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1.
Microbiology (Reading) ; 169(6)2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37279149

RESUMO

Salmonella injects over 40 virulence factors, termed effectors, into host cells to subvert diverse host cellular processes. Of these 40 Salmonella effectors, at least 25 have been described as mediating eukaryotic-like, biochemical post-translational modifications (PTMs) of host proteins, altering the outcome of infection. The downstream changes mediated by an effector's enzymatic activity range from highly specific to multifunctional, and altogether their combined action impacts the function of an impressive array of host cellular processes, including signal transduction, membrane trafficking, and both innate and adaptive immune responses. Salmonella and related Gram-negative pathogens have been a rich resource for the discovery of unique enzymatic activities, expanding our understanding of host signalling networks, bacterial pathogenesis as well as basic biochemistry. In this review, we provide an up-to-date assessment of host manipulation mediated by the Salmonella type III secretion system injectosome, exploring the cellular effects of diverse effector activities with a particular focus on PTMs and the implications for infection outcomes. We also highlight activities and functions of numerous effectors that remain poorly characterized.


Assuntos
Proteínas de Bactérias , Salmonella , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Salmonella/metabolismo , Bactérias/metabolismo , Sistemas de Secreção Tipo III/metabolismo , Fatores de Virulência/metabolismo , Interações Hospedeiro-Patógeno
2.
Front Immunol ; 12: 720655, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34650553

RESUMO

Interleukin 1ß (IL-1ß) plays a major role in inflammation and is secreted by immune cells, such as macrophages, upon recognition of danger signals. Its secretion is regulated by the inflammasome, the assembly of which results in caspase 1 activation leading to gasdermin D (GSDMD) pore formation and IL-1ß release. During inflammation, danger signals also activate the complement cascade, resulting in the formation of the membrane attack complex (MAC). Here, we report that stimulation of LPS-primed human macrophages with sub-lytic levels of MAC results in activation of the NOD-like receptor 3 (NLRP3) inflammasome and GSDMD-mediated IL-1ß release. The MAC is first internalized into endosomes and then colocalizes with inflammasome components; adapter protein apoptosis associated speck-like protein containing a CARD (ASC) and NLRP3. Pharmacological inhibitors established that MAC-triggered activation of the NLRP3 inflammasome was dependent on MAC endocytosis. Internalization of the MAC also caused dispersion of the trans-Golgi network. Thus, these data uncover a role for the MAC in activating the inflammasome and triggering IL-1ß release in human macrophages.


Assuntos
Complexo de Ataque à Membrana do Sistema Complemento/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Inflamassomos/metabolismo , Interleucina-1beta/biossíntese , Macrófagos/imunologia , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Biomarcadores , Linhagem Celular , Células Cultivadas , Proteínas do Sistema Complemento/imunologia , Endocitose , Endossomos/metabolismo , Humanos , Ativação de Macrófagos/imunologia , Modelos Biológicos , Transporte Proteico
4.
Front Immunol ; 11: 565924, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101286

RESUMO

Interleukin (IL)-18 and IL-1ß are potent pro-inflammatory cytokines that contribute to inflammatory conditions such as rheumatoid arthritis and Alzheimer's disease. They are produced as inactive precursors that are activated by large macromolecular complexes called inflammasomes upon sensing damage or pathogenic signals. NLRP3 inflammasome activation is regarded to require a priming step that causes NLRP3 and IL-1ß gene upregulation, and also NLRP3 post-translational licencing. A subsequent activation step leads to the assembly of the complex and the cleavage of pro-IL-18 and pro-IL-1ß by caspase-1 into their mature forms, allowing their release. Here we show that human monocytes, but not monocyte derived macrophages, are able to form canonical NLRP3 inflammasomes in the absence of priming. NLRP3 activator nigericin caused the processing and release of constitutively expressed IL-18 in an unprimed setting. This was mediated by the canonical NLRP3 inflammasome that was dependent on K+ and Cl- efflux and led to ASC oligomerization, caspase-1 and Gasdermin-D (GSDMD) cleavage. IL-18 release was impaired by the NLRP3 inhibitor MCC950 and by the absence of NLRP3, but also by deficiency of GSDMD, suggesting that pyroptosis is the mechanism of release. This work highlights the readiness of the NLRP3 inflammasome to assemble in the absence of priming in human monocytes and hence contribute to the very early stages of the inflammatory response when IL-1ß has not yet been produced. It is important to consider the unprimed setting when researching the mechanisms of NLRP3 activation, as to not overshadow the pathways that occur in the absence of priming stimuli, which might only enhance this response.


Assuntos
Inflamassomos/metabolismo , Macrófagos/imunologia , Monócitos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Caspase 1/metabolismo , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ativação de Macrófagos , Nigericina/farmacologia , Proteínas de Ligação a Fosfato/metabolismo , Multimerização Proteica , Piroptose , Transdução de Sinais , Células THP-1
5.
Vet Res ; 48(1): 86, 2017 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-29216932

RESUMO

Campylobacter infections are among the most prevalent foodborne infections in humans, resulting in a massive disease burden worldwide. Broilers have been identified as the major source of campylobacteriosis and reducing Campylobacter loads in the broiler caeca has been proposed as an effective measure to decrease the number of infections in humans. Failure of current methods to control Campylobacter in broilers stresses the urgency to develop novel mitigation measures. We obtained six nanobodies with a broad specificity, that recognize strains belonging to the two most relevant species, Campylobacter jejuni and Campylobacter coli. The target of the nanobodies was identified as the major outer membrane protein, a porin that contributes to bacterial virulence and viability. Multimerization of the nanobodies led to agglutination of C. jejuni cells, which may affect colonization in the chicken gut. These Campylobacter-specific nanobodies may be useful to develop a strategy for preserving chickens from Campylobacter colonization.


Assuntos
Anticorpos Antibacterianos/imunologia , Infecções por Campylobacter/veterinária , Campylobacter coli/imunologia , Campylobacter jejuni/imunologia , Galinhas , Doenças das Aves Domésticas/prevenção & controle , Anticorpos de Domínio Único/imunologia , Animais , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas de Bactérias/imunologia , Infecções por Campylobacter/imunologia , Infecções por Campylobacter/microbiologia , Infecções por Campylobacter/prevenção & controle , Epitopos/imunologia , Porinas/imunologia , Doenças das Aves Domésticas/imunologia , Doenças das Aves Domésticas/microbiologia
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