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1.
Vet Immunol Immunopathol ; 214: 109890, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31378218

RESUMO

Bovine mastitis is a significant cause of economic losses in the dairy industry. Staphylococcus aureus is one of the most common contagious mastitis pathogens, whereas Staphylococcus chromogenes increasingly became a significant cause of subclinical mastitis in dairy cows. Current mastitis control measures are not effective on all mastitis pathogens. There is no effective vaccine to control Staphylococcal mastitis in dairy cows. The objective of this study was to evaluate the immune responses and protection in dairy cows vaccinated with S. aureus surface proteins (SASP) or S. chromogenes surface proteins (SCSP). We divided eighteen Holstein dairy cows randomly into three groups of 6 animals each. We vaccinated group 1 and 2 animals with SASP and SCSP with Emulsigen-D adjuvant, respectively. We injected control (group 3) animals with PBS (pH 7.2) in Emulsigen®-D. We vaccinated animals three times at 28 and 14 days before drying off, and at dry off. Two weeks after the third vaccination, we challenged each animal by dipping all teats in S. aureus culture suspension once daily for 14 consecutive days. We evaluated milk or mammary secretion and serum antibody titers during vaccination and challenge periods. We evaluated milk samples for the number of bacteria shedding and somatic cell counts (SCC). Out of six cows vaccinated with SASP, one cow was removed from the study due to injury, two were infected clinically, another two were infected subclinically, and the remaining cow was not infected. No SCSP vaccinated cows developed clinical or subclinical mastitis. Out of six control cows, two developed clinical mastitis whereas four were infected subclinically. The SCSP vaccine cross-protected against S. aureus mastitis and reduced number of S. aureus shedding in milk. We concluded that the SCSP is a promising vaccine to control Staphylococcal mastitis in dairy cows.


Assuntos
Mastite Bovina/prevenção & controle , Proteínas de Membrana/imunologia , Infecções Estafilocócicas/veterinária , Vacinas Antiestafilocócicas/imunologia , Staphylococcus aureus/imunologia , Animais , Derrame de Bactérias , Bovinos , Contagem de Células , Indústria de Laticínios , Feminino , Proteínas de Membrana/administração & dosagem , Leite/microbiologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/prevenção & controle , Vacinação
2.
J Sci Food Agric ; 99(13): 5870-5880, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31206687

RESUMO

BACKGROUND: Sepsis is a set of serious organic manifestations caused by an infection, whose progression culminates in exacerbated inflammation and oxidative stress, poor prognosis, and high hospital costs. Antioxidants used against sepsis have been evaluated, including essential oils such as ß-caryophyllene (BCP), and polyunsaturated fatty acids, such as docosahexaenoic acid (DHA). The aim of this study was to evaluate the anti-inflammatory activity of the association of these two compounds. RESULTS: Treatment with BCP-DHA, at a dose of 200 µL/animal, significantly inhibited the migration of neutrophils in a Cg-induced peritonitis model. After Staphylococcus aureus infection, in the groups treated with BCP-DHA there was a significant decrease in the total and differential count of leukocytes, increased expression of cytokines TNF-α and IFN-γ in treated groups, an increase of IL-4 and IL-5 in B/D and B/D + SA groups, and an augmentation of IL-6 and IL-12 groups in B/D + SA groups. Histological and bacterial analysis revealed lower neutrophil migration and lower bacterial load in the infected and treated groups. CONCLUSION: In general, the BCP-DHA association presented anti-inflammatory activity against two different models of acute inflammation and infection, showing promising potential as a therapeutic adjuvant in sepsis. © 2019 Society of Chemical Industry.


Assuntos
Anti-Inflamatórios/administração & dosagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Peritonite/tratamento farmacológico , Sepse/tratamento farmacológico , Sesquiterpenos/administração & dosagem , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Animais , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Interleucina-12/genética , Interleucina-12/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Peritonite/genética , Peritonite/imunologia , Peritonite/microbiologia , Sepse/genética , Sepse/imunologia , Sepse/microbiologia , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
3.
Nat Commun ; 10(1): 2730, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227691

RESUMO

Recently our groups discovered lugdunin, a new cyclic peptide antibiotic that inhibits Staphylococcus aureus epithelial colonization in humans and rodents. In this work, we analyzed its immuno-modulatory and antimicrobial potential as a single agent or in combination with other microbiota- or host-derived factors. We show that pretreatment of primary human keratinocytes or mouse skin with lugdunin in combination with microbiota-derived factors results in a significant reduction of S. aureus colonization. Moreover, lugdunin increases expression and release of LL-37 and CXCL8/MIP-2 in human keratinocytes and mouse skin, and results in the recruitment of monocytes and neutrophils in vivo, both by a TLR/MyD88-dependent mechanism. Interestingly, S. aureus elimination by lugdunin is additionally achieved by synergistic antimicrobial activity with LL-37 and dermcidin-derived peptides. In summary, our results indicate that lugdunin provides multi-level protection against S. aureus and may thus become a promising treatment option for S. aureus skin infections in the future.


Assuntos
Antibacterianos/farmacologia , Imunidade Inata/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Tiazolidinas/farmacologia , Animais , Antibacterianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/imunologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Queratinócitos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microbiota/efeitos dos fármacos , Microbiota/imunologia , Peptídeos/imunologia , Peptídeos Cíclicos/uso terapêutico , Cultura Primária de Células , Pele/efeitos dos fármacos , Pele/imunologia , Pele/microbiologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Tiazolidinas/uso terapêutico
4.
Microb Pathog ; 132: 254-260, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31075429

RESUMO

Early nutritional aggressions promote epigenetic adjustments that culminate in the loss of phenotype plasticity (with permanent long-term modifications). Maternal diet and inadequate neonatal nutrition can result in fetal programming that presents susceptibility to infections in adult life. Thus, it becomes essential to verify the impacts of neonatal malnutrition (even following nutritional replacement) on the immunological response to methicillin resistant Staphylococcus aureus (MRSA) infections. Male rats were divided into two distinct groups: Nourished and Malnourished. After isolation of mononuclear cells, four systems were established: negative control, positive control and two testing systems, (MSSA and MRSA). Tests were performed to analyze expression of TLR-9, NF-kB, IL-1ß, IL-18 and IL-33. For statistical analysis, we used the Student t and ANOVA tests p < 0.05. Even after nutritional replacement, malnutrition in the neonatal period compromised the animals' weight gains p < 0.05. There was a reduction in the expression of the immunological response in the positive control, however deregulation was observed in the gene expression of MRSA-infected macrophages, with a reduction in TLR-9 expression, and overexpression in NF-kB and cytokines p < 0.05. Puppies inflicted with protein-calorie malnutrition were compromised; (long-term) body growth and immune response. In the infectious scenario, immune collapse is reflected in inflammatory response exacerbation with a likely histolytic character. Immune disabling (resulting from gene expression deregulation) causes susceptibility to infections due to ineffective recognition, intense pro-inflammatory mediation, and cell death. It is suggested that neonatal malnutrition can program susceptibility to multiresistant bacterial infections, and generally favors a triggering of more intense confrontations with fatal outcomes.


Assuntos
Citocinas/metabolismo , Macrófagos/metabolismo , Macrófagos/microbiologia , Desnutrição/metabolismo , Staphylococcus aureus Resistente à Meticilina/patogenicidade , NF-kappa B/metabolismo , Infecções Estafilocócicas/imunologia , Receptor Toll-Like 9/metabolismo , Animais , Animais Recém-Nascidos , Peso Corporal , Cães , Regulação da Expressão Gênica , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Interleucina-33/metabolismo , Macrófagos Alveolares/microbiologia , Masculino , Ratos , Ratos Wistar , Infecções Estafilocócicas/microbiologia
5.
PLoS Negl Trop Dis ; 13(5): e0007247, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31107882

RESUMO

Cutaneous leishmaniasis (CL) is a parasitic disease causing chronic, ulcerating skin lesions. Most humans infected with the causative Leishmania protozoa are asymptomatic. Leishmania spp. are usually introduced by sand flies into the dermis of mammalian hosts in the presence of bacteria from either the host skin, sand fly gut or both. We hypothesized that bacteria at the dermal inoculation site of Leishmania major will influence the severity of infection that ensues. A C57BL/6 mouse ear model of single or coinfection with Leishmania major, Staphylococcus aureus, or both showed that single pathogen infections caused localized lesions that peaked after 2-3 days for S. aureus and 3 weeks for L. major infection, but that coinfection produced lesions that were two-fold larger than single infection throughout 4 weeks after coinfection. Coinfection increased S. aureus burdens over 7 days, whereas L. major burdens (3, 7, 28 days) were the same in singly and coinfected ears. Inflammatory lesions throughout the first 4 weeks of coinfection had more neutrophils than did singly infected lesions, and the recruited neutrophils from early (day 1) lesions had similar phagocytic and NADPH oxidase capacities. However, most neutrophils were apoptotic, and transcription of immunomodulatory genes that promote efferocytosis was not upregulated, suggesting that the increased numbers of neutrophils may, in part, reflect defective clearance and resolution of the inflammatory response. In addition, the presence of more IL-17A-producing γδ and non-γδ T cells in early lesions (1-7 days), and L. major antigen-responsive Th17 cells after 28 days of coinfection, with a corresponding increase in IL-1ß, may recruit more naïve neutrophils into the inflammatory site. Neutralization studies suggest that IL-17A contributed to an enhanced inflammatory response, whereas IL-1ß has an important role in controlling bacterial replication. Taken together, these data suggest that coinfection of L. major infection with S. aureus exacerbates disease, both by promoting more inflammation and neutrophil recruitment and by increasing neutrophil apoptosis and delaying resolution of the inflammatory response. These data illustrate the profound impact that coinfecting microorganisms can exert on inflammatory lesion pathology and host adaptive immune responses.


Assuntos
Coinfecção/imunologia , Interleucina-17/imunologia , Leishmania major/fisiologia , Leishmaniose Cutânea/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/fisiologia , Animais , Coinfecção/microbiologia , Coinfecção/parasitologia , Coinfecção/patologia , Feminino , Humanos , Interleucina-17/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Leishmania major/genética , Leishmania major/isolamento & purificação , Leishmaniose Cutânea/genética , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/genética , Staphylococcus aureus/isolamento & purificação , Células Th17/imunologia
6.
Microb Pathog ; 133: 103543, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31102653

RESUMO

PURPOSE: Whole genome sequencing (WGS) analysis of Staphylococcus aureus is increasingly used in clinical practice. Although bioinformatics tools used in WGS analysis readily define the S. aureus virulome, the clinical value of this type of analysis is unclear. Here, virulence genes in S. aureus bacteremia (SAB) isolates were evaluated by WGS, with superantigens (SAgs) further evaluated by conventional PCR and functional assays, and results correlated with mortality. METHODS: 152 SAB isolates collected throughout 2015 at a large Minnesota medical center were studied and associated clinical data analyzed. Virulence genes were identified from previously-reported WGS data (https://doi.org/10.1371/journal.pone.0179003). SAg genes sea, seb, sec, sed, see, seg, seh, sei, sej, and tst were also assessed by individual PCR assays. Mitogenicity of SAgs was assessed using an in vitro proliferation assay with splenocytes from HLA-DR3 transgenic mice. RESULTS: Of the 152 SAB isolates studied, 106 (69%) were methicillin-susceptible S. aureus (MSSA). The number of deaths attributed and not attributed to SAB, and 30-day survivors were 24 (16%), 2 (1%), and 128 (83%), respectively. From WGS data, both MSSA and MRSA had high proportions of adhesion (>80%) and immune-evasion (>70%) genes. There was no difference in virulomes between survivor- and non-survivor-associated isolates. Although over 60% of SAB isolates produced functional SAgs, there were no differences in the distribution or prevalence of SAg genes between survivor- and non-survivor-associated isolates. CONCLUSION: In this study of one year of SAB isolates from a large medical center, the S. aureus virulome, as assessed by WGS, and also for SAgs using individual PCRs and phenotypic characterization, did not impact mortality.


Assuntos
Bacteriemia/microbiologia , Bacteriemia/mortalidade , Farmacorresistência Bacteriana/genética , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/mortalidade , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidade , Idoso , Idoso de 80 Anos ou mais , Animais , Bacteriemia/imunologia , Aderência Bacteriana/genética , Sequência de Bases , Proliferação de Células , Feminino , Antígeno HLA-DR3 , Humanos , Evasão da Resposta Imune/genética , Masculino , Staphylococcus aureus Resistente à Meticilina/genética , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Minnesota , Reação em Cadeia da Polimerase , Infecções Estafilocócicas/imunologia , Superantígenos/genética , Superantígenos/imunologia , Virulência/genética , Fatores de Virulência/genética
7.
J Biotechnol ; 300: 20-31, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31095980

RESUMO

Increasing levels of antibiotic resistance in pathogens, including Staphylococcus aureus, remains a serious problem for public health, leading to the need for better alternative antimicrobial strategies. The antimicrobial proteins produced by Lactobacillus plantarum USM8613 attributed to its anti-staphylococcal activity were identified as extracellular transglycosylase and glyceraldehyde-3-phosphate dehydrogenase (GADPH), both with different mechanisms of action. Extracellular transglycosylase, which contains a LysM domain, exerts a cell wall-mediated killing mechanism, while GADPH penetrates into S. aureus cells and subsequently induces the overexpression of autolysis regulators, resulting in S. aureus autolysis. Both extracellular transglycosylase and GADPH exert anti-inflammatory effects in S. aureus-infected HaCaT cells by reducing the expression and production of TLR-2, hBDs and various pro-inflammatory cytokines (IL-1α, IL-1ß, IL-6, TNF-α, and IL-8). Taken together, extracellular transglycosylase and GADPH produced by L. plantarum USM8613 could potentially be applied as an alternative therapeutic agent to treat S. aureus skin infections and promote skin health.


Assuntos
Antibacterianos/farmacologia , Gliceraldeído-3-Fosfato Desidrogenases/farmacologia , Glicosiltransferases/farmacologia , Lactobacillus plantarum/enzimologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/metabolismo , Linhagem Celular , Citocinas/metabolismo , Gliceraldeído-3-Fosfato Desidrogenases/química , Gliceraldeído-3-Fosfato Desidrogenases/isolamento & purificação , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Glicosiltransferases/química , Glicosiltransferases/isolamento & purificação , Glicosiltransferases/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia
8.
Mol Immunol ; 112: 131-139, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31102985

RESUMO

BACKGROUND: Sepsis is a dysregulated host response to infection. The aim of this study was to investigate the effects of complement- and CD14 inhibition on phagocytosis of live and dead Gram-negative and Gram-positive bacteria in human whole blood. METHODS: Lepirudin-anticoagulated blood was incubated with live or dead E. coli or S. aureus at 37 °C for 120 min with or without the C5aR1 antagonist PMX53 and/or anti-CD14. Granulocyte and monocyte phagocytosis were measured by flow cytometry, and five plasma cytokines by multiplex, yielding a total of 28 mediators of inflammation tested for. RESULTS: 16/28 conditions were reduced by PMX53, 7/28 by anti-CD14, and 24/28 by combined PMX53 and CD14 inhibition. The effect of complement inhibition was quantitatively more pronounced, in particular for the responses to S. aureus. The effect of anti-CD14 was modest, except for a marked reduction in INF-ß. The responses to live and dead S. aureus were equally inhibited, whereas the responses to live E. coli were inhibited less than those to dead E. coli. CONCLUSION: C5aR1 inhibited phagocytosis-induced inflammation by live and dead E. coli and S. aureus. CD14 blockade potentiated the effect of C5aR1 blockade, thus attenuating inflammation.


Assuntos
Escherichia coli/imunologia , Receptores de Lipopolissacarídeos/antagonistas & inibidores , Fagocitose/imunologia , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Citocinas/imunologia , Infecções por Escherichia coli/imunologia , Granulócitos/imunologia , Humanos , Inflamação/imunologia , Inflamação/microbiologia , Interferon beta/imunologia , Receptores de Lipopolissacarídeos/imunologia , Monócitos/imunologia , Monócitos/microbiologia , Peptídeos Cíclicos/imunologia , Receptor da Anafilatoxina C5a/imunologia , Sepse/imunologia , Sepse/microbiologia
9.
MBio ; 10(3)2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088921

RESUMO

Staphylococcus aureus is a major cause of skin and soft tissue infections and aggravator of the inflammatory skin disease atopic dermatitis (AD [eczema]). Epicutaneous exposure to S. aureus induces Th17 responses through skin Langerhans cells (LCs), which paradoxically contribute to host defense but also to AD pathogenesis. The molecular mechanisms underlying the interaction between S. aureus and LCs are poorly understood. Here we demonstrate that human LCs directly interact with S. aureus through the pattern recognition receptor langerin (CD207). Human, but not mouse, langerin interacts with S. aureus through the conserved ß-N-acetylglucosamine (GlcNAc) modifications on wall teichoic acid (WTA), thereby discriminating S. aureus from other staphylococcal species. Importantly, the specific S. aureus WTA glycoprofile strongly influences the level of proinflammatory cytokines that are produced by in vitro-generated LCs. Finally, in a murine epicutaneous infection model, S. aureus strongly upregulated transcripts of Cxcl1, Il6, and Il17, which required the presence of both human langerin and WTA ß-GlcNAc. Our findings provide molecular insight into the unique proinflammatory capacities of S. aureus in relation to skin inflammation.IMPORTANCE The bacterium Staphylococcus aureus is an important cause of skin infections and is also associated with the occurrence and severity of eczema. Langerhans cells (LCs), a specific subset of skin immune cells, participate in the immune response to S. aureus, but it is yet unclear how LCs recognize S. aureus Therefore, we investigated the molecular mechanism underlying the interaction between LCs and S. aureus We identified that wall teichoic acid, an abundant polymer on the S. aureus surface, is recognized by langerin, a receptor unique to LCs. This interaction allows LCs to discriminate S. aureus from other related staphylococcal species and initiates a proinflammatory response similar to that observed in patients with eczema. Our data therefore provide important new insights into the relationship between S. aureus, LCs, and eczema.


Assuntos
Antígenos CD/genética , Antígenos de Superfície/genética , Células de Langerhans/imunologia , Lectinas Tipo C/genética , Lectinas de Ligação a Manose/genética , Infecções Estafilocócicas/imunologia , Ácidos Teicoicos/imunologia , Acetilglucosamina , Animais , Antígenos CD/imunologia , Antígenos de Superfície/imunologia , Células Cultivadas , Citocinas/genética , Citocinas/imunologia , Humanos , Inflamação , Interleucina-17/genética , Interleucina-17/imunologia , Lectinas Tipo C/imunologia , Lectinas de Ligação a Manose/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pele/imunologia , Pele/microbiologia , Staphylococcus aureus
10.
PLoS Pathog ; 15(4): e1007744, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30978245

RESUMO

Staphylococcus aureus is able to infect virtually all organ systems and is a frequently isolated etiologic agent of osteomyelitis, a common and debilitating invasive infection of bone. Treatment of osteomyelitis requires invasive surgical procedures and prolonged antibiotic therapy, yet is frequently unsuccessful due to extensive pathogen-induced bone damage that can limit antibiotic penetration and immune cell influx to the infectious focus. We previously established that S. aureus triggers profound alterations in bone remodeling in a murine model of osteomyelitis, in part through the production of osteolytic toxins. However, staphylococcal strains lacking osteolytic toxins still incite significant bone destruction, suggesting that host immune responses are also major drivers of pathologic bone remodeling during osteomyelitis. The objective of this study was to identify host immune pathways that contribute to antibacterial immunity during S. aureus osteomyelitis, and to define how these immune responses alter bone homeostasis and contribute to bone destruction. We specifically focused on the interleukin-1 receptor (IL-1R) and downstream adapter protein MyD88 given the prominent role of this signaling pathway in both antibacterial immunity and osteo-immunologic crosstalk. We discovered that while IL-1R signaling is necessary for local control of bacterial replication during osteomyelitis, it also contributes to bone loss during infection. Mechanistically, we demonstrate that S. aureus enhances osteoclastogenesis of myeloid precursors in vitro, and increases the abundance of osteoclasts residing on bone surfaces in vivo. This enhanced osteoclast abundance translates to trabecular bone loss, and is dependent on intact IL-1R signaling. Collectively, these data define IL-1R signaling as a critical component of the host response to S. aureus osteomyelitis, but also demonstrate that IL-1R-dependent immune responses trigger collateral bone damage through activation of osteoclast-mediated bone resorption.


Assuntos
Reabsorção Óssea/imunologia , Fator 88 de Diferenciação Mieloide/fisiologia , Osteoclastos/imunologia , Osteomielite/imunologia , Receptores Tipo I de Interleucina-1/fisiologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Animais , Reabsorção Óssea/metabolismo , Reabsorção Óssea/microbiologia , Diferenciação Celular , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoclastos/metabolismo , Osteoclastos/microbiologia , Osteomielite/metabolismo , Osteomielite/microbiologia , Transdução de Sinais , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologia
11.
Reprod Domest Anim ; 54(6): 882-891, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30974481

RESUMO

Dairy cow mastitis is a detrimental factor in milk quality and food safety. Mastitis generally refers to inflammation caused by infection by pathogenic microorganisms. Our studies in recent years have revealed the role of miRNA regulation in Staphylococcus aureus-induced mastitis. In the present study, we overexpressed and suppressed miR-145 to investigate the function of miR-145 in Mac-T cells. Flow cytometry, ELISA and EdU staining were used to detect changes in the secretion of several Mac-T cytokines and in cell proliferation. We found that overexpression of miR-145 in Mac-T cells significantly reduced the secretion of IL-12 and TNF-α, but increased the secretion of IFN-γ; the proliferation of bovine mammary epithelial cells was also inhibited. Using quantitative real-time PCR (qRT-PCR), Western blotting and luciferase multiplex verification techniques, we found that miR-145 targeted and regulated FSCN1. Knock-down of FSCN1 significantly increased the secretion of IL-12, while the secretion of TNF-α was significantly downregulated in Mac-T cells. Upon S. aureus infection of mammary gland tissue, the body initiated inflammatory responses; Bta-miR-145 expression was downregulated, which reduced the inhibitory effect on the FSCN1 gene; and upregulation of FSCN1 expression promoted mammary epithelial cell proliferation to allow the recovery of damaged tissue. The results of the present study will aid in understanding the immune mechanism opposing S. aureus infection in dairy cows and will provide a laboratory research basis for the prevention and treatment of mastitis.


Assuntos
Proteínas de Transporte/metabolismo , Mastite Bovina/imunologia , MicroRNAs/metabolismo , Proteínas dos Microfilamentos/metabolismo , Infecções Estafilocócicas/veterinária , Animais , Proteínas de Transporte/genética , Bovinos , Linhagem Celular , Proliferação de Células , Citocinas/metabolismo , Células Epiteliais/fisiologia , Feminino , Proteínas dos Microfilamentos/genética , Infecções Estafilocócicas/imunologia , Staphylococcus aureus
12.
In Vivo ; 33(3): 749-755, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31028193

RESUMO

BACKGROUND/AIM: Staphylococcus aureus (S. aureus) is a major gram-positive pathogen, which can cause toxic and immunogenic injuries both in nosocomial and community-acquired infections. Peroxiredoxin (Prx) I plays crucial roles in cellular apoptosis, proliferation, and signal transduction as well as in immunoregulation. The present study aimed to investigate whether Prx I protects mice from death caused by the heat-killed Staphylococcus aureus. MATERIALS AND METHODS: In the present study, we challenged the wild-type and Prx I-deficient mice with heat-killed S. aureus (HKSA). The effects of Prx I were evaluated by a series of in vitro and in vivo experiments including western blot, Haematoxylin and Eosin staining, splenocyte analysis and cytokines analysis. RESULTS: Intra-peritoneal (ip) inoculation of HKSA resulted in increased mortality of Prx I-knockout (KO) mice with severe liver damage and highly populated spleens with lymphocytes. Furthermore, HKSA infections also bursted the production of both pro-inflammatory and anti-inflammatory serum cytokines in Prx I KO compared to wild-type mice. CONCLUSION: Enhanced mortality of S. aureus-infected mice with Prx I deficiency suggested that Prx I may protect against the infection-associated lethality of mice.


Assuntos
Peroxirredoxinas/imunologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Animais , Apoptose , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Camundongos , Mortalidade , Peroxirredoxinas/genética , Infecções Estafilocócicas/mortalidade , Staphylococcus aureus/genética
13.
Microb Pathog ; 131: 259-269, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31002964

RESUMO

Staphylococcus aureus (S.aureus) is a Gram-positive bacterium that causes many infections and diseases. This pathogen can cause many types of infections such as impetigo, toxic shock syndrome toxin (TSST1), pneumonia, endocarditis, and autoimmune diseases like lupus erythematosus and can infect other healthy individuals. In the pathogenic process, colonization is a main risk factor for invasive diseases. Various factors including the cell wall-associated factors and receptors of the epithelial cells facilitate adhesion and colonization of this pathogen. S. aureus has many enzymes, toxins, and strategies to evade from the immune system either by an enzyme that lyses cellular component or by hiding from the immune system via surface antigens like protein A and second immunoglobulin-binding protein (Sbi). The strategies of this bacterium can be divided into five groups: A: Inhibit neutrophil recruitment B: Inhibit phagocytosis C: Inhibit killing by ROS, D: Neutrophil killing, and E: Resistance to antimicrobial peptide. On the other hand, innate immune system via neutrophils, the most important polymorphonuclear leukocytes, fights against bacterial cells by neutrophil extracellular trap (NET). In this review, we try to explain the role of each factor in immune evasion.


Assuntos
Evasão da Resposta Imune , Neutrófilos/imunologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/patogenicidade , Antígenos de Bactérias/imunologia , Proteínas de Bactérias , Toxinas Bacterianas/imunologia , Enterotoxinas , Interações Hospedeiro-Patógeno/imunologia , Humanos , Evasão da Resposta Imune/imunologia , Imunidade Inata , Fagocitose , Proteína Estafilocócica A , Superantígenos
14.
Nat Microbiol ; 4(7): 1114-1119, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30936487

RESUMO

Social interactions play an increasingly recognized key role in bacterial physiology1. One of the best studied is quorum sensing (QS), a mechanism by which bacteria sense and respond to the status of cell density2. While QS is generally deemed crucial for bacterial survival, QS-dysfunctional mutants frequently arise in in vitro culture. This has been explained by the fitness cost an individual mutant, a 'quorum cheater', saves at the expense of the community3. QS mutants are also often isolated from biofilm-associated infections, including cystic fibrosis lung infection4, as well as medical device infection and associated bacteraemia5-7. However, despite the frequently proposed use of QS blockers to control virulence8, the mechanisms underlying QS dysfunctionality during infection have remained poorly understood. Here, we show that in the major human pathogen Staphylococcus aureus, quorum cheaters arise exclusively in biofilm infection, while in non-biofilm-associated infection there is a high selective pressure to maintain QS control. We demonstrate that this infection-type dependence is due to QS-dysfunctional bacteria having a significant survival advantage in biofilm infection because they form dense and enlarged biofilms that provide resistance to phagocyte attacks. Our results link the benefit of QS-dysfunctional mutants in vivo to biofilm-mediated immune evasion, thus to mechanisms that are specific to the in vivo setting. Our findings explain why QS mutants are frequently isolated from biofilm-associated infections and provide guidance for the therapeutic application of QS blockers.


Assuntos
Biofilmes/crescimento & desenvolvimento , Infecções Relacionadas a Cateter/microbiologia , Evasão da Resposta Imune , Leucócitos/imunologia , Percepção de Quorum/fisiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Animais , Proteínas de Bactérias/genética , Infecções Relacionadas a Cateter/imunologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Camundongos Endogâmicos C57BL , Viabilidade Microbiana , Mutação , Percepção de Quorum/genética , Infecções Estafilocócicas/imunologia , Infecções Cutâneas Estafilocócicas/imunologia , Infecções Cutâneas Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/fisiologia , Transativadores/genética
15.
Ren Fail ; 41(1): 303-313, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30991864

RESUMO

INTRODUCTION: Staphylococcal infections can cause significant morbidity in patients undergoing dialysis. This study evaluated the effects of HIV infection on nasal carriage of Staphylococcus aureus, staphylococcal peritonitis, and catheter infection rates in patients with end-stage renal failure managed with continuous ambulatory peritoneal dialysis (CAPD). METHODS: Sixty HIV-positive and 59 HIV-negative CAPD patients were enrolled and followed up for up to 18 months. S. aureus nasal carriage (detected by nasal swab culture), Staphylococcal peritonitis (diagnosed by clinical presentation, and CAPD effluent Staphylococcal culture and white blood cell count ≥100 cells/µL), and catheter infections (including exit site and tunnel infections) were assessed monthly. RESULTS: At 18 months, S. aureus nasal carriage rates were 43.3% and 30.5% (p = 0.147) and the methicillin-resistant S. aureus (MRSA) nasal carriage rates were 31.7% and 13.6% (p = 0.018) for the HIV-positive and HIV-negative cohorts, respectively. The HIV-positive cohort was associated with increased hazards for staphylococcal peritonitis, (adjusted hazard ratio [AHR] 2.85, 95% confidence interval [CI] 1.19-6.84, p = 0.019) due to increased coagulase-negative staphylococcal (CNS) peritonitis rate in the HIV-positive cohort compared with the HIV-negative cohort (0.435 vs. 0.089 episodes/person-years; AHR 7.64, CI 2.18-26.82, p = 0.001). On multivariable analysis, CD4+ cell count <200 cells/µL, diabetes, and S. aureus nasal carriage were found to be independent predictors of S. aureus peritonitis. CONCLUSIONS: These findings suggest that HIV infection may be a risk factor for MRSA nasal colonization and may increase the risks of CNS peritonitis, while a CD4+ cell count <200 cells/µL and S. aureus nasal carriage may be important predictors of S. aureus peritonitis.


Assuntos
Portador Sadio/epidemiologia , Infecções por HIV/imunologia , Falência Renal Crônica/terapia , Diálise Peritoneal Ambulatorial Contínua/efeitos adversos , Adulto , Portador Sadio/imunologia , Portador Sadio/microbiologia , Infecções Relacionadas a Cateter/epidemiologia , Infecções Relacionadas a Cateter/imunologia , Infecções Relacionadas a Cateter/microbiologia , Cateteres de Demora/efeitos adversos , Cateteres de Demora/microbiologia , Feminino , Seguimentos , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Pessoa de Meia-Idade , Nariz/microbiologia , Diálise Peritoneal Ambulatorial Contínua/instrumentação , Peritonite/epidemiologia , Peritonite/imunologia , Peritonite/microbiologia , Estudos Prospectivos , Fatores de Risco , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia
16.
Microbiol Spectr ; 7(2)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30873936

RESUMO

Staphylococcus aureus is a formidable pathogen capable of causing infections in different sites of the body in a variety of vertebrate animals, including humans and livestock. A major contribution to the success of S. aureus as a pathogen is the plethora of virulence factors that manipulate the host's innate and adaptive immune responses. Many of these immune modulating virulence factors are secreted toxins, cofactors for activating host zymogens, and exoenzymes. Secreted toxins such as pore-forming toxins and superantigens are highly inflammatory and can cause leukocyte cell death by cytolysis and clonal deletion, respectively. Coagulases and staphylokinases are cofactors that hijack the host's coagulation system. Exoenzymes, including nucleases and proteases, cleave and inactivate various immune defense and surveillance molecules, such as complement factors, antimicrobial peptides, and surface receptors that are important for leukocyte chemotaxis. Additionally, some of these secreted toxins and exoenzymes can cause disruption of endothelial and epithelial barriers through cell lysis and cleavage of junction proteins. A unique feature when examining the repertoire of S. aureus secreted virulence factors is the apparent functional redundancy exhibited by the majority of the toxins and exoenzymes. However, closer examination of each virulence factor revealed that each has unique properties that have important functional consequences. This chapter provides a brief overview of our current understanding of the major secreted virulence factors critical for S. aureus pathogenesis.


Assuntos
Toxinas Bacterianas/metabolismo , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/metabolismo , Animais , Toxinas Bacterianas/classificação , Toxinas Bacterianas/imunologia , Humanos , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/enzimologia , Staphylococcus aureus/imunologia
17.
Int Immunopharmacol ; 70: 295-301, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30851710

RESUMO

Problem due to disc degeneration is frequently found in the aging population. However, severe pain and accompanying end plate inflammation is only found in a small subset of patients, who can be of a younger age than most people with severe disc degeneration, with no apparent cause. We hypothesized that deficiencies in B regulatory (Breg) cells might contribute to the aberrant inflammation in these patients. However, we found that the frequency of CD24hiCD38hi Breg cells was significantly higher in patients than in controls. To investigate Breg function, CD24hiCD38hi Breg cells were stimulated via CD40L/αIg and via Staphylococcus aureus Cowan. Interestingly, the expression of IL-10 and TGF-ß1 was significantly lower in patients than in controls. The expression of PD-L1 was comparable between patient CD24hiCD38hi Bregs and control CD24hiCD38hi Bregs. Control CD24hiCD38hi Bregs, but not patient CD24hiCD38hi Bregs, could suppress the expression of TBX21 and RORC2 in stimulated CD4+ T cells, in a manner that was dependent on IL-10 and PD-L1. The expression of FOXP3, on the other hand, was dependent on TGF-ß. In addition, PD-L1 reduced the viability of CD4+ T cells. Together, we demonstrated that the patients with end plate inflammation did not present a reduction in CD19+CD24hiCD38hi Breg frequency, but presented a reduction in CD19+CD24hiCD38hi Breg function.


Assuntos
Linfócitos B Reguladores/imunologia , Inflamação/imunologia , Degeneração do Disco Intervertebral/imunologia , Disco Intervertebral/patologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/fisiologia , Linfócitos T Auxiliares-Indutores/imunologia , ADP-Ribosil Ciclase 1/metabolismo , Antígeno CD24/metabolismo , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Interleucina-10/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Comunicação Parácrina , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Fator de Crescimento Transformador beta/metabolismo
18.
Infect Immun ; 87(5)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30833333

RESUMO

Staphylococcus aureus is a major human pathogen of the skin. The global burden of diabetes is high, with S. aureus being a major complication of diabetic wound infections. We investigated how the diabetic environment influences S. aureus skin infection and observed an increased susceptibility to infection in mouse models of both type I and type II diabetes. A dual gene expression approach was taken to investigate transcriptional alterations in both the host and bacterium after infection. While analysis of the host response revealed only minor changes between infected control and diabetic mice, we observed that S. aureus isolated from diabetic mice had significant increases in the levels of genes associated with translation and posttranslational modification and chaperones and reductions in the levels of genes associated with amino acid transport and metabolism. One family of genes upregulated in S. aureus isolated from diabetic lesions encoded the Clp proteases, associated with the misfolded protein response. The Clp proteases were found to be partially glucose regulated as well as influencing the hemolytic activity of S. aureus Strains lacking the Clp proteases ClpX, ClpC, and ClpP were significantly attenuated in our animal model of skin infection, with significant reductions observed in dermonecrosis and bacterial burden. In particular, mutations in clpP and clpX were significantly attenuated and remained attenuated in both normal and diabetic mice. Our data suggest that the diabetic environment also causes changes to occur in invading pathogens, and one of these virulence determinants is the Clp protease system.


Assuntos
Diabetes Mellitus Experimental/complicações , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/genética , Staphylococcus aureus/imunologia , Virulência/genética , Virulência/imunologia , Animais , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno/imunologia , Humanos , Camundongos
19.
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
20.
Infect Immun ; 87(5)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30833335

RESUMO

Numerous factors have, to date, been identified as playing a role in the regulation of Agr activity in Staphylococcus aureus, including transcription factors, antisense RNAs, and host elements. Herein we investigated the product of SAUSA300_1984 (termed MroQ), a transmembrane Abi-domain/M79 protease-family protein, as a novel effector of this system. Using a USA300 mroQ mutant, we observed a drastic reduction in proteolysis, hemolysis, and pigmentation that was fully complementable. This appears to result from diminished agr activity, as transcriptional analysis revealed significant decreases in expression of both RNAII and RNAIII in the mroQ mutant. Such effects appear to be direct, rather than indirect, as known agr effectors demonstrated limited alterations in their activity upon mroQ disruption. A comparison of RNA sequencing data sets for both mroQ and agr mutants revealed a profound overlap in their regulomes, with the majority of factors affected being known virulence determinants. Importantly, the preponderance of alterations in expression were more striking in the agr mutant, indicating that MroQ is necessary, but not sufficient, for Agr function. Mechanism profiling revealed that putative residues for metalloprotease activity within MroQ are required for its Agr-controlling effect; however, this was not wielded at the level of AgrD processing. Virulence assessment demonstrated that both mroQ and agr mutants exhibited increased formation of renal abscesses but decreased skin abscess formation alongside diminished dermonecrosis. Collectively, we present the characterization of a novel agr effector in S. aureus which would appear to be a direct regulator, potentially functioning via interaction with the AgrC histidine kinase.


Assuntos
Proteínas de Bactérias/imunologia , Regulação Bacteriana da Expressão Gênica/imunologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/imunologia , Fatores de Transcrição/imunologia , Fatores de Virulência/imunologia , Animais , Proteínas de Bactérias/genética , Feminino , Regulação Bacteriana da Expressão Gênica/genética , Humanos , Camundongos , Modelos Animais , Infecções Estafilocócicas/genética , Staphylococcus aureus/genética , Fatores de Transcrição/genética , Fatores de Virulência/genética
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