Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 80
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
Cell Death Discov ; 10(1): 403, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39271670

RESUMO

Staphylococcus aureus is an important human commensal which persistently colonizes up to 30% of the human population, predominantly within the nasal cavity. The commensal lifestyle of S. aureus is complex, and the mechanisms underpinning colonization are not fully understood. S. aureus can induce an immunosuppressive environment in the nasal tissue (NT) by driving IL-10 and IL-27 to facilitate nasal colonization, indicating that S. aureus has the capacity to modulate the local immune environment for its commensal habitation. Mounting evidence suggests commensal bacteria drive type 1 interferons (IFN-I) to establish an immunosuppressive environment and whilst S. aureus can induce IFN-I during infection, its role in colonization has not yet been examined. Here, we show that S. aureus preferentially induces IFN signaling in macrophages. This IFN-I in turn upregulates expression of proapoptotic genes within macrophages culminating in caspase-3 cleavage. Importantly, S. aureus was found to drive phagocytic cell apoptosis in the nasal tissue during nasal colonization in an IFN-I dependent manner with colonization significantly reduced under caspase-3 inhibition. Overall, loss of IFN-I signaling significantly diminished S. aureus nasal colonization implicating a pivotal role for IFN-I in controlling S. aureus persistence during colonization through its ability to induce phagocyte apoptosis. Together, this study reveals a novel strategy utilized by S. aureus to circumvent host immunity in the nasal mucosa to facilitate nasal colonization.

2.
JCI Insight ; 9(13)2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38973612

RESUMO

Staphylococcus aureus is a major human pathogen. An effective anti-S. aureus vaccine remains elusive as the correlates of protection are ill-defined. Targeting specific T cell populations is an important strategy for improving anti-S. aureus vaccine efficacy. Potential bottlenecks that remain are S. aureus-induced immunosuppression and the impact this might have on vaccine-induced immunity. S. aureus induces IL-10, which impedes effector T cell responses, facilitating persistence during both colonization and infection. Thus, it was hypothesized that transient targeting of IL-10 might represent an innovative way to improve vaccine efficacy. In this study, IL-10 expression was elevated in the nares of persistent carriers of S. aureus, and this was associated with reduced systemic S. aureus-specific Th1 responses. This suggests that systemic responses are remodeled because of commensal exposure to S. aureus, which negatively implicates vaccine function. To provide proof of concept that targeting immunosuppressive responses during immunization may be a useful approach to improve vaccine efficacy, we immunized mice with T cell-activating vaccines in combination with IL-10-neutralizing antibodies. Blocking IL-10 during vaccination enhanced effector T cell responses and improved bacterial clearance during subsequent systemic and subcutaneous infection. Taken together, these results reveal a potentially novel strategy for improving anti-S. aureus vaccine efficacy.


Assuntos
Interleucina-10 , Infecções Estafilocócicas , Vacinas Antiestafilocócicas , Staphylococcus aureus , Interleucina-10/metabolismo , Interleucina-10/imunologia , Animais , Infecções Estafilocócicas/prevenção & controle , Infecções Estafilocócicas/imunologia , Vacinas Antiestafilocócicas/imunologia , Camundongos , Staphylococcus aureus/imunologia , Feminino , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Imunização/métodos , Humanos , Anticorpos Neutralizantes/imunologia , Eficácia de Vacinas , Vacinação/métodos
3.
JCI Insight ; 9(9)2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38716729

RESUMO

Atopic dermatitis (AD) is an inflammatory skin condition with a childhood prevalence of up to 25%. Microbial dysbiosis is characteristic of AD, with Staphylococcus aureus the most frequent pathogen associated with disease flares and increasingly implicated in disease pathogenesis. Therapeutics to mitigate the effects of S. aureus have had limited efficacy and S. aureus-associated temporal disease flares are synonymous with AD. An alternative approach is an anti-S. aureus vaccine, tailored to AD. Experimental vaccines have highlighted the importance of T cells in conferring protective anti-S. aureus responses; however, correlates of T cell immunity against S. aureus in AD have not been identified. We identify a systemic and cutaneous immunological signature associated with S. aureus skin infection (ADS.aureus) in a pediatric AD cohort, using a combined Bayesian multinomial analysis. ADS.aureus was most highly associated with elevated cutaneous chemokines IP10 and TARC, which preferentially direct Th1 and Th2 cells to skin. Systemic CD4+ and CD8+ T cells, except for Th2 cells, were suppressed in ADS.aureus, particularly circulating Th1, memory IL-10+ T cells, and skin-homing memory Th17 cells. Systemic γδ T cell expansion in ADS.aureus was also observed. This study suggests that augmentation of protective T cell subsets is a potential therapeutic strategy in the management of S. aureus in AD.


Assuntos
Dermatite Atópica , Infecções Cutâneas Estafilocócicas , Staphylococcus aureus , Dermatite Atópica/imunologia , Dermatite Atópica/microbiologia , Humanos , Staphylococcus aureus/imunologia , Criança , Feminino , Infecções Cutâneas Estafilocócicas/imunologia , Infecções Cutâneas Estafilocócicas/microbiologia , Masculino , Pré-Escolar , Pele/microbiologia , Pele/imunologia , Pele/patologia , Quimiocina CXCL10/imunologia , Quimiocina CXCL10/metabolismo , Células Th1/imunologia , Células Th2/imunologia , Células Th17/imunologia , Teorema de Bayes , Linfócitos T CD8-Positivos/imunologia , Interleucina-10/metabolismo , Interleucina-10/imunologia , Linfócitos Intraepiteliais/imunologia , Antígenos de Diferenciação de Linfócitos T , Glicoproteínas de Membrana
4.
J Infect Dis ; 230(3): e518-e523, 2024 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-38290045

RESUMO

The objective was to determine if antigen-specific tissue-resident memory T (TRM) cells persist in respiratory tissues of adults immunized as children with whole-cell pertussis (wP) or acellular pertussis (aP) vaccines. Mononuclear cells from tonsil or nasal tissue cells were cultured with Bordetella pertussis antigens and TRM cells quantified by flow cytometry. Adults immunized with wP vaccines as children had significantly more interleukin 17A (IL-17A) and interferon-γ (IFN-γ)-producing TRM cells that respond to B. pertussis antigens in respiratory tissues when compared with aP-primed donors. Our findings demonstrate that wP vaccines induce CD4 TRM cells that can persist in respiratory tissues for decades.


Assuntos
Bordetella pertussis , Linfócitos T CD4-Positivos , Interferon gama , Interleucina-17 , Vacina contra Coqueluche , Coqueluche , Adulto , Criança , Feminino , Humanos , Masculino , Adulto Jovem , Bordetella pertussis/imunologia , Linfócitos T CD4-Positivos/imunologia , Memória Imunológica , Interferon gama/metabolismo , Interferon gama/imunologia , Interleucina-17/metabolismo , Interleucina-17/imunologia , Células T de Memória/imunologia , Tonsila Palatina/imunologia , Vacina contra Coqueluche/imunologia , Vacina contra Coqueluche/administração & dosagem , Coqueluche/imunologia , Coqueluche/prevenção & controle
5.
mBio ; 15(1): e0257123, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38108639

RESUMO

IMPORTANCE: Staphylococcus aureus is one of the leading causes of antimicrobial-resistant infections whose success as a pathogen is facilitated by its massive array of immune evasion tactics, including intracellular survival within critical immune cells such as neutrophils, the immune system's first line of defense. In this study, we describe a novel pathway by which intracellular S. aureus can suppress the antimicrobial capabilities of human neutrophils by using the anti-inflammatory adenosine receptor, adora2a (A2aR). We show that signaling through A2aR suppresses the pentose phosphate pathway, a metabolic pathway used to fuel the antimicrobial NADPH oxidase complex that generates reactive oxygen species (ROS). As such, neutrophils show enhanced ROS production and reduced intracellular S. aureus when treated with an A2aR inhibitor. Taken together, we identify A2aR as a potential therapeutic target for combatting intracellular S. aureus infection.


Assuntos
Anti-Infecciosos , Infecções Estafilocócicas , Humanos , Neutrófilos , Staphylococcus aureus/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Via de Pentose Fosfato , Interações Hospedeiro-Patógeno , Anti-Infecciosos/metabolismo , Receptores Purinérgicos P1/metabolismo
6.
Redox Biol ; 67: 102905, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37820403

RESUMO

Inflammatory bowel diseases (IBD) are chronic intestinal disorders that result from an inappropriate inflammatory response to the microbiota in genetically susceptible individuals, often triggered by environmental stressors. Part of this response is the persistent inflammation and tissue injury associated with deficiency or excess of reactive oxygen species (ROS). The NADPH oxidase NOX1 is highly expressed in the intestinal epithelium, and inactivating NOX1 missense mutations are considered a risk factor for developing very early onset IBD. Albeit NOX1 has been linked to wound healing and host defence, many questions remain about its role in intestinal homeostasis and acute inflammatory conditions. Here, we used in vivo imaging in combination with inhibitor studies and germ-free conditions to conclusively identify NOX1 as essential superoxide generator for microbiota-dependent peroxynitrite production in homeostasis and during early endotoxemia. NOX1 loss-of-function variants cannot support peroxynitrite production, suggesting that the gut barrier is persistently weakened in these patients. One of the loss-of-function NOX1 variants, NOX1 p. Asn122His, features replacement of an asparagine residue located in a highly conserved HxxxHxxN motif. Modelling the NOX1-p22phox complex revealed near the distal heme an internal pocket restricted by His119 and Asn122 that is part of the oxygen reduction site. Functional studies in several human NADPH oxidases show that substitution of asparagine with amino acids with larger side chains is not tolerated, while smaller side chains can support catalytic activity. Thus, we identified a previously unrecognized structural feature required for the electron transfer mechanism in human NADPH oxidases.


Assuntos
Asparagina , Doenças Inflamatórias Intestinais , Humanos , Ácido Peroxinitroso , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Doenças Inflamatórias Intestinais/genética , Espécies Reativas de Oxigênio/metabolismo , NADPH Oxidase 1/genética
8.
Elife ; 122023 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-37401629

RESUMO

The bloodstream represents a hostile environment that bacteria must overcome to cause bacteraemia. To understand how the major human pathogen Staphylococcus aureus manages this we have utilised a functional genomics approach to identify a number of new loci that affect the ability of the bacteria to survive exposure to serum, the critical first step in the development of bacteraemia. The expression of one of these genes, tcaA, was found to be induced upon exposure to serum, and we show that it is involved in the elaboration of a critical virulence factor, the wall teichoic acids (WTA), within the cell envelope. The activity of the TcaA protein alters the sensitivity of the bacteria to cell wall attacking agents, including antimicrobial peptides, human defence fatty acids, and several antibiotics. This protein also affects the autolytic activity and lysostaphin sensitivity of the bacteria, suggesting that in addition to changing WTA abundance in the cell envelope, it also plays a role in peptidoglycan crosslinking. With TcaA rendering the bacteria more susceptible to serum killing, while simultaneously increasing the abundance of WTA in the cell envelope, it was unclear what effect this protein may have during infection. To explore this, we examined human data and performed murine experimental infections. Collectively, our data suggests that whilst mutations in tcaA are selected for during bacteraemia, this protein positively contributes to the virulence of S. aureus through its involvement in altering the cell wall architecture of the bacteria, a process that appears to play a key role in the development of bacteraemia.


Assuntos
Bacteriemia , Infecções Estafilocócicas , Animais , Humanos , Camundongos , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/metabolismo , Parede Celular/metabolismo , Antibacterianos/farmacologia , Ácidos Teicoicos/metabolismo
9.
Nat Commun ; 14(1): 3513, 2023 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-37316487

RESUMO

Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF; gene name F3) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation. The mechanism of release involves type I IFN-induced caspase-11 which promotes macrophage pyroptosis. Here we find that F3 is a type I IFN-stimulated gene. Furthermore, F3 induction by lipopolysaccharide (LPS) is inhibited by the anti-inflammatory agents dimethyl fumarate (DMF) and 4-octyl itaconate (4-OI). Mechanistically, inhibition of F3 by DMF and 4-OI involves suppression of Ifnb1 expression. Additionally, they block type I IFN- and caspase-11-mediated macrophage pyroptosis, and subsequent TF release. Thereby, DMF and 4-OI inhibit TF-dependent thrombin generation. In vivo, DMF and 4-OI suppress TF-dependent thrombin generation, pulmonary thromboinflammation, and lethality induced by LPS, E. coli, and S. aureus, with 4-OI additionally attenuating inflammation-associated coagulation in a model of SARS-CoV-2 infection. Our results identify the clinically approved drug DMF and the pre-clinical tool compound 4-OI as anticoagulants that inhibit TF-mediated coagulopathy via inhibition of the macrophage type I IFN-TF axis.


Assuntos
COVID-19 , Interferon Tipo I , Trombose , Humanos , Anticoagulantes , Tromboplastina , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Escherichia coli , Inflamação , Lipopolissacarídeos , Staphylococcus aureus , Trombina , SARS-CoV-2 , Macrófagos , Caspases
10.
Cell Rep ; 42(4): 112341, 2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-37018072

RESUMO

PYHIN proteins AIM2 and IFI204 sense pathogen DNA, while other PYHINs have been shown to regulate host gene expression through as-yet unclear mechanisms. We characterize mouse PYHIN IFI207, which we find is not involved in DNA sensing but rather is required for cytokine promoter induction in macrophages. IFI207 co-localizes with both active RNA polymerase II (RNA Pol II) and IRF7 in the nucleus and enhances IRF7-dependent gene promoter induction. Generation of Ifi207-/- mice shows no role for IFI207 in autoimmunity. Rather, IFI207 is required for the establishment of a Klebsiella pneumoniae lung infection and for Klebsiella macrophage phagocytosis. These insights into IFI207 function illustrate that PYHINs can have distinct roles in innate immunity independent of DNA sensing and highlight the need to better characterize the whole mouse locus, one gene at a time.


Assuntos
Citocinas , Klebsiella pneumoniae , Camundongos , Animais , Klebsiella pneumoniae/genética , Proteínas Nucleares/metabolismo , Imunidade Inata , DNA
11.
Mucosal Immunol ; 16(4): 399-407, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37088262

RESUMO

The respiratory tract is home to a diverse microbial community whose influence on local and systemic immune responses is only beginning to be appreciated. The airways have been linked with the trafficking of myelin-specific T-cells in the preclinical stages of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Th17 cells are important pathogenic effectors in MS and EAE but are innocuous immediately following differentiation. Upregulation of the cytokine GM-CSF appears to be a critical step in their acquisition of pathogenic potential, but little is known about the mechanisms that mediate this process. Here, primed myelin-specific Th17 cells were transferred to congenic recipient mice prior to exposure to various human respiratory tract-associated bacteria and T-cell trafficking, phenotype and the severity of resulting EAE were monitored. Disease was exacerbated in mice exposed to the Proteobacteria Moraxella catarrhalis and Klebsiella pneumoniae, but not the Firmicute Veillonella parvula, and this was associated with significantly increased GM-CSF+ and GM-CSF+IFNγ+ ex-Th17-like donor CD4 T cells in the lungs and central nervous system (CNS) of these mice. These findings support the concept that respiratory bacteria may contribute to the pathophysiology of CNS autoimmunity by modulating pathogenicity in crucial T-cell subsets that orchestrate neuroinflammation.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Camundongos , Humanos , Animais , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Moraxella catarrhalis , Klebsiella pneumoniae , Bainha de Mielina/patologia , Células Th17 , Virulência , Encefalomielite Autoimune Experimental/patologia , Esclerose Múltipla/patologia , Sistema Respiratório , Camundongos Endogâmicos C57BL , Células Th1
12.
bioRxiv ; 2023 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-36865143

RESUMO

The bloodstream represents a hostile environment that bacteria must overcome to cause bacteraemia. To understand how the major human pathogen Staphylococcus aureus manages this we have utilised a functional genomics approach to identify a number of new loci that affect the ability of the bacteria to survive exposure to serum, the critical first step in the development of bacteraemia. The expression of one of these genes, tcaA, was found to be induced upon exposure to serum, and we show that it is involved in the elaboration of a critical virulence factor, the wall teichoic acids (WTA), within the cell envelope. The activity of the TcaA protein alters the sensitivity of the bacteria to cell wall attacking agents, including antimicrobial peptides, human defence fatty acids, and several antibiotics. This protein also affects the autolytic activity and lysostaphin sensitivity of the bacteria, suggesting that in addition to changing WTA abundance in the cell envelope, it also plays a role in peptidoglycan crosslinking. With TcaA rendering the bacteria more susceptible to serum killing, while simultaneously increasing the abundance of WTA in the cell envelope, it was unclear what effect this protein may have during infection. To explore this, we examined human data and performed murine experimental infections. Collectively, our data suggests that whilst mutations in tcaA are selected for during bacteraemia, this protein positively contributes to the virulence of S. aureus through its involvement in altering the cell wall architecture of the bacteria, a process that appears to play a key role in the development of bacteraemia.

13.
Eur J Immunol ; 53(5): e2250247, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36681765

RESUMO

Tissue-resident memory CD4 T (TRM ) cells induced by infection with Bordetella pertussis persist in respiratory tissues and confer long-term protective immunity against reinfection. However, it is not clear how they are maintained in respiratory tissues. Here, we demonstrate that B. pertussis-specific CD4 TRM cells produce IL-17A in response to in vitro stimulation with LPS or heat-killed Klebsiella pneumoniae (HKKP) in the presence of dendritic cells. Furthermore, IL-17A-secreting CD4 TRM cells expand in the lung and nasal tissue of B. pertussis convalescent mice following in vivo administration of LPS or HKKP. Bystander activation of CD4 TRM cells was suppressed by anti-IL-12p40 but not by anti-MHCII antibodies. Furthermore, purified respiratory tissue-resident, but not circulating, CD4 T cells from convalescent mice produced IL-17A following direct stimulation with IL-23 and IL-1ß or IL-18. Intranasal immunization of mice with a whole-cell pertussis vaccine induced respiratory CD4 TRM cells that were reactivated following stimulation with K. pneumoniae. Furthermore, the nasal pertussis vaccine conferred protective immunity against B. pertussis but also attenuated infection with K. pneumoniae. Our findings demonstrate that CD4 TRM cells induced by respiratory infection or vaccination can undergo bystander activation and confer heterologous immunity to an unrelated respiratory pathogen.


Assuntos
Bordetella pertussis , Coqueluche , Animais , Camundongos , Bordetella pertussis/fisiologia , Coqueluche/prevenção & controle , Linfócitos T CD4-Positivos , Interleucina-17 , Klebsiella pneumoniae , Imunidade Heteróloga , Lipopolissacarídeos , Memória Imunológica , Vacina contra Coqueluche
14.
Clin Rev Allergy Immunol ; 64(2): 161-178, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35275333

RESUMO

The respiratory tract is home to a diverse microbial community whose influence on local and systemic immune responses is only beginning to be appreciated. Increasing reports have linked changes in this microbiome to a range of pulmonary and extrapulmonary disorders, including asthma, chronic obstructive pulmonary disease and rheumatoid arthritis. Central to many of these findings is the role of IL-17-type immunity as an important driver of inflammation. Despite the crucial role played by IL-17-mediated immune responses in protection against infection, overt Th17 cell responses have been implicated in the pathogenesis of several chronic inflammatory diseases. However, our knowledge of the influence of bacteria that commonly colonise the respiratory tract on IL-17-driven inflammatory responses remains sparse. In this article, we review the current knowledge on the role of specific members of the airway microbiota in the modulation of IL-17-type immunity and discuss how this line of research may support the testing of susceptible individuals and targeting of inflammation at its earliest stages in the hope of preventing the development of chronic disease.


Assuntos
Inflamação , Interleucina-17 , Pulmão , Microbiota , Humanos , Doença Crônica , Inflamação/imunologia , Interleucina-17/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Microbiota/imunologia , Sistema Respiratório/imunologia , Sistema Respiratório/microbiologia
15.
PLoS Pathog ; 18(7): e1010647, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35776778

RESUMO

Staphylococcus aureus persistently colonises the anterior nares of a significant proportion of the healthy population, however the local immune response elicited during S. aureus nasal colonisation remains ill-defined. Local activation of IL-17/IL-22 producing T cells are critical for controlling bacterial clearance from the nasal cavity. However, recurrent and long-term colonisation is commonplace indicating efficient clearance does not invariably occur. Here we identify a central role for the regulatory cytokine IL-10 in facilitating bacterial persistence during S. aureus nasal colonisation in a murine model. IL-10 is produced rapidly within the nasal cavity following S. aureus colonisation, primarily by myeloid cells. Colonised IL-10-/- mice demonstrate enhanced IL-17+ and IL-22+ T cell responses and more rapidly clear bacteria from the nasal tissues as compared with wild-type mice. S. aureus also induces the regulatory cytokine IL-27 within the nasal tissue, which acts upstream of IL-10 promoting its production. IL-27 blockade reduces IL-10 production within the nasal cavity and improves bacterial clearance. TLR2 signalling was confirmed to be central to controlling the IL-10 response. Our findings conclude that during nasal colonisation S. aureus creates an immunosuppressive microenvironment through the local induction of IL-27 and IL-10, to dampen protective T cell responses and facilitate its persistence.


Assuntos
Interleucina-27 , Infecções Estafilocócicas , Animais , Citocinas , Terapia de Imunossupressão , Interleucina-10 , Interleucina-17 , Camundongos , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus
16.
Heliyon ; 8(4): e09230, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35386227

RESUMO

SARS-CoV-2 infection causes a wide spectrum of disease severity. Identifying the immunological characteristics of severe disease and the risk factors for their development are important in the management of COVID-19. This study aimed to identify and rank clinical and immunological features associated with progression to severe COVID-19 in order to investigate an immunological signature of severe disease. One hundred and eight patients with positive SARS-CoV-2 PCR were recruited. Routine clinical and laboratory markers were measured, as well as myeloid and lymphoid whole-blood immunophenotyping and measurement of the pro-inflammatory cytokines IL-6 and soluble CD25. All analysis was carried out in a routine hospital diagnostic laboratory. Univariate analysis demonstrated that severe disease was most strongly associated with elevated CRP and IL-6, loss of DLA-DR expression on monocytes and CD10 expression on neutrophils. Unbiased machine learning demonstrated that these four features were strongly associated with severe disease, with an average prediction score for severe disease of 0.925. These results demonstrate that these four markers could be used to identify patients developing severe COVID-19 and allow timely delivery of therapeutics.

17.
Microb Genom ; 8(4)2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35416147

RESUMO

Streptococcus pneumoniae is a major human pathogen that can cause severe invasive diseases such as pneumonia, septicaemia and meningitis. Young children are at a particularly high risk, with an estimated 3-4 million cases of severe disease and between 300 000 and 500 000 deaths attributable to pneumococcal disease each year. The haemolytic toxin pneumolysin (Ply) is a primary virulence factor for this bacterium, yet despite its key role in pathogenesis, immune evasion and transmission, the regulation of Ply production is not well defined. Using a genome-wide association approach, we identified a large number of potential affectors of Ply activity, including a gene acquired horizontally on the antibiotic resistance-conferring Integrative and Conjugative Element (ICE) ICESp23FST81. This gene encodes a novel modular protein, ZomB, which has an N-terminal UvrD-like helicase domain followed by two Cas4-like domains with potent ATP-dependent nuclease activity. We found the regulatory effect of ZomB to be specific for the ply operon, potentially mediated by its high affinity for the BOX repeats encoded therein. Using a murine model of pneumococcal colonization, we further demonstrate that a ZomB mutant strain colonizes both the upper respiratory tract and lungs at higher levels when compared to the wild-type strain. While the antibiotic resistance-conferring aspects of ICESp23FST81 are often credited with contributing to the success of the S. pneumoniae lineages that acquire it, its ability to control the expression of a major virulence factor implicated in bacterial transmission is also likely to have played an important role.


Assuntos
Estudo de Associação Genômica Ampla , Streptococcus pneumoniae , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sequências Repetitivas Dispersas/genética , Camundongos , Streptococcus pneumoniae/genética , Estreptolisinas , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
18.
Microorganisms ; 10(1)2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35056597

RESUMO

Mucosal-Associated Invariant T (MAIT) cells have been shown to play protective roles during infection with diverse pathogens through their propensity for rapid innate-like cytokine production and cytotoxicity. Among the potential applications for MAIT cells is to defend against Staphylococcus aureus, a pathogen of serious clinical significance. However, it is unknown how MAIT cell responses to S. aureus are elicited, nor has it been investigated whether MAIT cell cytotoxicity is mobilized against intracellular S. aureus. In this study, we investigate the capacity of human MAIT cells to respond directly to S. aureus. MAIT cells co-cultured with dendritic cells (DCs) infected with S. aureus rapidly upregulate CD69, express IFNγ and Granzyme B and degranulate. DC secretion of IL-12, but not IL-18, was implicated in this immune response, while TCR binding of MR1 is required to commence cytokine production. MAIT cell cytotoxicity resulted in apoptosis of S. aureus-infected cells, and reduced intracellular persistence of S. aureus. These findings implicate these unconventional T cells in important, rapid anti-S. aureus responses that may be of great relevance to the ongoing development of novel anti-S. aureus treatments.

19.
Vet Immunol Immunopathol ; 238: 110287, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34214911

RESUMO

Interleukin-8 (IL-8) is an inflammatory chemokine released during the primary innate immune response to recruit neutrophils to the site of infection. Two distinct gene promoter haplotypes have been previously reported to segregate in the Holstein-Friesian breed (IL8-h1 and IL8-h2). Our earlier work showed how these divergent IL8 haplotypes influence IL-8 concentration and other immune response parameters at a systemic level. While a close relationship has been established between vitamin D and IL-8 in other species, the role of genetic haplotype on temporal variation in vitamin D concentrations and its impact on immunity remains unexplored in cattle. Therefore this study had two objectives - 1: to establish the temporal variation in IL-8 concentration profile in healthy calves of each IL-8 haplotype (n = 5/6 per group) and 2: to identify the relationship between systemic 25(OH)D concentration and IL8 haplotype in blood at 10 time points across their first year of life. Elevated IL-8 protein concentration profiles were apparent in IL8-h2 calves at multiple time points throughout the year (P < 0.05). In contrast, circulating concentrations of 25(OH) vitamin D were negatively correlated (0.38) with IL-8, with elevated concentrations in calves of the IL8-h1 haplotype. Increased numbers of innate immune cells - specifically monocytes and basophils, were also detected in blood from IL8-h2 calves (P < 0.05). Importantly, circulating concentrations of vitamin D were substantially below recommended concentrations of 30 ng/mL serum for optimal immunity in the first five months of life, indicating a window of potentially heightened disease susceptibility - particularly in calves of the IL8-h1 haplotype. In conclusion, this study has established that IL8 haplotype confers divergent chemokine concentrations and which contrasts with circulating concentrations of vitamin D. Accounting for both IL8 haplotype and vitamin D concentration may be critical to provide dairy calves with optimal immune protection in early life.


Assuntos
Bovinos/sangue , Haplótipos , Interleucina-8/sangue , Interleucina-8/genética , Período Periparto/sangue , Vitamina D/análogos & derivados , Animais , Bovinos/fisiologia , Feminino , Imunidade Inata , Interleucina-8/metabolismo , Período Periparto/fisiologia , Vitamina D/sangue
20.
Front Immunol ; 12: 667387, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220813

RESUMO

The success of Staphylococcus aureus as a human commensal and an opportunistic pathogen relies on its ability to adapt to several niches within the host. The innate immune response plays a key role in protecting the host against S. aureus infection; however, S. aureus adeptness at evading the innate immune system is indisputably evident. The "Trojan horse" theory has been postulated to describe a mechanism by which S. aureus takes advantage of phagocytes as a survival niche within the host to facilitate dissemination of S. aureus to secondary sites during systemic infection. Several studies have determined that S. aureus can parasitize both professional and non-professional phagocytes by manipulating the host autophagy pathway in order to create an intracellular survival niche. Neutrophils represent a critical cell type in S. aureus infection as demonstrated by the increased risk of infection among patients with congenital neutrophil disorders. However, S. aureus has been repeatedly shown to survive intracellularly within neutrophils with evidence now supporting a pathogenic role of host autophagy. By manipulating this pathway, S. aureus can also alter the apoptotic fate of the neutrophil and potentially skew other important signalling pathways for its own gain. Understanding these critical host-pathogen interactions could lead to the development of new host directed therapeutics for the treatment of S. aureus infection by removing its intracellular niche and restoring host bactericidal functions. This review discusses the current findings surrounding intracellular survival of S. aureus within neutrophils, the pathogenic role autophagy plays in this process and considers the therapeutic potential for targeting this immune evasion mechanism.


Assuntos
Autofagia , Neutrófilos/imunologia , Neutrófilos/microbiologia , Staphylococcus aureus/imunologia , Humanos , Evasão da Resposta Imune , Imunidade Inata
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA