruT) are important for fructose uptake at low fructose concentrations, as those found in seawater. FruT is downregulated by FruI, which is upregulated when O2 concentrations are low (as in the intestine) by ArcAB, a two-component system known to respond to changes in oxygen levels. As a result, the bacteria predominantly use FruT for fructose uptake under seawater conditions (low fructose, high O2), and use a known fructose phosphotransferase system (PTS, Fpr) for fructose uptake under conditions found in the intestine. PTS activity leads to reduced levels of intracellular cAMP, which in turn upregulate virulence genes. Our results indicate that the FruT/FruI system may be important for survival of pandemic V. cholerae in seawater.


Assuntos
Proteínas de Bactérias/metabolismo , Frutose/metabolismo , Simportadores/metabolismo , Vibrio cholerae/metabolismo , Animais , Proteínas de Bactérias/genética , Cólera/epidemiologia , Cólera/microbiologia , Feminino , Regulação Bacteriana da Expressão Gênica , Genoma Bacteriano/genética , Genômica/métodos , Humanos , Masculino , Camundongos , Viabilidade Microbiana/genética , Pandemias , Regiões Promotoras Genéticas/genética , Ligação Proteica , Água do Mar/microbiologia , Simportadores/genética , Vibrio cholerae/genética , Vibrio cholerae/patogenicidade , Virulência/genética
14.
Antonie Van Leeuwenhoek ; 114(9): 1417-1429, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34255280

RESUMO

Some Vibrio species are important human pathogens owing to they cause infectious diseases such as gastroenteritis, wound infections, septicemia or even death. Many of these illnesses are associated with consumption of contaminated seafood. In the present study, we evaluated the presence of pathogenic Vibrio species, their virulence and antimicrobial susceptibility from 285 different kind of seafood samples from "La Nueva Viga" market in Mexico City. The PCR assay was used for amplification the vppC (collagenase), vmh (hemolysin), tlh (thermolabile hemolysin), and vvhA (hemolytic cytolysin) genes that are specific to Vibrio alginolyticus (detected in 27%), Vibrio mimicus (23.2%), Vibrio parahaemolyticus (28.8%) and Vibrio vulnificus (21.1%), respectively. Several genes encoding virulence factors were amplified. These included V. alginolyticus: pvuA (17.9%), pvsA (50%), wza and lafA (100%); V. mimicus: iut A (60%), toxR (100%); V. parahaemolyticus: pvuA (58.7%), pvsA (26.1%), wza (2.2%), and lafA (100%); and V. vulnificus: wcrA (77.5%), gmhD (57.5%), lafA (100%) and motA (30%). The antibiotic susceptibility of the Vibrio species isolates revealed that most of them were resistant to ampicillin, cephalothin and carbenicillin but susceptible to pefloxacin and trimethoprim-sulfamethoxazole. Our results indicated a high prevalence of pathogenic Vibrio species in seafood, a high presence of virulence genes and that Vibrio species continuously exposed to antibiotics, therefore, consumption of these kind of seafood carries a potential risk for foodborne illness.


Assuntos
Vibrio parahaemolyticus , Vibrio , Antibacterianos/farmacologia , Humanos , México , Prevalência , Alimentos Marinhos , Vibrio/genética , Vibrio parahaemolyticus/genética , Virulência/genética
15.
Immunity ; 54(8): 1853-1868.e7, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34331873

RESUMO

Antibodies elicited by infection accumulate somatic mutations in germinal centers that can increase affinity for cognate antigens. We analyzed 6 independent groups of clonally related severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) Spike receptor-binding domain (RBD)-specific antibodies from 5 individuals shortly after infection and later in convalescence to determine the impact of maturation over months. In addition to increased affinity and neutralization potency, antibody evolution changed the mutational pathways for the acquisition of viral resistance and restricted neutralization escape options. For some antibodies, maturation imposed a requirement for multiple substitutions to enable escape. For certain antibodies, affinity maturation enabled the neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. Antibody-antigen structures revealed that these properties resulted from substitutions that allowed additional variability at the interface with the RBD. These findings suggest that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.


Assuntos
Afinidade de Anticorpos/imunologia , COVID-19/imunologia , COVID-19/virologia , Interações Hospedeiro-Patógeno/imunologia , Mutação , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Antígenos Virais/química , Antígenos Virais/genética , Antígenos Virais/imunologia , Epitopos/química , Epitopos/imunologia , Humanos , Modelos Moleculares , Testes de Neutralização , Ligação Proteica , Conformação Proteica , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Relação Estrutura-Atividade , Virulência/genética
16.
BMC Ecol Evol ; 21(1): 139, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238209

RESUMO

BACKGROUND: The most severe form of human malaria is caused by the protozoan parasite Plasmodium falciparum. This unicellular organism is a member of a subgenus of Plasmodium called the Laverania that infects apes, with P. falciparum being the only member that infects humans. The exceptional virulence of this species to humans can be largely attributed to a family of variant surface antigens placed by the parasites onto the surface of infected red blood cells that mediate adherence to the vascular endothelium. These proteins are encoded by a large, multicopy gene family called var, with each var gene encoding a different form of the protein. By changing which var gene is expressed, parasites avoid immune recognition, a process called antigenic variation that underlies the chronic nature of malaria infections. RESULTS: Here we show that the common ancestor of the branch of the Laverania lineage that includes the human parasite underwent a remarkable change in the organization and structure of elements linked to the complex transcriptional regulation displayed by the var gene family. Unlike the other members of the Laverania, the clade that gave rise to P. falciparum evolved distinct subsets of var genes distinguishable by different upstream transcriptional regulatory regions that have been associated with different expression profiles and virulence properties. In addition, two uniquely conserved var genes that have been proposed to play a role in coordinating transcriptional switching similarly arose uniquely within this clade. We hypothesize that these changes originated at a time of dramatic climatic change on the African continent that is predicted to have led to significant changes in transmission dynamics, thus selecting for patterns of antigenic variation that enabled lengthier, more chronic infections. CONCLUSIONS: These observations suggest that changes in transmission dynamics selected for significant alterations in the transcriptional regulatory mechanisms that mediate antigenic variation in the parasite lineage that includes P. falciparum. These changes likely underlie the chronic nature of these infections as well as their exceptional virulence.


Assuntos
Hominidae , Malária , Parasitos , Animais , Variação Antigênica/genética , Humanos , Proteínas de Protozoários/genética , Virulência/genética
17.
BMC Genomics ; 22(1): 522, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34238216

RESUMO

BACKGROUND: Streptococcus intermedius, a member of the S. anginosus group, is a commensal bacterium present in the normal microbiota of human mucosal surfaces of the oral, gastrointestinal, and urogenital tracts. However, it has been associated with various infections such as liver and brain abscesses, bacteremia, osteo-articular infections, and endocarditis. Since 2005, high throughput genome sequencing methods enabled understanding the genetic landscape and diversity of bacteria as well as their pathogenic role. Here, in order to determine whether specific virulence genes could be related to specific clinical manifestations, we compared the genomes from 27 S. intermedius strains isolated from patients with various types of infections, including 13 that were sequenced in our institute and 14 available in GenBank. RESULTS: We estimated the theoretical pangenome size to be of 4,020 genes, including 1,355 core genes, 1,054 strain-specific genes and 1,611 accessory genes shared by 2 or more strains. The pangenome analysis demonstrated that the genomic diversity of S. intermedius represents an "open" pangenome model. We identified a core virulome of 70 genes and 78 unique virulence markers. The phylogenetic clusters based upon core-genome sequences and SNPs were independent from disease types and sample sources. However, using Principal Component analysis based on presence/ absence of virulence genes, we identified the sda histidine kinase, adhesion protein LAP and capsular polysaccharide biosynthesis protein cps4E as being associated to brain abscess or broncho-pulmonary infection. In contrast, liver and abdominal abscess were associated to presence of the fibronectin binding protein fbp54 and capsular polysaccharide biosynthesis protein cap8D and cpsB. CONCLUSIONS: Based on the virulence gene content of 27 S. intermedius strains causing various diseases, we identified putative disease-specific genetic profiles discriminating those causing brain abscess or broncho-pulmonary infection from those causing liver and abdominal abscess. These results provide an insight into S. intermedius pathogenesis and highlights putative targets in a diagnostic perspective.


Assuntos
Genômica , Streptococcus intermedius , Genoma Bacteriano , Humanos , Filogenia , Streptococcus intermedius/genética , Virulência/genética , Fatores de Virulência/genética
18.
Eur Rev Med Pharmacol Sci ; 25(12): 4405-4412, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34227076

RESUMO

SARS-CoV-2 are enveloped RNA viruses that belong to the family Coronaviridae of genus Beta coronavirus, responsible for the COVID-19 pandemic. The mutation rate is high among RNA viruses and in particular, coronavirus replication is error prone with an estimated mutation rate of 4x10-4 nucleotide substitutions per site per year. Variants of SARS-CoV-2 have been reported from various countries like United Kingdom, South Africa, Denmark, Brazil and India. These variants evolved due to mutations in spike gene of SARS-CoV-2. The most concerning variants are Variant of Concern (VOC) 202012/01 from United Kingdom and B.1.617 variant of India. Other variants include B.1.351 lineages, cluster 5/SARS-CoV-2 variant of Denmark, 501.V2 variant/SARS-CoV-2 variant of South Africa, lineage B.1.1.248/lineage P.1 of Brazil. Mutations in S protein may result in changes in the transmissibility and virulence of SARS-CoV-2. To date, alterations in virulence or pathogenicity have been reported among the variants from many parts of the globe. In our opinion, since the S protein is significantly altered, the suitability of existing vaccine specifically targeting the S protein of SARS-CoV-2 variants is a major concern. The mutations in SARS-CoV-2 are a continuous and evolving process that may result in the transformation of naïve SARS-CoV-2 into totally new subsets of antigenically different SARS-CoV-2 viruses over a period of time.


Assuntos
COVID-19/epidemiologia , COVID-19/genética , Mutação/genética , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , COVID-19/transmissão , Humanos , Índia/epidemiologia , Estrutura Secundária de Proteína , SARS-CoV-2/química , Reino Unido/epidemiologia , Virulência/genética
19.
Sheng Wu Gong Cheng Xue Bao ; 37(7): 2414-2424, 2021 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-34327906

RESUMO

Clustered regularly interspaced short palindromic repeats (CRISPR) and its associated protein gene system can limit the horizontal gene transfer, thereby effectively preventing the invasion of foreign gene elements such as bacteriophages. CRISPR arrays of different bacteria are diverse. Based on the differences in the CRISPR system, this review summarizes the application of CRISPR in food-borne pathogen evolution analysis, detection and typing, virulence and antibiotic resistance in recent years. We also address bacterial detection typing method developed based on the characteristics of CRISPR arrays and the association of CRISPR with virulence and drug resistance of food-borne pathogens. The shortcomings of CRISPR in evolution, detection and typing, virulence and resistance applications are analyzed. In addition, we suggest standardizing CRISPR typing methods, improving and expanding the CRISPR database of pathogenic bacteria, and further exploring the co-evolution relationship between phages and bacteria, to provide references for further exploration of CRISPR functions.


Assuntos
Bacteriófagos , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Bactérias/genética , Bacteriófagos/genética , Sistemas CRISPR-Cas/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Resistência Microbiana a Medicamentos/genética , Virulência/genética
20.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299357

RESUMO

The airborne fungus Aspergillus fumigatus causes opportunistic infections in humans with high mortality rates in immunocompromised patients. Previous work established that the bZIP transcription factor HapX is essential for virulence via adaptation to iron limitation by repressing iron-consuming pathways and activating iron acquisition mechanisms. Moreover, HapX was shown to be essential for transcriptional activation of vacuolar iron storage and iron-dependent pathways in response to iron availability. Here, we demonstrate that HapX has a very short half-life during iron starvation, which is further decreased in response to iron, while siderophore biosynthetic enzymes are very stable. We identified Fbx22 and SumO as HapX interactors and, in agreement, HapX post-translational modifications including ubiquitination of lysine161, sumoylation of lysine242 and phosphorylation of threonine319. All three modifications were enriched in the immediate adaptation from iron-limiting to iron-replete conditions. Interfering with these post-translational modifications, either by point mutations or by inactivation, of Fbx22 or SumO, altered HapX degradation, heme biosynthesis and iron resistance to different extents. Consistent with the need to precisely regulate HapX protein levels, overexpression of hapX caused significant growth defects under iron sufficiency. Taken together, our results indicate that post-translational regulation of HapX is important to control iron homeostasis in A. fumigatus.


Assuntos
Aspergillus fumigatus/genética , Fatores de Transcrição de Zíper de Leucina Básica/genética , Homeostase/genética , Ferro/metabolismo , Processamento de Proteína Pós-Traducional/genética , Adaptação Fisiológica/genética , Aspergillus fumigatus/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica/genética , Mutação Puntual/genética , Sideróforos/genética , Treonina/genética , Virulência/genética
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