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1.
Adv Exp Med Biol ; 1197: 165-178, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31732941

RESUMO

Periodontitis is a multifactorial chronic inflammatory infectious disease that compromises the integrity of tooth-supporting tissues. The disease progression depends on the disruption of host-microbe homeostasis in the periodontal tissue. This disruption is marked by a shift in the composition of the polymicrobial oral community from a symbiotic to a dysbiotic, more complex community that is capable of evading killing while promoting inflammation. Neutrophils are the main phagocytic cell in the periodontal pocket, and the outcome of the interaction with the oral microbiota is an important determinant of oral health. Novel culture-independent techniques have facilitated the identification of new bacterial species at periodontal lesions and induced a reappraisal of the microbial etiology of periodontitis. In this chapter, we discuss how neutrophils interact with two emerging oral pathogens, Filifactor alocis and Peptoanaerobacter stomatis, and the different strategies deploy by these organisms to modulate neutrophil effector functions, with the goal to outline a new paradigm in our knowledge about neutrophil responses to putative periodontal pathogens and their contribution to disease progression.


Assuntos
Neutrófilos , Periodontite , Clostridiales/imunologia , Disbiose , Humanos , Microbiota/imunologia , Neutrófilos/imunologia , Neutrófilos/microbiologia , Periodontite/imunologia , Periodontite/microbiologia , Periodonto/microbiologia
2.
Nature ; 574(7776): 57-62, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31534221

RESUMO

The causative agent of plague, Yersinia pestis, uses a type III secretion system to selectively destroy immune cells in humans, thus enabling Y. pestis to reproduce in the bloodstream and be transmitted to new hosts through fleabites. The host factors that are responsible for the selective destruction of immune cells by plague bacteria are unknown. Here we show that LcrV, the needle cap protein of the Y. pestis type III secretion system, binds to the N-formylpeptide receptor (FPR1) on human immune cells to promote the translocation of bacterial effectors. Plague infection in mice is characterized by high mortality; however, Fpr1-deficient mice have increased survival and antibody responses that are protective against plague. We identified FPR1R190W as a candidate resistance allele in humans that protects neutrophils from destruction by the Y. pestis type III secretion system. Thus, FPR1 is a plague receptor on immune cells in both humans and mice, and its absence or mutation provides protection against Y. pestis. Furthermore, plague selection of FPR1 alleles appears to have shaped human immune responses towards other infectious diseases and malignant neoplasms.


Assuntos
Macrófagos/metabolismo , Neutrófilos/metabolismo , Peste/microbiologia , Receptores de Formil Peptídeo/metabolismo , Yersinia pestis/metabolismo , Alelos , Animais , Antígenos de Bactérias/metabolismo , Aderência Bacteriana , Sistemas CRISPR-Cas , Quimiotaxia/imunologia , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/citologia , Neutrófilos/imunologia , Neutrófilos/microbiologia , Peste/imunologia , Peste/prevenção & controle , Polimorfismo de Nucleotídeo Único/genética , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Receptores de Formil Peptídeo/antagonistas & inibidores , Receptores de Formil Peptídeo/deficiência , Receptores de Formil Peptídeo/genética , Sistemas de Secreção Tipo III/efeitos dos fármacos , Células U937 , Yersinia pestis/química , Yersinia pestis/imunologia , Yersinia pestis/patogenicidade
3.
BMC Infect Dis ; 19(1): 745, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455239

RESUMO

BACKGROUND: Due to the similar clinical, lung imaging, and pathological characteristics, talaromycosis is most commonly misdiagnosed as tuberculosis. This study aimed to identify the characteristics of talaromycosis pleural effusion (TMPE) and to distinguish TMPE from tuberculosis pleural effusion (TPE). METHODS: We enrolled 19 cases each of TMPE and TPE from Guangxi, China. Patients' clinical records, pleural effusion tests, biomarker test results, and receiver operating characteristic curves were analyzed. RESULTS: In total, 39.8% (65/163) of patients exhibited serous effusion, of whom 61 were non-human immunodeficiency virus (HIV)-infected patients; 68.85% of the non-HIV-infected patients (42/61) had TMPE. Thoracentesis was performed only in 19 patients, all of whom were misdiagnosed with tuberculosis and received long-term anti-tuberculosis treatment. In four of these patients, interleukin (IL)-23, IL-27, and interferon-gamma (IFN-γ) measurements were not performed since pleural effusion samples could not be collected because the effusion had been drained prior to the study. In the remaining 15 patients, pleural effusion samples were collected. Talaromyces marneffei was isolated from the pleural effusion and pleural nodules. Most TMPEs were characterized by yellowish fluid, with marked elevation of protein content and nucleated cell counts. However, neutrophils were predominantly found in TMPEs, and lymphocytes were predominantly found in TPEs (both p < 0.05). Adenosine deaminase (ADA) and IFN-γ levels in TMPEs were significantly lower than those in TPEs (all p < 0.05) and provided similar accuracies for distinguishing TMPEs from TPEs. IL-23 concentration in TMPEs was significantly higher than that in TPEs (p < 0.05), and it provided similar accuracy for diagnosing TMPEs. IL-27 concentrations in TMPEs were significantly lower than those in TPEs (all p < 0.05) but was not useful for distinguishing TMPE from TPE. CONCLUSIONS: Talaromycosis can infringe on the pleural cavity via the translocation of T. marneffei into the pleural space. Nonetheless, this phenomenon is still commonly neglected by clinicians. TMPE is a yellowish fluid with exudative PEs and predominant neutrophils. Higher neutrophil counts and IL-23 may suggest talaromycosis. Higher lymphocyte counts, ADA activity, and IFN-γ concentration may suggest tuberculosis.


Assuntos
Micoses/etiologia , Derrame Pleural/microbiologia , Tuberculose Pleural/diagnóstico , Adenosina Desaminase/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Interferon gama/metabolismo , Subunidade p19 da Interleucina-23/metabolismo , Interleucinas/metabolismo , Linfócitos/microbiologia , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Micoses/tratamento farmacológico , Micoses/microbiologia , Neutrófilos/microbiologia , Neutrófilos/patologia , Derrame Pleural/diagnóstico , Derrame Pleural/tratamento farmacológico , Curva ROC , Talaromyces/patogenicidade , Tuberculose Pleural/tratamento farmacológico , Tuberculose Pleural/etiologia
4.
Nat Commun ; 10(1): 3831, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444339

RESUMO

When injured, fish release an alarm substance (Schreckstoff) that elicits fear in members of their shoal. Although Schreckstoff has been proposed to be produced by club cells in the skin, several observations indicate that these giant cells function primarily in immunity. Previous data indicate that the alarm substance can be isolated from mucus. Here we show that mucus, as well as bacteria, are transported from the external surface into club cells, by cytoplasmic transfer or invasion of cells, including neutrophils. The presence of bacteria inside club cells raises the possibility that the alarm substance may contain a bacterial component. Indeed, lysate from a zebrafish Staphylococcus isolate is sufficient to elicit alarm behaviour, acting in concert with a substance from fish. These results suggest that Schreckstoff, which allows one individual to unwittingly change the emotional state of the surrounding population, derives from two kingdoms and is associated with processes that protect the host from bacteria.


Assuntos
Comunicação Animal , Pele/metabolismo , Staphylococcus/metabolismo , Peixe-Zebra/fisiologia , Animais , Animais Geneticamente Modificados , Medo/fisiologia , Células Gigantes/metabolismo , Células Gigantes/microbiologia , Microscopia Intravital , Muco/citologia , Muco/metabolismo , Muco/microbiologia , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Imagem Óptica , Reflexo de Sobressalto/fisiologia , Pele/citologia , Pele/microbiologia , Simbiose/fisiologia , Peixe-Zebra/lesões , Peixe-Zebra/microbiologia
5.
Infect Immun ; 87(10)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31331954

RESUMO

Group A Streptococcus (GAS) commonly causes pharyngitis and skin infections. Little is known why streptococcal pharyngitis usually does not lead to pneumonia and why the skin is a favorite niche for GAS. To partially address these questions, the effectiveness of neutrophils in clearing wild-type (wt) M1T1 GAS strain MGAS2221 from the lung and from the skin was examined in murine models of intratracheal pneumonia and subcutaneous infection. Ninety-nine point seven percent of the MGAS2221 inoculum was cleared from the lungs of C57BL/6J mice at 24 h after inoculation, while there was no MGAS2221 clearance from skin infection sites. The bronchial termini had robust neutrophil infiltration, and depletion of neutrophils abolished MGAS2221 clearance from the lung. Phagocyte NADPH oxidase but not myeloperoxidase was required for MGAS2221 clearance. Thus, wt M1T1 GAS can be cleared by neutrophils using an NADPH oxidase-dependent mechanism in the lung. MGAS2221 induced robust neutrophil infiltration at the edge of skin infection sites and throughout infection sites at 24 h and 48 h after inoculation, respectively. Neutrophils within MGAS2221 infection sites had no nuclear staining. Skin infection sites of streptolysin S-deficient MGAS2221 ΔsagA were full of neutrophils with nuclear staining, whereas MGAS2221 ΔsagA infection was not cleared. Gp91phox knockout (KO) and control mice had similar GAS numbers at skin infection sites and similar abilities to select SpeB activity-negative (SpeBA-) variants. These results indicate that phagocyte NADPH oxidase-mediated GAS killing is compromised in the skin. Our findings support a model for GAS skin tropism in which GAS generates an anoxic niche to evade phagocyte NADPH oxidase-mediated clearance.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Pulmão/enzimologia , NADPH Oxidases/imunologia , Neutrófilos/enzimologia , Infecções Estreptocócicas/enzimologia , Streptococcus pyogenes/patogenicidade , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Feminino , Pulmão/imunologia , Pulmão/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidases/genética , Infiltração de Neutrófilos , Neutrófilos/imunologia , Neutrófilos/microbiologia , Especificidade de Órgãos , Fagócitos/enzimologia , Fagócitos/imunologia , Pele/imunologia , Pele/microbiologia , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/imunologia , Estreptolisinas/deficiência , Estreptolisinas/genética , Estreptolisinas/imunologia
6.
Vet Microbiol ; 234: 34-43, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31213270

RESUMO

Mannheimia haemolytica is an important cause of bovine respiratory disease (BRD). BRD is usually a multifactorial disease with host factors and viral infections influencing pathogenesis. Previous studies that have attempted to experimentally induce pneumonia using aerosolized M. haemolytica alone have produced inconsistent results, yet an aerosol model would be useful to study the details of early infection and to investigate the role of innate defences in pathogenesis. The objective of these studies was to develop and characterize an aerosolized M. haemolytica disease model. In an initial study, conventionally raised calves with higher levels of antibody against M. haemolytica leukotoxin developed acute respiratory distress and diffuse alveolar damage, but did not develop bronchopneumonia, following challenge with M. haemolytica serotype 1. Clean-catch colostrum-deprived calves challenged with 1 × 1010 colony forming units of M. haemolytica serotype 1 consistently developed bronchopneumonia, with elevations in rectal temperature, serum haptoglobin, plasma fibrinogen, and blood neutrophils. Mannheimia haemolytica serotype 1 was consistently isolated from the nasal cavities and lungs of challenged calves. Despite distribution of aerosol and isolation of M. haemolytica in all lung lobes, gross lesions were mainly observed in the cranioventral area of lung. Gross and histologic lesions included neutrophilic bronchopneumonia and fibrinous pleuritis, with oat cells (necrotic neutrophils with streaming nuclei), and areas of coagulative necrosis, which are similar to lesions in naturally occurring BRD. Thus, challenge with M. haemolytica serotype 1 and use of clean-catch colostrum-deprived calves with low or absent antibody titres allowed development of an effective aerosol challenge model that induced typical clinical disease and lesions.


Assuntos
Broncopneumonia/veterinária , Colostro , Modelos Animais de Doenças , Mannheimia haemolytica/patogenicidade , Pneumonia Bacteriana/veterinária , Aerossóis , Fatores Etários , Animais , Broncopneumonia/microbiologia , Bovinos , Doenças dos Bovinos/microbiologia , Feminino , Fibrinogênio/análise , Haptoglobinas/análise , Pulmão/microbiologia , Pulmão/patologia , Neutrófilos/microbiologia , Neutrófilos/patologia , Alvéolos Pulmonares/microbiologia , Alvéolos Pulmonares/patologia
7.
J Immunol Res ; 2019: 6193186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31198794

RESUMO

Meningococcal disease such as sepsis and meningitidis is hallmarked by an excessive inflammatory response. The causative agent, Neisseria meningitidis, expresses the endotoxin lipooligosaccharide (LOS) that is responsible for activation of immune cells and the release of proinflammatory cytokines. One of the most potent proinflammatory cytokines, interleukin-1ß (IL-1ß), is activated following caspase-1 activity in the intracellular multiprotein complex called inflammasome. Inflammasomes are activated by a number of microbial factors as well as danger molecules by a two-step mechanism-priming and licensing of inflammasome activation-but there are no data available regarding a role for inflammasome activation in meningococcal disease. The aim of this study was to investigate if N. meningitidis activates the inflammasome and, if so, the role of bacterial LOS in this activation. Cells were subjected to N. meningitidis, both wild-type (FAM20) and its LOS-deficient mutant (lpxA), and priming as well as licensing of inflammasome activation was investigated. The wild-type LOS-expressing parental FAM20 serogroup C N. meningitidis (FAM20) strain significantly enhanced the caspase-1 activity in human neutrophils and monocytes, whereas lpxA was unable to induce caspase-1 activity as well as to induce IL-1ß release. While the lpxA mutant induced a priming response, measured as increased expression of NLRP3 and IL1B, the LOS-expressing FAM20 further increased this priming. We conclude that although non-LOS components of N. meningitidis contribute to the priming of the inflammasome activity, LOS per se is to be considered as the central component of N. meningitidis virulence, responsible for both priming and licensing of inflammasome activation.


Assuntos
Antígenos de Bactérias/metabolismo , Inflamassomos/metabolismo , Lipopolissacarídeos/metabolismo , Meningite Meningocócica/imunologia , Neisseria meningitidis/fisiologia , Neutrófilos/imunologia , Fatores de Virulência/metabolismo , Antígenos de Bactérias/genética , Caspase 1/genética , Caspase 1/metabolismo , Humanos , Imunidade Inata , Interleucina-1beta/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neisseria meningitidis/patogenicidade , Neutrófilos/microbiologia , Transdução de Sinais , Células THP-1
8.
Medicina (Kaunas) ; 55(5)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072037

RESUMO

Background and objective: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are new readily available inflammatory markers that have been analyzed in pregnancy-induced hypertensive disorders such as preeclampsia. Studies on the NLR/PLR ratio in hemolysis, elevated liver enzymes, low-platelet count (HELLP) syndrome are limited in the current literature. We compared NLR/PLR and other complete blood count (CBC) components between women with HELLP syndrome and women with healthy pregnancies. Methods: We conducted a retrospective matched case-control study at a tertiary care hospital in NY (USA) in the time frame between January 2016 and December 2018. The study compared pregnant women with HELLP syndrome (cases) to women with healthy pregnancies in the third trimester (controls), matched by age, body mass index (BMI), parity, and race. Patient with preeclampsia, infection, and fever were excluded. Venous blood samples were obtained as part of the routine work-up at admission for delivery, which included a CBC. The main outcomes were NLR and PLR. The secondary outcomes were hemoglobin, red cell distribution width (RDW), platelet count, mean platelet volume (MPV), neutrophils, lymphocytes. Results: There were 14 patients in each group. They were matched by age, race, BMI, and parity. NLR (5.8 vs. 3.6, p-value = 0.002) and neutrophil count (10.7 vs. 6.8, p-value = 0.001) were higher in women with HELLP compared to controls. PLR (34 vs. 130.2, p-value < 0.001) and platelet count (71 vs. 223, p-value < 0.001) were lower in the study group compared to controls. Conclusions: NLR was higher, and PLR was lower in women with HELLP syndrome. These inflammatory markers can be incorporated into the diagnostic algorithm for HELLP syndrome. Future studies are needed to evaluate their ability to predict HELLP syndrome.


Assuntos
Plaquetas/microbiologia , Síndrome HELLP/sangue , Linfócitos/microbiologia , Neutrófilos/microbiologia , Adulto , Biomarcadores/análise , Biomarcadores/sangue , Contagem de Células Sanguíneas/métodos , Estudos de Casos e Controles , Feminino , Humanos , New York , Gravidez , Estudos Retrospectivos
9.
Nat Commun ; 10(1): 2121, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31073183

RESUMO

Pulmonary immune control is crucial for protection against pathogens. Here we identify a pathway that promotes host responses during pulmonary bacterial infection; the expression of CD200 receptor (CD200R), which is known to dampen pulmonary immune responses, promotes effective clearance of the lethal intracellular bacterium Francisella tularensis. We show that depletion of CD200R in mice increases in vitro and in vivo infectious burden. In vivo, CD200R deficiency leads to enhanced bacterial burden in neutrophils, suggesting CD200R normally limits the neutrophil niche for infection. Indeed, depletion of this neutrophil niche in CD200R-/- mice restores F. tularensis infection to levels seen in wild-type mice. Mechanistically, CD200R-deficient neutrophils display significantly reduced reactive oxygen species production (ROS), suggesting that CD200R-mediated ROS production in neutrophils is necessary for limiting F. tularensis colonisation and proliferation. Overall, our data show that CD200R promotes the antimicrobial properties of neutrophils and may represent a novel antibacterial therapeutic target.


Assuntos
Francisella tularensis/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Glicoproteínas de Membrana/imunologia , Neutrófilos/imunologia , Tularemia/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Francisella tularensis/imunologia , Humanos , Fragmentos Fc das Imunoglobulinas , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/microbiologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Cultura Primária de Células , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Tularemia/microbiologia
10.
PLoS Pathog ; 15(5): e1007773, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31107907

RESUMO

Neutrophil-derived networks of DNA-composed extracellular fibers covered with antimicrobial molecules, referred to as neutrophil extracellular traps (NETs), are recognized as a physiological microbicidal mechanism of innate immunity. The formation of NETs is also classified as a model of a cell death called NETosis. Despite intensive research on the NETs formation in response to pathogens, the role of specific bacteria-derived virulence factors in this process, although postulated, is still poorly understood. The aim of our study was to determine the role of gingipains, cysteine proteases responsible for the virulence of P. gingivalis, on the NETosis process induced by this major periodontopathogen. We showed that NETosis triggered by P. gingivalis is gingipain dependent since in the stark contrast to the wild-type strain (W83) the gingipain-null mutant strain only slightly induced the NETs formation. Furthermore, the direct effect of proteases on NETosis was documented using purified gingipains. Notably, the induction of NETosis was dependent on the catalytic activity of gingipains, since proteolytically inactive forms of enzymes showed reduced ability to trigger the NETs formation. Mechanistically, gingipain-induced NETosis was dependent on proteolytic activation of protease-activated receptor-2 (PAR-2). Intriguingly, both P. gingivalis and purified Arg-specific gingipains (Rgp) induced NETs that not only lacked bactericidal activity but instead stimulated the growth of bacteria species otherwise susceptible to killing in NETs. This protection was executed by proteolysis of bactericidal components of NETs. Taken together, gingipains play a dual role in NETosis: they are the potent direct inducers of NETs formation but in the same time, their activity prevents P. gingivalis entrapment and subsequent killing. This may explain a paradox that despite the massive accumulation of neutrophils and NETs formation in periodontal pockets periodontal pathogens and associated pathobionts thrive in this environment.


Assuntos
Adesinas Bacterianas/imunologia , Infecções por Bacteroidaceae/imunologia , Cisteína Endopeptidases/imunologia , Armadilhas Extracelulares/imunologia , Neutrófilos/imunologia , Peritonite/imunologia , Porphyromonas gingivalis/imunologia , Porphyromonas gingivalis/patogenicidade , Receptor PAR-2/metabolismo , Adesinas Bacterianas/metabolismo , Animais , Infecções por Bacteroidaceae/metabolismo , Infecções por Bacteroidaceae/microbiologia , Infecções por Bacteroidaceae/patologia , Células Cultivadas , Cisteína Endopeptidases/metabolismo , Armadilhas Extracelulares/microbiologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/microbiologia , Neutrófilos/patologia , Peritonite/metabolismo , Peritonite/microbiologia , Receptor PAR-2/imunologia , Transdução de Sinais
11.
PLoS Pathog ; 15(4): e1007745, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31009517

RESUMO

The mechanisms by which the gut luminal environment is disturbed by the immune system to foster pathogenic bacterial growth and survival remain incompletely understood. Here, we show that STAT2 dependent type I IFN signaling contributes to the inflammatory environment by disrupting hypoxia enabling the pathogenic S. Typhimurium to outgrow the microbiota. Stat2-/- mice infected with S. Typhimurium exhibited impaired type I IFN induced transcriptional responses in cecal tissue and reduced bacterial burden in the intestinal lumen compared to infected wild-type mice. Although inflammatory pathology was similar between wild-type and Stat2-/- mice, we observed decreased hypoxia in the gut tissue of Stat2-/- mice. Neutrophil numbers were similar in wild-type and Stat2-/- mice, yet Stat2-/- mice showed reduced levels of myeloperoxidase activity. In vitro, the neutrophils from Stat2-/- mice produced lower levels of superoxide anion upon stimulation with the bacterial ligand N-formylmethionyl-leucyl-phenylalanine (fMLP) in the presence of IFNα compared to neutrophils from wild-type mice, indicating that the neutrophils were less functional in Stat2-/- mice. Cytochrome bd-II oxidase-mediated respiration enhances S. Typhimurium fitness in wild-type mice, while in Stat2-/- deficiency, this respiratory pathway did not provide a fitness advantage. Furthermore, luminal expansion of S. Typhimurium in wild-type mice was blunted in Stat2-/- mice. Compared to wild-type mice which exhibited a significant perturbation in Bacteroidetes abundance, Stat2-/- mice exhibited significantly less perturbation and higher levels of Bacteroidetes upon S. Typhimurium infection. Our results highlight STAT2 dependent type I IFN mediated inflammation in the gut as a novel mechanism promoting luminal expansion of S. Typhimurium.


Assuntos
Disbiose/imunologia , Gastroenterite/imunologia , Inflamação/imunologia , Interferon Tipo I/imunologia , Fator de Transcrição STAT2/fisiologia , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Animais , Células Cultivadas , Disbiose/metabolismo , Disbiose/patologia , Feminino , Gastroenterite/metabolismo , Gastroenterite/microbiologia , Gastroenterite/patologia , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/patologia , Interferon Tipo I/metabolismo , Intestinos/imunologia , Intestinos/microbiologia , Intestinos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Neutrófilos/patologia , Fator de Transcrição STAT1/fisiologia , Infecções por Salmonella/metabolismo , Infecções por Salmonella/microbiologia , Infecções por Salmonella/patologia
12.
Nat Immunol ; 20(5): 559-570, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30996332

RESUMO

The C-type lectin receptor-Syk (spleen tyrosine kinase) adaptor CARD9 facilitates protective antifungal immunity within the central nervous system (CNS), as human deficiency in CARD9 causes susceptibility to fungus-specific, CNS-targeted infection. CARD9 promotes the recruitment of neutrophils to the fungus-infected CNS, which mediates fungal clearance. In the present study we investigated host and pathogen factors that promote protective neutrophil recruitment during invasion of the CNS by Candida albicans. The cytokine IL-1ß served an essential function in CNS antifungal immunity by driving production of the chemokine CXCL1, which recruited neutrophils expressing the chemokine receptor CXCR2. Neutrophil-recruiting production of IL-1ß and CXCL1 was induced in microglia by the fungus-secreted toxin Candidalysin, in a manner dependent on the kinase p38 and the transcription factor c-Fos. Notably, microglia relied on CARD9 for production of IL-1ß, via both transcriptional regulation of Il1b and inflammasome activation, and of CXCL1 in the fungus-infected CNS. Microglia-specific Card9 deletion impaired the production of IL-1ß and CXCL1 and neutrophil recruitment, and increased fungal proliferation in the CNS. Thus, an intricate network of host-pathogen interactions promotes antifungal immunity in the CNS; this is impaired in human deficiency in CARD9, which leads to fungal disease of the CNS.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/imunologia , Candidíase/imunologia , Quimiocina CXCL1/imunologia , Interleucina-1beta/imunologia , Microglia/imunologia , Neutrófilos/imunologia , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/microbiologia , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Candida albicans/imunologia , Candida albicans/fisiologia , Candidíase/genética , Candidíase/microbiologia , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Inflamassomos/genética , Inflamassomos/imunologia , Inflamassomos/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Microglia/metabolismo , Microglia/microbiologia , Infiltração de Neutrófilos/genética , Infiltração de Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/microbiologia
13.
Nat Commun ; 10(1): 1667, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971685

RESUMO

Neutrophils are crucial mediators of host defense that are recruited to the central nervous system (CNS) in large numbers during acute bacterial meningitis caused by Streptococcus pneumoniae. Neutrophils release neutrophil extracellular traps (NETs) during infections to trap and kill bacteria. Intact NETs are fibrous structures composed of decondensed DNA and neutrophil-derived antimicrobial proteins. Here we show NETs in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis, and their absence in other forms of meningitis with neutrophil influx into the CSF caused by viruses, Borrelia and subarachnoid hemorrhage. In a rat model of meningitis, a clinical strain of pneumococci induced NET formation in the CSF. Disrupting NETs using DNase I significantly reduces bacterial load, demonstrating that NETs contribute to pneumococcal meningitis pathogenesis in vivo. We conclude that NETs in the CNS reduce bacterial clearance and degrading NETs using DNase I may have significant therapeutic implications.


Assuntos
Líquido Cefalorraquidiano/citologia , Armadilhas Extracelulares/microbiologia , Evasão da Resposta Imune , Meningite Pneumocócica/imunologia , Neutrófilos/imunologia , Streptococcus pneumoniae/imunologia , Adolescente , Adulto , Idoso , Animais , Grupo Borrelia Burgdorferi/imunologia , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/microbiologia , Líquido Cefalorraquidiano/imunologia , Líquido Cefalorraquidiano/microbiologia , Desoxirribonuclease I/administração & dosagem , Modelos Animais de Doenças , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/imunologia , Feminino , Humanos , Neuroborreliose de Lyme/líquido cefalorraquidiano , Neuroborreliose de Lyme/imunologia , Neuroborreliose de Lyme/microbiologia , Masculino , Meningite Pneumocócica/líquido cefalorraquidiano , Meningite Pneumocócica/tratamento farmacológico , Meningite Pneumocócica/microbiologia , Meningite Viral/líquido cefalorraquidiano , Meningite Viral/imunologia , Pessoa de Meia-Idade , Neutrófilos/microbiologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Punção Espinal , Streptococcus pneumoniae/isolamento & purificação , Hemorragia Subaracnóidea/líquido cefalorraquidiano , Adulto Jovem
14.
Microbiol Spectr ; 7(2)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30927347

RESUMO

Staphylococcus aureus has become a serious threat to human health. In addition to having increased antibiotic resistance, the bacterium is a master at adapting to its host by evading almost every facet of the immune system, the so-called immune evasion proteins. Many of these immune evasion proteins target neutrophils, the most important immune cells in clearing S. aureus infections. The neutrophil attacks pathogens via a plethora of strategies. Therefore, it is no surprise that S. aureus has evolved numerous immune evasion strategies at almost every level imaginable. In this review we discuss step by step the aspects of neutrophil-mediated killing of S. aureus, such as neutrophil activation, migration to the site of infection, bacterial opsonization, phagocytosis, and subsequent neutrophil-mediated killing. After each section we discuss how S. aureus evasion molecules are able to resist the neutrophil attack of these different steps. To date, around 40 immune evasion molecules of S. aureus are known, but its repertoire is still expanding due to the discovery of new evasion proteins and the addition of new functions to already identified evasion proteins. Interestingly, because the different parts of neutrophil attack are redundant, the evasion molecules display redundant functions as well. Knowing how and with which proteins S. aureus is evading the immune system is important in understanding the pathophysiology of this pathogen. This knowledge is crucial for the development of therapeutic approaches that aim to clear staphylococcal infections.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Evasão da Resposta Imune/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Quimiotaxia/imunologia , Endotélio/imunologia , Humanos , Imunidade Inata/imunologia , Neutrófilos/imunologia , Neutrófilos/microbiologia , Fagocitose/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/patogenicidade
15.
Nat Immunol ; 20(5): 546-558, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30911105

RESUMO

Neutrophils are essential first-line defense cells against invading pathogens, yet when inappropriately activated, their strong immune response can cause collateral tissue damage and contributes to immunological diseases. However, whether neutrophils can intrinsically titrate their immune response remains unknown. Here we conditionally deleted the Spi1 gene, which encodes the myeloid transcription factor PU.1, from neutrophils of mice undergoing fungal infection and then performed comprehensive epigenomic profiling. We found that as well as providing the transcriptional prerequisite for eradicating pathogens, the predominant function of PU.1 was to restrain the neutrophil defense by broadly inhibiting the accessibility of enhancers via the recruitment of histone deacetylase 1. Such epigenetic modifications impeded the immunostimulatory AP-1 transcription factor JUNB from entering chromatin and activating its targets. Thus, neutrophils rely on a PU.1-installed inhibitor program to safeguard their epigenome from undergoing uncontrolled activation, protecting the host against an exorbitant innate immune response.


Assuntos
Epigênese Genética/imunologia , Epigenômica/métodos , Neutrófilos/imunologia , Proteínas Proto-Oncogênicas/imunologia , Transativadores/imunologia , Animais , Candida albicans/imunologia , Candida albicans/fisiologia , Candidíase/genética , Candidíase/imunologia , Candidíase/microbiologia , Resistência à Doença/genética , Resistência à Doença/imunologia , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Análise de Sobrevida , Transativadores/deficiência , Transativadores/genética , Transcriptoma/genética , Transcriptoma/imunologia
16.
Blood ; 133(20): 2168-2177, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-30898860

RESUMO

The microbiota has emerged as an important regulator of the host immunity by the induction, functional modulation, or suppression of local and systemic immune responses. In return, the host immune system restricts translocation and fine tunes the composition and distribution of the microbiota to maintain a beneficial symbiosis. This paradigm applies to neutrophils, a critical component of the innate immunity, allowing their production and function to be influenced by microbial components and metabolites derived from the microbiota, and engaging them in the process of microbiota containment and regulation. The cross talk between neutrophils and the microbiota adjusts the magnitude of neutrophil-mediated inflammation on challenge while preventing neutrophil responses against commensals under steady state. Here, we review the major molecular and cellular mediators of the interactions between neutrophils and the microbiota and discuss their interplay and contribution in chronic inflammatory diseases and cancer.


Assuntos
Inflamação/imunologia , Microbiota , Neoplasias/imunologia , Neutrófilos/imunologia , Animais , Humanos , Inflamação/microbiologia , Mediadores da Inflamação/imunologia , Neoplasias/microbiologia , Neutrófilos/microbiologia
17.
Cell Mol Life Sci ; 76(11): 2031-2042, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30877336

RESUMO

Pyroptosis is a caspase-1 or caspase-4/5/11-dependent programmed cell death associated with inflammation, which is initiated by inflammasomes or cytosolic LPS in innate immunity. Sepsis is a life-threatening organ dysfunction caused by an imbalance in the body's response to infection. It is a complex interaction between the pathogen and the host's immune system. Neutrophils play the role of a double-edged sword in sepsis, and a number of studies have previously shown that regulation of neutrophils is the most crucial part of sepsis treatment. Pyroptosis is one of the important forms for neutrophils to function, which is increasingly understood as a host active immune response. There is ample evidence that neutrophil pyroptosis may play an important role in sepsis. In recent years, a breakthrough in pyroptosis research has revealed the main mechanism of pyroptosis. However, the potential value of neutrophil pyroptosis in the treatment of sepsis did not draw enough attention. A literature review was performed on the main mechanism of pyroptosis in sepsis and the potential value of neutrophils pyroptosis in sepsis, which may be suitable targets for sepsis treatment in future.


Assuntos
Infecções Bacterianas/imunologia , Caspases/imunologia , Inflamassomos/imunologia , Neutrófilos/imunologia , Piroptose/imunologia , Sepse/imunologia , Animais , Anti-Inflamatórios/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/genética , Infecções Bacterianas/patologia , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/imunologia , Caspases/genética , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Inflamassomos/efeitos dos fármacos , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Lipopolissacarídeos/farmacologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/microbiologia , Piroptose/efeitos dos fármacos , Sepse/tratamento farmacológico , Sepse/genética , Sepse/patologia
18.
J Med Microbiol ; 68(4): 600-608, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30843785

RESUMO

PURPOSE: Mechanisms underlying systemic infections by oral species of Mitis (Streptococcus mitis, Streptococcus oralis) and Sanguinis (Streptococcus gordonii, Streptococcus sanguinis) commensal streptococci are poorly understood. This study investigates profiles of susceptibility to complement-mediated host immunity in representative strains of these four species, which were isolated from oral sites or from the bloodstream. METHODOLOGY: Deposition of complement opsonins (C3b/iC3b), and surface binding to C-reactive protein (CRP) and to IgG antibodies were quantified by flow cytometry in 34 strains treated with human serum (HS), and compared to rates of opsonophagocytosis by human PMN mediated by complement (CR1/3) and/or IgG Fc (FcγRII/III) receptors. RESULTS: S. sanguinis strains showed reduced susceptibility to complement opsonization and low binding to CRP and to IgG compared to other species. Surface levels of C3b/iC3b in S. sanguinis strains were 4.5- and 7.8-fold lower than that observed in S. gordonii and Mitis strains, respectively. Diversity in C3b/iC3b deposition was evident among Mitis species, in which C3b/iC3b deposition was significantly associated with CR/FcγR-dependent opsonophagocytosis by PMN (P<0.05). Importantly, S. gordonii and Mitis group strains isolated from systemic infections showed resistance to complement opsonization when compared to oral isolates of the respective species (P<0.05). CONCLUSIONS: This study establishes species-specific profiles of susceptibility to complement immunity in Mitis and Sanguinis streptococci, and indicates that strains associated with systemic infections have increased capacity to evade complement immunity. These findings highlight the need for studies identifying molecular functions involved in complement evasion in oral streptococci.


Assuntos
Complemento C3b/imunologia , Variação Genética , Boca/microbiologia , Estreptococos Viridans/genética , Estreptococos Viridans/imunologia , Aderência Bacteriana , Biofilmes , Proteína C-Reativa/metabolismo , Humanos , Evasão da Resposta Imune , Imunoglobulina G/imunologia , Neutrófilos/imunologia , Neutrófilos/microbiologia , Fagocitose , Infecções Estreptocócicas/sangue , Infecções Estreptocócicas/imunologia , Streptococcus gordonii/genética , Streptococcus gordonii/imunologia , Streptococcus mitis/genética , Streptococcus mitis/imunologia , Streptococcus sanguis/genética , Streptococcus sanguis/imunologia
19.
Microbiol Immunol ; 63(3-4): 100-110, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30817027

RESUMO

Aggregatibacter actinomycetemcomitans is considered to be associated with periodontitis. Leukotoxin (LtxA), which destroys leukocytes in humans, is one of this bacterium's major virulence factors. Amounts of neutrophil elastase (NE), which is normally localized in the cytoplasm of neutrophils, are reportedly increased in the saliva of patients with periodontitis. However, the mechanism by which NE is released from human neutrophils and the role of NE in periodontitis is unclear. In the present study, it was hypothesized that LtxA induces NE release from human neutrophils, which subsequently causes the breakdown of periodontal tissues. LtxA-treatment did not induce significant cytotoxicity against human gingival epithelial cells (HGECs) or human gingival fibroblasts (HGFs). However, it did induce significant cytotoxicity against human neutrophils, leading to NE release. Furthermore, NE and the supernatant from LtxA-treated human neutrophils induced detachment and death of HGECs and HGFs, these effects being inhibited by administration of an NE inhibitor, sivelestat. The present results suggest that LtxA mediates human neutrophil lysis and induces the subsequent release of NE, which eventually results in detachment and death of HGECs and HGFs. Thus, LtxA-induced release of NE could cause breakdown of periodontal tissue and thereby exacerbate periodontitis.


Assuntos
Aggregatibacter actinomycetemcomitans/metabolismo , Células Epiteliais/patologia , Exotoxinas/metabolismo , Fibroblastos/patologia , Gengiva/microbiologia , Elastase de Leucócito/metabolismo , Neutrófilos/patologia , Periodontite/microbiologia , Aggregatibacter actinomycetemcomitans/patogenicidade , Morte Celular/fisiologia , Linhagem Celular , Células Epiteliais/microbiologia , Fibroblastos/microbiologia , Gengiva/citologia , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Elastase de Leucócito/antagonistas & inibidores , Neutrófilos/microbiologia , Sulfonamidas/farmacologia , Fatores de Virulência/metabolismo
20.
Lab Chip ; 19(7): 1205-1216, 2019 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-30865740

RESUMO

Measurements of neutrophil activities such as cell migration and phagocytosis are generally performed using low-content bulk assays, which provide little detail activity at the single cell level, or flow cytometry methods, which have the single cell resolution but lack perspective on the kinetics of the process. Here, we present a microfluidic assay for measuring the essential functions that contribute to the antimicrobial activity of neutrophils: migration towards the target, and killing of microbes. The assay interrogates the interactions between isolated human neutrophils and populations of live, proliferating microbes. The outcome is measured in a binary mode that is reflective of in vivo infections, which are either cleared or endure the host response. The outcome of the interactions is also characterized at single cell resolution for both the neutrophils and the microbes. We applied the assay to test the response of neutrophils from intensive care patients to live Staphylococcus aureus, and observed alterations of antimicrobial neutrophil activity in patients, including those with sepsis. By directly measuring neutrophil activity against live targets at high spatial and temporal resolution, this assay provides unique insights into the life-or-death contest shaping the outcome of interactions between populations of neutrophils and microbes.


Assuntos
Dispositivos Lab-On-A-Chip , Neutrófilos/microbiologia , Staphylococcus aureus/fisiologia , Adulto , Idoso , Antibacterianos/farmacologia , Movimento Celular , Humanos , Pessoa de Meia-Idade , Neutrófilos/citologia , Fagocitose , Staphylococcus aureus/efeitos dos fármacos , Adulto Jovem
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