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1.
Immunity ; 48(6): 1070-1072, 2018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29924970

RESUMO

Shigella pathogenesis has confounded researchers for years because of its narrow host selectivity and extraordinary infectious capability. In this issue of Immunity, Xu et al. (2018) identify a cunning mechanism whereby Shigella hijacks human α-defensin 5 to enhance its adhesion and subsequent invasion.


Assuntos
Aderência Bacteriana , Disenteria Bacilar , Humanos , Shigella , alfa-Defensinas
2.
PLoS Pathog ; 11(11): e1005226, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26539822

RESUMO

Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans.


Assuntos
Memória Imunológica , Infecções Estafilocócicas/imunologia , Infecções Cutâneas Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Células Th1/imunologia , Adjuvantes Imunológicos/farmacologia , Transferência Adotiva , Adulto , Idoso , Animais , Antígenos/imunologia , Feminino , Humanos , Interleucina-17/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Infecções Cutâneas Estafilocócicas/imunologia , Células Th1/efeitos dos fármacos
3.
J Immunol ; 192(8): 3697-708, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24623128

RESUMO

The development of vaccines against Staphylococcus aureus has consistently failed in clinical trials, likely due to inefficient induction of cellular immunity. T cell-derived IL-17 is one of the few known correlates of antistaphylococcoal immunity, conferring protection against S. aureus infections through its ability to promote phagocytic cell effector functions. A comprehensive understanding of the discrete T cell subsets critical for site-specific IL-17-mediated bacterial clearance will therefore be necessary to inform the development of vaccines that efficiently target cellular immunity. In this study, we have identified a population of CD44+ CD27- memory γδ T cells, expanded upon infection of C57BL/6 mice with S. aureus, which produce high levels of IL-17 and mediate enhanced bacterial clearance upon reinfection with the bacterium. These cells are comprised largely of the Vγ4+ subset and accumulate at the site of infection subsequent to an initial Vγ1.1+ and Vγ2+ T cell response. Moreover, these Vγ4+ T cells are retained in the peritoneum and draining mediastinal lymph nodes for a prolonged period following bacterial clearance. In contrast to its critical requirement for γδ T cell activation during the primary infection, IL-1 signaling was dispensable for activation and expansion of memory γδ T cells upon re-exposure to S. aureus. Our findings demonstrate that a γδ T cell memory response can be induced upon exposure to S. aureus, in a fashion analogous to that associated with classical αß T cells, and suggest that induction of IL-17-expressing γδ T cells may be an important property of a protective vaccine against S. aureus.


Assuntos
Memória Imunológica , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transferência Adotiva , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Imunidade Inata , Interleucina-17/biossíntese , Interleucina-17/genética , Masculino , Camundongos , Camundongos Knockout , Peritonite/imunologia , Peritonite/microbiologia , Transdução de Sinais , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/terapia
4.
Infect Immun ; 83(9): 3445-57, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26099586

RESUMO

The capacity for intracellular survival within phagocytes is likely a critical factor facilitating the dissemination of Staphylococcus aureus in the host. To date, the majority of work on S. aureus-phagocyte interactions has focused on neutrophils and, to a lesser extent, macrophages, yet we understand little about the role played by dendritic cells (DCs) in the direct killing of this bacterium. Using bone marrow-derived DCs (BMDCs), we demonstrate for the first time that DCs can effectively kill S. aureus but that certain strains of S. aureus have the capacity to evade DC (and macrophage) killing by manipulation of autophagic pathways. Strains with high levels of Agr activity were capable of causing autophagosome accumulation, were not killed by BMDCs, and subsequently escaped from the phagocyte, exerting significant cytotoxic effects. Conversely, strains that exhibited low levels of Agr activity failed to accumulate autophagosomes and were killed by BMDCs. Inhibition of the autophagic pathway by treatment with 3-methyladenine restored the bactericidal effects of BMDCs. Using an in vivo model of systemic infection, we demonstrated that the ability of S. aureus strains to evade phagocytic cell killing and to survive temporarily within phagocytes correlated with persistence in the periphery and that this effect is critically Agr dependent. Taken together, our data suggest that strains of S. aureus exhibiting high levels of Agr activity are capable of blocking autophagic flux, leading to the accumulation of autophagosomes. Within these autophagosomes, the bacteria are protected from phagocytic killing, thus providing an intracellular survival niche within professional phagocytes, which ultimately facilitates dissemination.


Assuntos
Autofagia/fisiologia , Proteínas de Bactérias/metabolismo , Células Dendríticas/microbiologia , Infecções Estafilocócicas/imunologia , Transativadores/metabolismo , Animais , Bacteriemia/metabolismo , Bacteriemia/microbiologia , Western Blotting , Células da Medula Óssea/microbiologia , Células Cultivadas , Modelos Animais de Doenças , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia
5.
J Infect Dis ; 209(9): 1479-84, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24273045

RESUMO

Despite showing promise in preclinical models, anti-Staphylococcus aureus vaccines have failed in clinical trials. To date, approaches have focused on neutralizing/opsonizing antibodies; however, vaccines exclusively inducing cellular immunity have not been studied to formally test whether a cellular-only response can protect against infection. We demonstrate that nasal vaccination with targeted nanoparticles loaded with Staphylococcus aureus antigen protects against acute systemic S. aureus infection in the absence of any antigen-specific antibodies. These findings can help inform future developments in staphylococcal vaccine development and studies into the requirements for protective immunity against S. aureus.


Assuntos
Infecções Estafilocócicas/prevenção & controle , Vacinas Antiestafilocócicas/administração & dosagem , Staphylococcus aureus/imunologia , Administração Intranasal , Animais , Anticorpos Neutralizantes/sangue , Carga Bacteriana/imunologia , Feminino , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Vacinas Antiestafilocócicas/química , Vacinas Antiestafilocócicas/imunologia
6.
Infect Immun ; 81(12): 4478-89, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24082072

RESUMO

Recent work has identified T cells and the cytokines they produce as important correlates of immune protection during Staphylococcus aureus infections through the ability of these T cells to regulate local neutrophil responses. However, the specific T-cell subsets that are involved in coordinating protection at distinct sites of infection remains to be established. In this study, we identify for the first time an important role for γδT cells in controlling S. aureus surgical site infection (SSI). γδT cells are recruited to the wound site following S. aureus challenge, where they represent the primary source of interleukin 17 (IL-17), with a small contribution from other non-γδT cells. The IL-17 response is entirely dependent upon IL-1 receptor signaling. Using IL-17 receptor-deficient mice, we demonstrate that IL-17 is required to control bacterial clearance during S. aureus SSI. However, we demonstrate a strain-dependent requirement for γδT cells in this process due to the differential abilities of individual strains to activate IL-1ß production. IL-1ß processing relies upon activation of the Nlrp3 inflammasome complex, and we demonstrate that Nlrp3-deficient and IL-1 receptor-deficient mice have an impaired ability to control S. aureus SSI due to reduced production of IL-17 by γδT cells at the site of infection. Given that IL-17 has been identified as an important correlate of immune protection during S. aureus infection, it is vital that the unique cellular sources of this cytokine and mechanisms inducing its activation are identified at distinct sites of infection. Our study demonstrates that while IL-17 may be critically important for mediating immune protection during S. aureus SSI, the relative contribution of γδT cells to these protective effects may be strain dependent.


Assuntos
Proteínas de Transporte/metabolismo , Interleucina-17/imunologia , Infecções Estafilocócicas/imunologia , Infecção da Ferida Cirúrgica/imunologia , Linfócitos T/imunologia , Animais , Proteínas de Transporte/genética , Interleucina-17/biossíntese , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Neutrófilos/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Interleucina-1/deficiência , Receptores de Interleucina-1/genética , Transdução de Sinais/imunologia , Staphylococcus aureus/imunologia , Linfócitos T/metabolismo
8.
Front Immunol ; 8: 1168, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28979266

RESUMO

Pattern recognition receptors (PRR), such as NOD-like receptors (NLRs), sense conserved microbial signatures, and host danger signals leading to the coordination of appropriate immune responses. Upon activation, a subset of NLR initiate the assembly of a multimeric protein complex known as the inflammasome, which processes pro-inflammatory cytokines and mediates a specialized form of cell death known as pyroptosis. The identification of inflammasome-associated genes as inflammatory bowel disease susceptibility genes implicates a role for the inflammasome in intestinal inflammation. Despite the fact that the functional importance of inflammasomes within immune cells has been well established, the contribution of inflammasome expression in non-hematopoietic cells remains comparatively understudied. Given that intestinal epithelial cells (IEC) act as a barrier between the host and the intestinal microbiota, inflammasome expression by these cells is likely important for intestinal immune homeostasis. Accumulating evidence suggests that the inflammasome plays a key role in shaping epithelial responses at the host-lumen interface with many inflammasome components highly expressed by IEC. Recent studies have exposed functional roles of IEC inflammasomes in mucosal immune defense, inflammation, and tumorigenesis. In this review, we present the main features of the predominant inflammasomes and their effector mechanisms contributing to intestinal homeostasis and inflammation. We also discuss existing controversies in the field and open questions related to their implications in disease. A comprehensive understanding of the molecular basis of intestinal inflammasome signaling could hold therapeutic potential for clinical translation.

9.
PLoS One ; 6(11): e27866, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22114715

RESUMO

The nucleoside analogue Ribavirin significantly increases patient response to IFN-α treatment of HCV, by directly inhibiting viral replication. Recent studies indicate that Ribavirin also regulates immunity and we propose that Ribavirin enhances specific interferon sensitive gene (ISG) expression by amplifying the IFN-α-JAK/STAT pathway. We found that IFN-α-induced STAT1 and STAT3 phosphorylation was increased in hepatocytes co-treated with Ribavirin and IFN-α, compared to IFN-α alone. Ribavirin specifically enhanced IFN-α induced mRNA and protein of the anti-viral mediator MxA, which co-localised with HCV core protein. These novel findings indicate for the first time that Ribavirin, in addition to its viral incorporation, also enhances IFN-α-JAK/STAT signalling, leading to a novel MxA-mediated immuno-modulatory mechanism that may enhance IFN-α anti-viral activity against HCV.


Assuntos
Antivirais/farmacologia , Proteínas de Ligação ao GTP/metabolismo , Hepatite C/tratamento farmacológico , Hepatócitos/efeitos dos fármacos , Hepatócitos/imunologia , Interferon-alfa/farmacologia , Ribavirina/farmacologia , Western Blotting , Células Cultivadas , Imunofluorescência , Proteínas de Ligação ao GTP/genética , Hepacivirus/efeitos dos fármacos , Hepacivirus/imunologia , Hepacivirus/metabolismo , Hepatite C/imunologia , Hepatite C/virologia , Hepatócitos/metabolismo , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Proteínas de Resistência a Myxovirus , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteínas do Core Viral/genética , Proteínas do Core Viral/metabolismo , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologia
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