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1.
Int J Mol Sci ; 22(2)2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33467014

RESUMO

Chronic tic disorder and Tourette syndrome are common childhood-onset neurological diseases. However, the pathophysiology underlying these disorders is unclear, and most studies have focused on the disinhibition of the corticostriatal-thalamocortical circuit. An autoimmune dysfunction has been proposed in the pathogenetic mechanism of Tourette syndrome and related neuropsychiatric disorders such as obsessive-compulsive disorder, autism, and attention-deficit/hyperactivity disorder. This is based on evidence from animal model studies and clinical findings. Herein, we review and give an update on the clinical characteristics, clinical evidence, and genetic studies in vitro as well as animal studies regarding immune dysfunction in Tourette syndrome.


Assuntos
Doenças Autoimunes/imunologia , Transtorno Obsessivo-Compulsivo/imunologia , Infecções Estreptocócicas/imunologia , Síndrome de Tourette/imunologia , Animais , Doenças Autoimunes/epidemiologia , Humanos , Linfócitos/imunologia , Microglia/imunologia , Neurônios/imunologia , Transtorno Obsessivo-Compulsivo/epidemiologia , Infecções Estreptocócicas/epidemiologia , Síndrome de Tourette/epidemiologia , Síndrome de Tourette/genética
2.
mBio ; 12(1)2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402537

RESUMO

Invasive bacterial infections during pregnancy are a major risk factor for preterm birth, stillbirth, and fetal injury. Group B streptococci (GBS) are Gram-positive bacteria that asymptomatically colonize the lower genital tract but infect the amniotic fluid and induce preterm birth or stillbirth. Experimental models that closely emulate human pregnancy are pivotal for the development of successful strategies to prevent these adverse pregnancy outcomes. Using a unique nonhuman primate model that mimics human pregnancy and informs temporal events surrounding amniotic cavity invasion and preterm labor, we show that the animals inoculated with hyaluronidase (HylB)-expressing GBS consistently exhibited microbial invasion into the amniotic cavity, fetal bacteremia, and preterm labor. Although delayed cytokine responses were observed at the maternal-fetal interface, increased prostaglandin and matrix metalloproteinase levels in these animals likely mediated preterm labor. HylB-proficient GBS dampened reactive oxygen species production and exhibited increased resistance to neutrophils compared to an isogenic mutant. Together, these findings demonstrate how a bacterial enzyme promotes GBS amniotic cavity invasion and preterm labor in a model that closely resembles human pregnancy.IMPORTANCE Group B streptococci (GBS) are bacteria that commonly reside in the female lower genital tract as asymptomatic members of the microbiota. However, during pregnancy, GBS can infect tissues at the maternal-fetal interface, leading to preterm birth, stillbirth, or fetal injury. Understanding how GBS evade host defenses during pregnancy is key to developing improved preventive therapies for these adverse outcomes. In this study, we used a unique nonhuman primate model to show that an enzyme secreted by GBS, hyaluronidase (HylB) promotes bacterial invasion into the amniotic cavity and fetus. Although delayed immune responses were seen at the maternal-fetal interface, animals infected with hyaluronidase-expressing GBS exhibited premature cervical ripening and preterm labor. These observations reveal that HylB is a crucial GBS virulence factor that promotes bacterial invasion and preterm labor in a pregnancy model that closely emulates human pregnancy. Therefore, hyaluronidase inhibitors may be useful in therapeutic strategies against ascending GBS infection.


Assuntos
Hialuronoglucosaminidase/metabolismo , Neutrófilos/imunologia , Trabalho de Parto Prematuro/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus agalactiae/metabolismo , Líquido Amniótico/microbiologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Hialuronoglucosaminidase/genética , Inflamação , Pulmão/microbiologia , Pulmão/patologia , Macaca nemestrina , Neutrófilos/microbiologia , Gravidez , Nascimento Prematuro , Primatas , Infecções Estreptocócicas/metabolismo , Infecções Estreptocócicas/microbiologia , Streptococcus agalactiae/enzimologia , Streptococcus agalactiae/genética , Streptococcus agalactiae/imunologia
3.
J Fish Dis ; 44(1): 45-52, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32959439

RESUMO

Streptococcus agalactiae is a Gram-positive facultative intracellular bacterium that leads to severe economic loss of tilapia worldwide. Previous studies demonstrated that CD40 contributes to host protection against intracellular injection. In this study, CD40 was characterized from Nile tilapia (Oreochromis niloticus), named OnCD40. Sequence analysis showed that open reading frame of OnCD40 was 933 bp, containing a single peptide, a transmembrane domain and four cysteine-rich domains. The qRT-PCR revealed that OnCD40 was expressed in all examined tissues with the most abundant ones in spleen and thymus. After S. agalactiae stimulation, the expression of OnCD40 was significantly induced in most of the detected organs. Moreover, OnCD40-overexpressing fish elicited significant protection against subsequent S. agalactiae challenge; approximately 10000-fold fewer bacteria were detected in spleen of OnCD40-overexpressing fish in comparison with control fish. Thus, CD40 had protecting function in Nile tilapia against intracellular pathogens.


Assuntos
Antígenos CD40/imunologia , Ciclídeos/imunologia , Doenças dos Peixes/imunologia , Proteínas de Peixes/imunologia , Infecções Estreptocócicas/veterinária , Sequência de Aminoácidos , Animais , Antígenos CD40/genética , Ciclídeos/microbiologia , Doenças dos Peixes/microbiologia , Proteínas de Peixes/genética , Fases de Leitura Aberta , Infecções Estreptocócicas/imunologia , Streptococcus agalactiae/patogenicidade
4.
Nat Commun ; 11(1): 4697, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943639

RESUMO

Unassisted metastasis through the lymphatic system is a mechanism of dissemination thus far ascribed only to cancer cells. Here, we report that Streptococcus pyogenes also hijack lymphatic vessels to escape a local infection site, transiting through sequential lymph nodes and efferent lymphatic vessels to enter the bloodstream. Contrasting with previously reported mechanisms of intracellular pathogen carriage by phagocytes, we show S. pyogenes remain extracellular during transit, first in afferent and then efferent lymphatics that carry the bacteria through successive draining lymph nodes. We identify streptococcal virulence mechanisms important for bacterial lymphatic dissemination and show that metastatic streptococci within infected lymph nodes resist and subvert clearance by phagocytes, enabling replication that can seed intense bloodstream infection. The findings establish the lymphatic system as both a survival niche and conduit to the bloodstream for S. pyogenes, explaining the phenomenon of occult bacteraemia. This work provides new perspectives in streptococcal pathogenesis with implications for immunity.


Assuntos
Linfonodos/microbiologia , Metástase Linfática , Vasos Linfáticos/microbiologia , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/patogenicidade , Animais , Bacteriemia/microbiologia , Bacteriemia/patologia , Modelos Animais de Doenças , Feminino , Interleucina-8/metabolismo , Linfonodos/imunologia , Linfonodos/patologia , Metástase Linfática/patologia , Sistema Linfático , Vasos Linfáticos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neutrófilos/microbiologia , Fagocitose , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/patologia , Streptococcus pyogenes/genética , Virulência
5.
Arch Dis Child ; 105(9): 825-829, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32601082

RESUMO

OBJECTIVE: Despite substantial variation of streptococcal antibody titres among global populations, there is no data on normal values in sub-Saharan Africa. The objective of this study was to establish normal values for antistreptolysin O (ASO) and antideoxyribonuclease B (ADB) antibodies in Uganda. DESIGN: This was an observational cross-sectional study. SETTING: This study was conducted at Mulago National Referral Hospital, which is located in the capital city, Kampala, and includes the Uganda Heart Institute. PATIENTS: Participants (aged 0-50 years) were recruited. Of 428 participants, 22 were excluded from analysis, and 183 (44.4%) of the remaining were children aged 5-15 years. MAIN OUTCOME MEASURES: ASO was measured in-country by nephelometric technique. ADB samples were sent to Australia (PathWest) for analysis by enzyme inhibition assay: 80% upper limit values were established. RESULTS: The median ASO titre in this age group was 220 IU/mL, with the 80th percentile value of 389 IU/mL. The median ADB titre in this age group was 375 IU/mL, with the 80th percentile value of 568 IU/mL. CONCLUSIONS: The estimated Ugandan paediatric population standardised 80% upper-limit-of-normal ASO and ADB titres is higher than many global populations. Appropriateness of using population-specific antibody cutoffs is yet to be determined and has important implications for the sensitivity and specificity of rheumatic fever diagnosis.


Assuntos
Anticorpos Antibacterianos/sangue , Streptococcus pyogenes/imunologia , Adolescente , Adulto , Fatores Etários , Anticorpos Antibacterianos/imunologia , Antiestreptolisina/imunologia , Criança , Pré-Escolar , Estudos Transversais , Desoxirribonucleases/imunologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Valores de Referência , Infecções Estreptocócicas/sangue , Infecções Estreptocócicas/epidemiologia , Infecções Estreptocócicas/imunologia , Uganda/epidemiologia , Adulto Jovem
6.
PLoS One ; 15(6): e0235139, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574205

RESUMO

Viral infections complicated by a bacterial infection are typically referred to as coinfections or superinfections. Streptococcus pyogenes, the group A streptococcus (GAS), is not the most common bacteria associated with influenza A virus (IAV) superinfections but did cause significant mortality during the 2009 influenza pandemic even though all isolates are susceptible to penicillin. One approach to improve the outcome of these infections is to use passive immunization targeting GAS. To test this idea, we assessed the efficacy of passive immunotherapy using antisera against either the streptococcal M protein or streptolysin O (SLO) in a murine model of IAV-GAS superinfection. Prophylactic treatment of mice with antiserum to either SLO or the M protein decreased morbidity compared to mice treated with non-immune sera; however, neither significantly decreased mortality. Therapeutic use of antisera to SLO decreased morbidity compared to mice treated with non-immune sera but neither antisera significantly reduced mortality. Overall, the results suggest that further development of antibodies targeting the M protein or SLO may be a useful adjunct in the treatment of invasive GAS diseases, including IAV-GAS superinfections, which may be particularly important during influenza pandemics.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas de Transporte/imunologia , Imunoterapia/métodos , Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus pyogenes/imunologia , Estreptolisinas/imunologia , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/metabolismo , Proteínas da Membrana Bacteriana Externa/antagonistas & inibidores , Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/metabolismo , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Coinfecção/microbiologia , Coinfecção/terapia , Coinfecção/virologia , Feminino , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Soros Imunes/imunologia , Soros Imunes/farmacologia , Vírus da Influenza A/fisiologia , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/terapia , Infecções por Orthomyxoviridae/virologia , Coelhos , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/terapia , Streptococcus pyogenes/metabolismo , Streptococcus pyogenes/fisiologia , Estreptolisinas/antagonistas & inibidores , Estreptolisinas/metabolismo , Superinfecção/microbiologia , Superinfecção/terapia , Superinfecção/virologia
7.
PLoS Comput Biol ; 16(6): e1007182, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32502148

RESUMO

Group A Streptococcus (GAS) skin infections are caused by a diverse array of strain types and are highly prevalent in disadvantaged populations. The role of strain-specific immunity in preventing GAS infections is poorly understood, representing a critical knowledge gap in vaccine development. A recent GAS murine challenge study showed evidence that sterilising strain-specific and enduring immunity required two skin infections by the same GAS strain within three weeks. This mechanism of developing enduring immunity may be a significant impediment to the accumulation of immunity in populations. We used an agent-based mathematical model of GAS transmission to investigate the epidemiological consequences of enduring strain-specific immunity developing only after two infections with the same strain within a specified interval. Accounting for uncertainty when correlating murine timeframes to humans, we varied this maximum inter-infection interval from 3 to 420 weeks to assess its impact on prevalence and strain diversity, and considered additional scenarios where no maximum inter-infection interval was specified. Model outputs were compared with longitudinal GAS surveillance observations from northern Australia, a region with endemic infection. We also assessed the likely impact of a targeted strain-specific multivalent vaccine in this context. Our model produced patterns of transmission consistent with observations when the maximum inter-infection interval for developing enduring immunity was 19 weeks. Our vaccine analysis suggests that the leading multivalent GAS vaccine may have limited impact on the prevalence of GAS in populations in northern Australia if strain-specific immunity requires repeated episodes of infection. Our results suggest that observed GAS epidemiology from disease endemic settings is consistent with enduring strain-specific immunity being dependent on repeated infections with the same strain, and provide additional motivation for relevant human studies to confirm the human immune response to GAS skin infection.


Assuntos
Dermatopatias/epidemiologia , Infecções Estreptocócicas/epidemiologia , Streptococcus pyogenes , Animais , Austrália/epidemiologia , Austrália/etnologia , Número Básico de Reprodução , Modelos Animais de Doenças , Humanos , Camundongos , Modelos Teóricos , Dinâmica Populacional , Grupos Populacionais , Dermatopatias/imunologia , Dermatopatias/microbiologia , Dermatopatias/prevenção & controle , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/prevenção & controle , Vacinas Estreptocócicas
8.
Res Vet Sci ; 131: 177-185, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32388020

RESUMO

Heat-killed (HK) Bacillus sp. SJ-10 (B), HK Lactobacillus plantarum (P), and their combination were dietary supplemented to olive flounder (Paralichthys olivaceus) to quantify the effects on growth, innate immunity, and disease resistance. Four test diets were supplied: a control feed free of HK probiotics, 1 × 108 CFUs g-1 single treatments of each of HK B (HKB) and HK P (HKP), and an equal proportion of (0.5 HKB + 0.5 HKP) × 108 CFUs g-1 (HKB0.5 HKP0.5). At 8 weeks of completion feeding trail, HKB0.5 HKP0.5 significantly (P < .05) improved growth, feed utilization, and nonspecific immune parameters (respiratory burst and superoxide dismutase) compared to the control group. Similarly, serum lysozyme and myeloperoxidase activities were higher in both HKB and HKB0.5HKP0.5 groups. The levels of pro-inflammatory cytokine IL-6 in the liver and IL-1ß in the liver, kidney, and spleen were also improved in the treatments, but microvilli length was only increased in HKB0.5HKP0.5. After Streptococcus iniae 1 × 108 CFUs mL-1 challenged; HKB and HKB0.5HKP0.5 had a higher survival than control and HKP. Overall, dietary administration of synergy HK probiotics elevated growth, cellular and humoral immunity, and streptococcosis resistance in olive flounder.


Assuntos
Bacillus , Dieta/veterinária , Linguado , Lactobacillus plantarum , Probióticos/farmacologia , Animais , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Suplementos Nutricionais , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Doenças dos Peixes/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Infecções Estreptocócicas/imunologia , Streptococcus iniae
9.
Am J Trop Med Hyg ; 102(6): 1208-1209, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32314699

RESUMO

The early shortage of novel coronavirus disease (COVID-19) tests in the United States led many hospitals to first screen for common respiratory pathogens, and only if this screen was negative to proceed with COVID-19 testing. We report a case of a 56-year-old woman with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) coinfection with group A Streptococcus. The initial testing strategy resulted in delays in both diagnosis and implementation of appropriate precautions. Underlined is the importance of testing for both SARS-CoV-2 and other common respiratory pathogens during the current pandemic.


Assuntos
Betacoronavirus/patogenicidade , Dor Crônica/diagnóstico por imagem , Infecções por Coronavirus/diagnóstico por imagem , Hipertensão/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pneumonia Viral/diagnóstico por imagem , Infecções Estreptocócicas/diagnóstico por imagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Azitromicina/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/isolamento & purificação , Ceftriaxona/uso terapêutico , Chicago , Dor Crônica/imunologia , Dor Crônica/patologia , Dor Crônica/terapia , Coinfecção , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/terapia , Oxigenação por Membrana Extracorpórea , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Hipertensão/imunologia , Hipertensão/patologia , Hipertensão/terapia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/terapia , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/patologia , Infecções Estreptocócicas/terapia , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus pyogenes/isolamento & purificação , Streptococcus pyogenes/patogenicidade , Tomografia Computadorizada por Raios X , Resultado do Tratamento
10.
PLoS One ; 15(4): e0231101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32302339

RESUMO

Mast cells and basophils are central players in allergic reactions triggered by immunoglobulin E (IgE). They have intracellular granules containing allergic mediators (e.g., histamine, serotonin, inflammatory cytokines, proteases and ß-hexosaminidase), and stimulation by IgE-allergen complex leads to the release of such allergic mediators from the granules, that is, degranulation. Mast cells are residents of mucosal surfaces, including those of nasal and oral cavities, and play an important role in the innate defense system. Members of the mitis group streptococci such as Streptococcus oralis, are primary colonizers of the human oral cavity. They produce hydrogen peroxide (H2O2) as a by-product of sugar metabolism. In this study, we investigated the effects of streptococcal infection on RBL-2H3 mast cell/basophil cell line. Infection by oral streptococci did not induce degranulation of the cells. Stimulation of the RBL-2H3 cells with anti-dinitrophenol (DNP) IgE and DNP-conjugated human serum albumin triggers degranulation with the release of ß-hexosaminidase. We found that S. oralis and other mitis group streptococci inhibited the IgE-triggered degranulation of RBL-2H3 cells. Since mitis group streptococci produce H2O2, we examined the effect of S. oralis mutant strain deficient in producing H2O2, and found that they lost the ability to suppress the degranulation. Moreover, H2O2 alone inhibited the IgE-induced degranulation. Subsequent analysis suggested that the inhibition of degranulation was related to the cytotoxicity of streptococcal H2O2. Activated RBL-2H3 cells produce interleukin-4 (IL-4); however, IL-4 production was not induced by streptococcal H2O2. Furthermore, an in vivo study using the murine pollen-induced allergic rhinitis model suggested that the streptococcal H2O2 reduces nasal allergic reaction. These findings reveal that H2O2 produced by oral mitis group streptococci inhibits IgE-stimulated degranulation by inducing cell death. Consequently, streptococcal H2O2 can be considered to modulate the allergic reaction in mucosal surfaces.


Assuntos
Alérgenos/metabolismo , Hipersensibilidade/imunologia , Imunoglobulina E/imunologia , Infecções Estreptocócicas/tratamento farmacológico , Alérgenos/imunologia , Animais , Basófilos/imunologia , Basófilos/microbiologia , Basófilos/patologia , Degranulação Celular/imunologia , Sobrevivência Celular/imunologia , Dinitrofenóis/farmacologia , Humanos , Peróxido de Hidrogênio/metabolismo , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/patologia , Imunoglobulina E/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Mastócitos/imunologia , Mastócitos/microbiologia , Mastócitos/patologia , Camundongos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Albumina Sérica Humana/imunologia , Albumina Sérica Humana/metabolismo , Infecções Estreptocócicas/imunologia , Streptococcus oralis/imunologia , Streptococcus oralis/patogenicidade , Açúcares/metabolismo
11.
Vet Microbiol ; 243: 108653, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32273000

RESUMO

Porcine circovirus type 2 (PCV-2) and Streptococcus suis (S. suis) are common pathogens in pigs. Both pathogens are associated with the porcine respiratory disease complex. Clinically, coinfection of PCV-2 and S. suis are often detected in pigs with respiratory symptoms, while interactions between the two pathogens during coinfection and the coinfection pathogenesis are poorly understood. In this study, a piglet model coinfected with PCV-2 and Streptococcus suis serotype 2 (SS2) was established; coinfection of piglets increased the contents of SS2 in blood, and piglets showed more severe pneumonia, myocarditis and arthritis. Peripheral blood mononuclear cells (PBMCs) were collected and coinfected piglets showed high expression levels of inflammatory cytokines and TLR2, TLR4, while levels of CD4, CD8 and MHC II were reduced. In addition, in order to further explore the mechanisms of coinfection induced cytokine overexpression, an in vitro model of coinfection with PCV-2 and SS2 was established using cells of the porcine monocytic line 3D4/21. Similar to the in vivo results,coinfected cells exhibited increased expression of the cytokines IL-6, IL-8, TNF-α and the receptors TLR2, TLR4, while they showed a lower expression of MHC II than cells infected with SS2 alone. Furthermore, in coinfected 3D4/21 cells, both MAPK and NF-κB signaling pathways were activated, and the increased expression of IL-8 was related to TLR4. In general, coinfection with PCV-2 and SS2 exacerbated the inflammatory response and probably impaired macrophage antigen presentation, resulting in immune dysregulation and increasing the severity of host infection.


Assuntos
Infecções por Circoviridae/veterinária , Circovirus/patogenicidade , Coinfecção/veterinária , Infecções Estreptocócicas/veterinária , Streptococcus suis/patogenicidade , Animais , Infecções por Circoviridae/imunologia , Circovirus/imunologia , Coinfecção/imunologia , Citocinas/genética , Citocinas/imunologia , Sorogrupo , Infecções Estreptocócicas/imunologia , Streptococcus suis/imunologia , Suínos , Doenças dos Suínos/imunologia , Doenças dos Suínos/microbiologia , Doenças dos Suínos/virologia , Virulência
12.
Nat Commun ; 11(1): 1502, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32198389

RESUMO

Although certain microbial lipids are toxins, the structural features important for cytotoxicity remain unknown. Increased functional understanding is essential for developing therapeutics against toxic microbial lipids. Group B Streptococci (GBS) are bacteria associated with preterm births, stillbirths, and severe infections in neonates and adults. GBS produce a pigmented, cytotoxic lipid, known as granadaene. Despite its importance to all manifestations of GBS disease, studies towards understanding granadaene's toxic activity are hindered by its instability and insolubility in purified form. Here, we report the synthesis and screening of lipid derivatives inspired by granadaene, which reveal features central to toxin function, namely the polyene chain length. Furthermore, we show that vaccination with a non-toxic synthetic analog confers the production of antibodies that inhibit granadaene-mediated hemolysis ex vivo and diminish GBS infection in vivo. This work provides unique structural and functional insight into granadaene and a strategy to mitigate GBS infection, which will be relevant to other toxic lipids encoded by human pathogens.


Assuntos
Hemólise , Lipídeos/química , Polienos/química , Nascimento Prematuro/microbiologia , Infecções Estreptocócicas/metabolismo , Adulto , Animais , Linfócitos B , Toxinas Bacterianas/química , Vacinas Bacterianas , Linfócitos T CD4-Positivos , Modelos Animais de Doenças , Feminino , Humanos , Recém-Nascido , Lipídeos/imunologia , Lipídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polienos/imunologia , Gravidez , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/prevenção & controle , Streptococcus agalactiae , Vacinação
13.
Int J Mol Sci ; 21(4)2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32098238

RESUMO

The objective of this paper is to review and summarize conclusions from the available literature regarding Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). The authors have independently reviewed articles from 1977 onwards, primarily focusing on the etiopathology, symptoms, differentiation between similar psychiatric conditions, immunological reactions, alterations in the nervous system and gut microbiota, genetics, and the available treatment for PANDAS. Recent research indicates that PANDAS patients show noticeable alterations within the structures of the central nervous system, including caudate, putamen, globus pallidus, and striatum, as well as bilateral and lentiform nuclei. Likewise, the presence of autoantibodies that interact with basal ganglia was observed in PANDAS patients. Several studies also suggest a relationship between the presence of obsessive-compulsive disorders like PANDAS and alterations to the gut microbiota. Further, genetic predispositions-including variations in the MBL gene and TNF-α-seem to be relevant regarding PANDAS syndrome. Even though the literature is still scarce, the authors have attempted to provide a thorough insight into the PANDAS syndrome, bearing in mind the diagnostic difficulties of this condition.


Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes , Gânglios da Base/imunologia , Microbioma Gastrointestinal/imunologia , Doenças do Sistema Nervoso , Transtorno Obsessivo-Compulsivo , Infecções Estreptocócicas , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/psicologia , Humanos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/imunologia , Doenças do Sistema Nervoso/psicologia , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/genética , Transtorno Obsessivo-Compulsivo/imunologia , Transtorno Obsessivo-Compulsivo/psicologia , Infecções Estreptocócicas/diagnóstico , Infecções Estreptocócicas/genética , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/psicologia , Síndrome
14.
Fish Shellfish Immunol ; 99: 562-571, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32109611

RESUMO

Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1), a kind of protein tyrosine phosphatases (PTPs), is a critical regulator of antigen receptor signal transduction. Signal transduction of BCR is regulated by phosphatases in teleost as in mammals. In this study, SHP1 from Nile tilapia (Oreochromis niloticus) (OnSHP1) was identified and characterized, including the expression pattern against bacterial infection and regulation function in BCR signaling pathway. The open reading frame of OnSHP1 contains 1749 bp of nucleotide sequence, encoding a protein of 582 amino acids. The OnSHP1 protein was highly conversed compared to that of other species, including two amino-terminal SH2 domains at the N terminus and a PTP catalytic domain. Transcriptional expression analysis revealed that OnSHP1 was detected in all examined tissues and highly expressed in spleen. The up-regulated OnSHP1 expression was observed in peripheral blood, spleen and anterior kidney following challenge with Streptococcus agalactiae or lipopolysaccharide (LPS) in vivo, as well as that displayed in leukocytes stimulated with S. agalactiae or LPS in vitro. Further, after induction with mouse anti-tilapia IgM monoclonal antibody in vitro, OnSHP1 was significantly up-regulated in leukocytes. When spleen leukocytes treated with PTP Inhibitor II in vitro, the phosphorylation level of OnSHP1 at the phosphorylation sites (Y535 and Y557) and the cytoplasmic free Ca2+ concentration were up-regulated significantly. Overall, the findings of this study indicate that SHP1 gets involved in host defense against bacterial infection and BCR signaling pathway in Nile tilapia.


Assuntos
Ciclídeos/imunologia , Doenças dos Peixes/imunologia , Proteínas de Peixes/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/imunologia , Transdução de Sinais/imunologia , Infecções Estreptocócicas/veterinária , Animais , Doenças dos Peixes/microbiologia , Proteínas de Peixes/genética , Imunidade Inata , Leucócitos/imunologia , Filogenia , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Infecções Estreptocócicas/imunologia , Streptococcus agalactiae
15.
Sci Rep ; 10(1): 603, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953479

RESUMO

Streptococcus agalactiae is a causative agent of streptococcosis disease in various fish species, including Nile tilapia (Oreochromis niloticus Linn.). Vaccination is an effective disease prevention and control method, but limitations remain for protecting against catastrophic mortality of fish infected with different strains of streptococci. Immunoproteomics analysis of S. agalactiae was used to identify antigenic proteins and construct a chimeric multiepitope vaccine. Epitopes from five antigenic proteins were shuffled in five helices of a flavodoxin backbone, and in silico analysis predicted a suitable RNA and protein structure for protein expression. 45F2 and 42E2 were identified as the best candidates for a chimeric multiepitope vaccine. Recombinant plasmids were constructed to produce a recombinant protein vaccine and DNA vaccine system. Overexpressed proteins were determined to be 30 kDa and 25 kDa in the E. coli and TK1 systems, respectively. The efficacy of the chimeric multiepitope construct as a recombinant protein vaccine and DNA vaccine was evaluated in Nile tilapia, followed by S. agalactiae challenge at 1 × 107 CFU/mL. Relative percentage survival (RPS) and cumulative mortality were recorded at approximately 57-76% and 17-30%, respectively. These chimeric multiepitope vaccines should be applied in streptococcosis disease control and developed into a multivalent vaccine to control multiple diseases.


Assuntos
Antígenos de Bactérias/química , Epitopos/administração & dosagem , Doenças dos Peixes/virologia , Infecções Estreptocócicas/prevenção & controle , Streptococcus/imunologia , Animais , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/imunologia , Cromatografia Líquida , Ciclídeos , Epitopos/genética , Epitopos/imunologia , Modelos Moleculares , Proteômica , Infecções Estreptocócicas/imunologia , Espectrometria de Massas em Tandem , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia
16.
Fish Shellfish Immunol ; 97: 322-335, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31805413

RESUMO

Cathepsin L (CTSL) is one of the crucial enzymes in cathepsin family, which has been widely known for its involvement in the innate immunity. However, it still remains poorly understood how CTSL modulates the immune system of teleosts. In this study, we captured three cathepsin L genes (SmCTSL, SmCTSL.1 and SmCTSL1) from turbot (Scophthalmus maximus). The coding sequences of SmCTSL, SmCTSL.1 and SmCTSL1 are 1,026 bp, 1,005 bp and 1,017 bp in length and encode 341, 334 and 338 amino acids, respectively. In details, transcripts of CTSL genes share same domains as other CTSL genes, one signal peptide, one propeptide and one papain family cysteine protease domain. Protein interaction network analysis indicated that turbot CTSL genes may play important roles in apoptotic signaling and involve in innate immune response. Evidence from subcellular localization demonstrated that the three Cathepsin L proteins were ubiquitous in nucleus and cytoplasm. The cathepsin L genes were widely expressed in all the tested tissues with the highest expression level of SmCTSL in spleen, and SmCTSL.1 and SmCTSL1 in intestine. Following Vibrio anguillarum, Edwardsiella tarda and Streptococcus iniae challenge, these cathepsin L genes were significantly regulated in mucosal tissues in all the challenges, especially significant down-regulation occurred rapidly in intestine in all the three challenges. In addition, the three cathepsin L genes showed strong binding ability to all the examined microbial ligands (LPS, PGN and LTA). Further studies should be used to analyze the specific function of these three cathepsin L genes. By then, we can use their function to maintain the integrity of the mucosal barrier, thereby promoting the disease resistance line and family selection in turbot.


Assuntos
Catepsina L/genética , Doenças dos Peixes/imunologia , Linguados/genética , Linguados/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade nas Mucosas/genética , Animais , Catepsina L/imunologia , Edwardsiella tarda/fisiologia , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/veterinária , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Estrutura Quaternária de Proteína , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/veterinária , Streptococcus iniae/fisiologia , Vibrio/fisiologia , Vibrioses/imunologia , Vibrioses/veterinária
17.
Fish Shellfish Immunol ; 98: 899-907, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31765793

RESUMO

Streptococcus dysgalactiae is an important pathogenic bacterium that has caused economic loss for the cobia industry in Taiwan, ROC. This study presents a highly effective subunit vaccine composed of a moonlight protein, α-enolase, for the prevention of S. dysgalactiae infection. First, α-enolase was cloned, transformed, and expressed in E. coli for production of recombinant protein. Then, the protective efficacies of α-enolase recombinant protein were evaluated in combination with either a pro-inflammatory cytokine, TNF-α, or an oil adjuvant, ISA 763 AVG. The results showed that the combination of α-enolase and ISA 763 AVG was highly protective (RPS = 88.89%), while a negative effect was found in the group immunised with α-enolase adjuvanted with TNF-α (RPS = 22.22%). A further study was conducted with double dose of ISA 763 AVG, which led to an increased RPS value of 97.37%. Moreover, immunised cobia exhibited significantly greater lysozyme activity, antibody responses, and expression of certain immune-related genes post-challenge. Altogether, our results demonstrated that a combination of α-enolase recombinant protein with ISA 763 AVG adjuvant is a promising vaccine that can be employed for protection of cobia against S. dysgalactiae infection.


Assuntos
Vacinas Bacterianas/farmacologia , Doenças dos Peixes/prevenção & controle , Peixes/imunologia , Fosfopiruvato Hidratase/farmacologia , Infecções Estreptocócicas/veterinária , Streptococcus/efeitos dos fármacos , Animais , Vacinas Bacterianas/administração & dosagem , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Fosfopiruvato Hidratase/administração & dosagem , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/prevenção & controle
18.
Fish Shellfish Immunol ; 97: 1-11, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31846770

RESUMO

Deteriorating water quality, especially from high concentrations of nitrite, is currently largely blamed for disease outbreaks in farmed tilapia (Oreochromis niloticus). In this study, the underlying mechanism of nitrite on the susceptibility of tilapia leucocytes to Streptococcus agalactiae (S. agalactiae) was studied. We found that a high dose of heat-killed S. agalactiae decreased tilapia leucocytes cell viability, whereas nitrite decreased the cell viability of leucocytes exposed to a low dose of bacteria. Bacterial challenge increased the production of nitric oxide (NO), whereas nitrite and bacteria coexposure caused higher NO production than nitrite or bacterial exposure alone. Cell viability increased after elimination of NO, and negative correlations existed between cell viability and the NO content, suggesting that nitrite increased the susceptibility of the leucocytes against S. agalactiae was NO-dependent. For a more comprehensive understanding of the mechanism of nitrite affecting disease resistance in tilapia leucocytes, an RNA-Seq-based transcriptome was generated. The results showed that 6173 transcripts were differently expressed, and the differentially expressed transcripts (DETs) of the bacterial group, nitrite group and bacteria-nitrite co-treatment group compared to the control group were selected for GO and KEGG analyses. The DETs in the bacterial group and bacteria-nitrite cotreatment group were highly involved with the membrane component, signal transduction, and immune responses. KEGG analysis showed that the protein processing in the endoplasmic reticulum and the AMPK signaling pathway, which are related to autophagy, were significantly enriched in the cotreatment group but not in bacterial group. In addition, the mRNA expression of ten DETs and several autophagy and apoptosis related genes validated by q-PCR showed the high reliability of the RNA-seq. Taken together, the results of this study suggest that nitrite may increase the susceptibility of tilapia leucocytes to S. agalactiae by generating excess NO to affect the autophagy and apoptosis process.


Assuntos
Ciclídeos/microbiologia , Doenças dos Peixes/microbiologia , Leucócitos/patologia , Nitritos/metabolismo , Infecções Estreptocócicas/veterinária , Animais , Aquicultura , Sobrevivência Celular , Resistência à Doença , Doenças dos Peixes/imunologia , Perfilação da Expressão Gênica , Óxido Nítrico/metabolismo , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Transdução de Sinais , Infecções Estreptocócicas/imunologia , Streptococcus agalactiae
19.
Fish Shellfish Immunol ; 97: 135-145, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31846774

RESUMO

Interleukin-1 receptor-associated kinase 1 (IRAK1) and IRAK4 are critical signalling mediators and play pivotal roles in the innate immune and inflammatory responses mediated by TLR/IL-1R. In the present study, two IRAK family members, OnIRAK1 and OnIRAK4, were identified in the Nile tilapia Oreochromis niloticus with a conserved N-terminal death domain and a protein kinase domain, similar to those of other fishes and mammals. The gene structures of OnIRAK1 and OnIRAK4 are organized into fifteen exons split by fourteen introns and ten exons split by nine introns. OnIRAK1 and OnIRAK4 were broadly expressed in all of the tissues tested, with the highest expression levels being observed in the blood and the lowest expression levels being observed in the liver. Both genes could be detected from 2 d post-fertilization (dpf) to 8 dpf during embryonic development. Moreover, the expression levels of OnIRAK1 and OnIRAK4 were clearly altered in all five tissues after Streptococcus agalactiae infection in vivo and could be induced by LPS, Poly I: C, S. agalactiae WC1535 and △CPS in Nile tilapia macrophages. The overexpression of OnIRAK1 and OnIRAK4 in 293T cells showed that they were both distributed in the cytoplasm and could significantly increase NF-κB activation. Interestingly, after transfection, OnIRAK1 significantly upregulated OnMyd88-induced NF-κB activation, while OnIRAK4 had no effect on OnMyd88-induced NF-κB activation. Co-immunoprecipitation (Co-IP) assays showed that OnMyd88 did not interact with either OnIRAK1 or OnIRAK4 and that OnIRAK1 did not interact with OnIRAK4. Taken together, these findings suggest that OnIRAK1 and OnIRAK4 could play important roles in TLR/IL-1R signalling pathways and the immune response to pathogen invasion.


Assuntos
Ciclídeos/genética , Ciclídeos/imunologia , Proteínas de Peixes/genética , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Infecções Estreptocócicas/veterinária , Animais , Clonagem Molecular , Regulação para Baixo , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Proteínas de Peixes/imunologia , Regulação da Expressão Gênica , Imunidade Inata , Filogenia , Alinhamento de Sequência , Transdução de Sinais/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus agalactiae , Regulação para Cima
20.
Fish Shellfish Immunol ; 97: 515-522, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31846775

RESUMO

CD48 is a glycosylphosphatidylinositol-anchored protein involved in lymphocyte adhesion, activation, and costimulation. In this study, the CD48 gene of tilapia (Oreochromis niloticus, named On-CD48), was cloned from the head kidney of tilapia. The coding sequences is 654 bp and encoding 217 amino acids. The deduced amino acid sequence of On-CD48 with an estimated molecular weight of 24.4 kDa and a theoretical pI of 5.03. Amino acid alignment indicated that it had two immunoglobulin-like domain conserved region. In healthy tilapia, the On-CD48 could be detected in all the examined tissues and the highest expression level in the spleen. The expression of On-CD48 in the spleen and head kidney was decreased after immunized by formalin-inactivated Streptococcus agalactiae, and the peak was observed in the spleen at 24 h and appeared again at 96 h, and in the head kidney gradual decline before 48 h then gradually increased to the original level. qPCR analysis of inactivated S. agalactiae, LPS and Poly I:C stimulated at the whole lymphocyte level showed that the stimulation of the Poly I:C was more sensitive. Prokaryotic expression results showed that efficient expression of On-CD48 protein could be realized after induced with 0.5 mmol L-1 IPTG in E. coli BL21 (DE3) for 10 h at 18 °C. The result of subcellular localization showed that On-CD48 were evenly distributed in the whole cell of HEK-293T. Western Blot confirmed that the molecular weight of the recombinant On-CD48 was about 21 kDa, consistent with the predicted result. The results of this study will lay a strong foundation for the further study of On-CD48 molecular function in tilapia.


Assuntos
Antígeno CD48/genética , Ciclídeos/imunologia , Proteínas de Peixes/genética , Infecções Estreptocócicas/veterinária , Animais , Antígeno CD48/imunologia , Ciclídeos/genética , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Proteínas de Peixes/imunologia , Regulação da Expressão Gênica , Células HEK293 , Humanos , Lipopolissacarídeos/farmacologia , Linfócitos/efeitos dos fármacos , Filogenia , Poli I-C/farmacologia , Infecções Estreptocócicas/imunologia
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