RESUMO
Neisseria meningitidis has several strategies to evade complement-mediated killing, and these contribute to its ability to cause septicaemic disease and meningitis. However, the meningococcus is primarily an obligate commensal of the human nasopharynx, and it is unclear why the bacterium has evolved exquisite mechanisms to avoid host immunity. Here we demonstrate that mechanisms of meningococcal immune evasion and resistance against complement increase in response to an increase in ambient temperature. We have identified three independent RNA thermosensors located in the 5' untranslated regions of genes necessary for capsule biosynthesis, the expression of factor H binding protein, and sialylation of lipopolysaccharide, which are essential for meningococcal resistance against immune killing. Therefore increased temperature (which occurs during inflammation) acts as a 'danger signal' for the meningococcus, enhancing its defence against human immune killing. Infection with viral pathogens, such as influenza, leads to inflammation in the nasopharynx with an increased temperature and recruitment of immune effectors. Thermoregulation of immune defence could offer an adaptive advantage to the meningococcus during co-infection with other pathogens, and promote the emergence of virulence in an otherwise commensal bacterium.
Assuntos
Evasão da Resposta Imune/fisiologia , Infecções Meningocócicas/imunologia , Neisseria meningitidis/fisiologia , Temperatura , Regiões 5' não Traduzidas/genética , Cápsulas Bacterianas/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Humanos , Evasão da Resposta Imune/genética , Lipopolissacarídeos/metabolismo , Infecções Meningocócicas/microbiologia , Neisseria meningitidis/genética , RNA Bacteriano/química , RNA Bacteriano/genética , Sensação Térmica/genéticaRESUMO
The complement system is an essential component of the innate and acquired immune system, and consists of a series of proteolytic cascades that are initiated by the presence of microorganisms. In health, activation of complement is precisely controlled through membrane-bound and soluble plasma-regulatory proteins including complement factor H (fH; ref. 2), a 155 kDa protein composed of 20 domains (termed complement control protein repeats). Many pathogens have evolved the ability to avoid immune-killing by recruiting host complement regulators and several pathogens have adapted to avoid complement-mediated killing by sequestering fH to their surface. Here we present the structure of a complement regulator in complex with its pathogen surface-protein ligand. This reveals how the important human pathogen Neisseria meningitidis subverts immune responses by mimicking the host, using protein instead of charged-carbohydrate chemistry to recruit the host complement regulator, fH. The structure also indicates the molecular basis of the host-specificity of the interaction between fH and the meningococcus, and informs attempts to develop novel therapeutics and vaccines.
Assuntos
Antígenos de Bactérias/química , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Carboidratos/química , Fator H do Complemento/química , Fator H do Complemento/metabolismo , Mimetismo Molecular , Neisseria meningitidis/metabolismo , Sítios de Ligação , Fator H do Complemento/imunologia , Cristalografia por Raios X , Ligantes , Modelos Moleculares , Neisseria meningitidis/química , Neisseria meningitidis/imunologia , Ressonância Magnética Nuclear Biomolecular , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Highly effective glycoconjugate vaccines exist against four of the five major pathogenic groups of meningococci: A, C, W-135, and Y. An equivalent vaccine against group B meningococci (menB) has remained elusive due to the poorly immunogenic capsular polysaccharide. A promising alternative, the investigational recombinant menB (rMenB)- outer membrane vesicle (OMV) vaccine, contains fHBP, NHBA (previously GNA2132), NadA, and outer membrane vesicles (OMVs) from the New Zealand MeNZB vaccine. MenB currently accounts for 90% of meningococcal disease in England and Wales, where the multilocus sequence type (ST) 269 (ST269) clonal complex (cc269) has recently expanded to account for a third of menB cases. To assess the potential cc269 coverage of the rMenB-OMV vaccine, English and Welsh cc269 isolates from the past decade were genetically characterized with respect to fHBP, NHBA, and NadA. All of the isolates harbored fHbp and nhba alleles, while 98% of the cc269 isolates were devoid of nadA. Subvariant profiling of fHbp, nhba, and porA against STs revealed the presence of two broadly distinct and well-defined clusters of isolates, centered around ST269 and ST275, respectively. An additional molecular marker, insertion sequence IS1301, was found to be present in 100% and <2% of isolates of the respective clusters. On the basis of the genetic data, the potential rMenB-OMV coverage of cc269 in England and Wales is high (up to 100%) within both clusters. Expression studies and serum bactericidal antibody assays will serve to enhance predictions of coverage and will augment ongoing studies regarding the significance of IS1301 within the ST269 cluster.
Assuntos
Proteínas de Bactérias/genética , Técnicas de Tipagem Bacteriana , Elementos de DNA Transponíveis , Infecções Meningocócicas/epidemiologia , Infecções Meningocócicas/microbiologia , Neisseria meningitidis/classificação , Neisseria meningitidis/isolamento & purificação , Análise por Conglomerados , Impressões Digitais de DNA , Inglaterra/epidemiologia , Genótipo , Humanos , Infecções Meningocócicas/prevenção & controle , Vacinas Meningocócicas/imunologia , Epidemiologia Molecular , Dados de Sequência Molecular , Neisseria meningitidis/genética , Neisseria meningitidis/imunologia , Análise de Sequência de DNA , Homologia de Sequência , País de Gales/epidemiologiaRESUMO
Experimental evolution is a powerful approach to study the dynamics and mechanisms of bacterial niche specialization. By serial passage in mice, we evolved 18 independent lineages of Salmonella typhimurium LT2 and examined the rate and extent of adaptation to a mainly reticuloendothelial host environment. Bacterial mutation rates and population sizes were varied by using wild-type and DNA repair-defective mutator (mutS) strains with normal and high mutation rates, respectively, and by varying the number of bacteria intraperitoneally injected into mice. After <200 generations of adaptation all lineages showed an increased fitness as measured by a faster growth rate in mice (selection coefficients 0.11-0.58). Using a generally applicable mathematical model we calculated the adaptive mutation rate for the wild-type bacterium to be >10(-6)/cell/generation, suggesting that the majority of adaptive mutations are not simple point mutations. For the mutator lineages, adaptation to mice was associated with a loss of fitness in secondary environments as seen by a reduced metabolic capability. During adaptation there was no indication that a high mutation rate was counterselected. These data show that S. typhimurium can rapidly and extensively increase its fitness in mice but this niche specialization is, at least in mutators, associated with a cost.
Assuntos
Adaptação Fisiológica , Camundongos/microbiologia , Infecções por Salmonella , Salmonella typhimurium/patogenicidade , Animais , Interpretação Estatística de Dados , Evolução Molecular , Cinética , Modelos Genéticos , Mutação , Salmonella typhimurium/genética , Salmonella typhimurium/fisiologiaRESUMO
Skin immunity can be promoted by bacterial skin commensals that induce distinct CD8+ T cell responses and by adipocytes that produce antimicrobial peptides.
Assuntos
Adipócitos/imunologia , Catelicidinas/imunologia , Derme/imunologia , Infecções Cutâneas Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , AnimaisRESUMO
Persisters are multidrug-tolerant bacteria that could account for the relapse of infections. For a long time, persisters have been assumed to be nonreplicating dormant bacteria, but the growth status of these recalcitrant cells is still debated. Toxin-antitoxin (TA) modules have an important role in the formation of persisters and several studies show that they can form in response to different triggers. These findings, together with the invention of new tools to study persisters, could have important implications for the development of novel therapeutics to eradicate persisting subpopulations.
Assuntos
Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Infecções Bacterianas/microbiologia , Infecções Bacterianas/terapia , Farmacorresistência Bacteriana Múltipla , HumanosAssuntos
Diabetes Mellitus Tipo 1 , Microbioma Gastrointestinal , Microbiota , Dieta , Humanos , Linfócitos TRESUMO
Duplications are often attributed to "unequal recombination" between separated, directly repeated sequence elements (>100 bp), events that leave a recombinant element at the duplication junction. However, in the bacterial chromosome, duplications form at high rates (10(-3)-10(-5)/cell/division) even without recombination (RecA). Here we describe 1800 spontaneous lac duplications trapped nonselectively on the low-copy F'(128) plasmid, where lac is flanked by direct repeats of the transposable element IS3 (1258 bp) and by numerous quasipalindromic REP elements (30 bp). Duplications form at a high rate (10(-4)/cell/division) that is reduced only about 11-fold in the absence of RecA. With and without RecA, most duplications arise by recombination between IS3 elements (97%). Formation of these duplications is stimulated by IS3 transposase (Tnp) and plasmid transfer functions (TraI). Three duplication pathways are proposed. First, plasmid dimers form at a high rate stimulated by RecA and are then modified by deletions between IS3 elements (resolution) that leave a monomeric plasmid with an IS3-flanked lac duplication. Second, without RecA, duplications occur by single-strand annealing of DNA ends generated in different sister chromosomes after transposase nicks DNA near participating IS3 elements. The absence of RecA may stimulate annealing by allowing chromosome breaks to persist. Third, a minority of lac duplications (3%) have short (0-36 bp) junction sequences (SJ), some of which are located within REP elements. These duplication types form without RecA, Tnp, or Tra by a pathway in which the palindromic junctions of a tandem inversion duplication (TID) may stimulate deletions that leave the final duplication.