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1.
Sci Rep ; 11(1): 17214, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446765

RESUMO

Salmonella enterica serovar Gallinarum is a host-restricted bacterial pathogen that causes a serious systemic disease exclusively in birds of all ages. Salmonella enterica serovar Typhimurium is a host-generalist serovar. Dendritic cells (DCs) are key antigen-presenting cells that play an important part in Salmonella host-restriction. We evaluated the differential response of chicken blood monocyte-derived dendritic cells (chMoDCs) exposed to S. Gallinarum or S. Typhimurium. S. Typhimurium was found to be more invasive while S. Gallinarum was more cytotoxic at the early phase of infection and later showed higher resistance against chMoDCs killing. S. Typhimurium promoted relatively higher upregulation of costimulatory and other immune function genes on chMoDCs in comparison to S. Gallinarum during early phase of infection (6 h) as analyzed by real-time PCR. Both Salmonella serovars strongly upregulated the proinflammatory transcripts, however, quantum was relatively narrower with S. Gallinarum. S. Typhimurium-infected chMoDCs promoted relatively higher proliferation of naïve T-cells in comparison to S. Gallinarum as assessed by mixed lymphocyte reaction. Our findings indicated that host restriction of S. Gallinarum to chicken is linked with its profound ability to interfere the DCs function. Present findings provide a valuable roadmap for future work aimed at improved vaccine strategies against this pathogen.


Assuntos
Células Dendríticas/imunologia , Monócitos/imunologia , Salmonella typhimurium/imunologia , Salmonella/imunologia , Animais , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Antígenos CD40/genética , Antígenos CD40/imunologia , Galinhas , Citocinas/genética , Citocinas/imunologia , Citotoxicidade Imunológica/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/microbiologia , Expressão Gênica/imunologia , Interações Hospedeiro-Patógeno/imunologia , Viabilidade Microbiana/imunologia , Monócitos/citologia , Salmonella/fisiologia , Salmonella typhimurium/fisiologia , Especificidade da Espécie , Linfócitos T/imunologia , Linfócitos T/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia
2.
Infect Immun ; 89(8): e0081220, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34097459

RESUMO

Although nontuberculous mycobacteria (NTM) are considered opportunistic infections, incidence and prevalence of NTM infection are increasing worldwide becoming a major public health threat. Innate immunity plays an essential role in mediating the initial host response against these intracellular bacteria. Specifically, macrophages phagocytose and eliminate NTM and act as antigen-presenting cells, which trigger downstream activation of cellular and humoral adaptive immune responses. Identification of macrophage receptors, mycobacterial ligands, phagosome maturation, autophagy/necrosis, and escape mechanisms are important components of this immunity network. The role of the macrophage in mycobacterial disease has mainly been studied in tuberculosis (TB), but limited information exists on its role in NTM. In this review, we focus on NTM immunity, the role of macrophages, and host interaction in NTM infection.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Macrófagos/imunologia , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Micobactérias não Tuberculosas/imunologia , Imunidade Adaptativa , Humanos , Macrófagos/metabolismo , Macrófagos/microbiologia , Viabilidade Microbiana/imunologia , Fagocitose
3.
Front Immunol ; 12: 676679, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149712

RESUMO

Introduction: Protective host responses in those exposed to or infected with tuberculosis (TB) is thought to require a delicate balance between pro-inflammatory and regulatory immune responses. Myeloid-derived suppressor cells (MDSCs), regulatory cells that dampen T-cell function, have been described in cancer and other infectious diseases but there are limited data on their role in TB. Methods: Peripheral blood was obtained from patients with active pulmonary TB and participants with presumed latent TB infection (LTBI) from Cape Town, South Africa. MDSC frequency was ascertained by flow cytometry. Purified MDSCs were used to assess (i) their suppressive effect on T-cell proliferation using a Ki67 flow cytometric assay and (ii) their effect on mycobacterial containment by co-culturing with H37Rv-infected monocyte-derived macrophages and autologous pre-primed effector T-cells with or without MDSCs. Mycobacterial containment was measured by plating colony forming units (CFU). Results: MDSCs (CD15+HLA-DR-CD33+) had significantly higher median frequencies (IQR) in patients with active TB (n=10) versus LTBI (n= 10) [8.2% (6.8-10.7) versus 42.2% (27-56) respectively; p=0.001]. Compared to MDSC-depleted peripheral blood mononuclear and effector T cell populations, dilutions of purified MDSCs isolated from active TB patients suppressed T-cell proliferation by up to 72% (n=6; p=0.03) and significantly subverted effector T-cell-mediated containment of H37Rv in monocyte-derived macrophages (n=7; 0.6% versus 8.5%; p=0.02). Conclusion: Collectively, these data suggest that circulating MDSCs are induced during active TB disease and can functionally suppress T-cell proliferation and subvert mycobacterial containment. These data may inform the design of vaccines and immunotherapeutic interventions against TB but further studies are required to understand the mechanisms underpinning the effects of MDSCs.


Assuntos
Granulócitos/imunologia , Tuberculose Latente/imunologia , Viabilidade Microbiana/imunologia , Mycobacterium tuberculosis/genética , Células Supressoras Mieloides/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Proliferação de Células , Técnicas de Cocultura , Feminino , Antígenos HLA-DR/metabolismo , Humanos , Hidrolases/imunologia , Tuberculose Latente/sangue , Tuberculose Latente/epidemiologia , Tuberculose Latente/microbiologia , Antígenos CD15/metabolismo , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Dados Preliminares , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , África do Sul/epidemiologia , Linfócitos T/imunologia , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/microbiologia
4.
Infect Immun ; 89(8): e0014621, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34001560

RESUMO

The generation of oxidative stress is a host strategy used to control Staphylococcus aureus infections. Sulfur-containing amino acids, cysteine and methionine, are particularly susceptible to oxidation because of the inherent reactivity of sulfur. Due to the constant threat of protein oxidation, many systems evolved to protect S. aureus from protein oxidation or to repair protein oxidation after it occurs. The S. aureus peptide methionine sulfoxide reductase (Msr) system reduces methionine sulfoxide to methionine. Staphylococci have four Msr enzymes, which all perform this reaction. Deleting all four msr genes in USA300 LAC (Δmsr) sensitizes S. aureus to hypochlorous acid (HOCl) killing; however, the Δmsr strain does not exhibit increased sensitivity to H2O2 stress or superoxide anion stress generated by paraquat or pyocyanin. Consistent with increased susceptibility to HOCl killing, the Δmsr strain is slower to recover following coculture with both murine and human neutrophils than USA300 wild type. The Δmsr strain is attenuated for dissemination to the spleen following murine intraperitoneal infection and exhibits reduced bacterial burdens in a murine skin infection model. Notably, no differences in bacterial burdens were observed in any organ following murine intravenous infection. Consistent with these observations, USA300 wild-type and Δmsr strains have similar survival phenotypes when incubated with murine whole blood. However, the Δmsr strain is killed more efficiently by human whole blood. These findings indicate that species-specific immune cell composition of the blood may influence the importance of Msr enzymes during S. aureus infection of the human host.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Metionina Sulfóxido Redutases/metabolismo , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/enzimologia , Staphylococcus aureus/imunologia , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Peróxido de Hidrogênio/metabolismo , Metionina Sulfóxido Redutases/genética , Metionina Sulfóxido Redutases/imunologia , Camundongos , Viabilidade Microbiana/imunologia , Mutação , Oxirredução , Estresse Oxidativo , Staphylococcus aureus/genética
5.
Front Immunol ; 12: 648710, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868285

RESUMO

The global rise of antibiotic-resistant strains of Salmonella has necessitated the development of alternative therapeutic strategies. Recent studies have shown that targeting host factors may provide an alternative approach for the treatment of intracellular pathogens. Host-directed therapy (HDT) modulates host cellular factors that are essential to support the replication of the intracellular pathogens. In the current study, we identified Gefitinib as a potential host directed therapeutic drug against Salmonella. Further, using the proteome analysis of Salmonella-infected macrophages, we identified EGFR, a host factor, promoting intracellular survival of Salmonella via mTOR-HIF-1α axis. Blocking of EGFR, mTOR or HIF-1α inhibits the intracellular survival of Salmonella within the macrophages and in mice. Global proteo-metabolomics profiling indicated the upregulation of host factors predominantly associated with ATP turn over, glycolysis, urea cycle, which ultimately promote the activation of EGFR-HIF1α signaling upon infection. Importantly, inhibition of EGFR and HIF1α restored both proteomics and metabolomics changes caused by Salmonella infection. Taken together, this study identifies Gefitinib as a host directed drug that holds potential translational values against Salmonella infection and might be useful for the treatment of other intracellular infections.


Assuntos
Gefitinibe/farmacologia , Metabolômica/métodos , Proteômica/métodos , Infecções por Salmonella/prevenção & controle , Salmonella/efeitos dos fármacos , Animais , Células Cultivadas , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos Endogâmicos C57BL , Viabilidade Microbiana/efeitos dos fármacos , Viabilidade Microbiana/imunologia , Inibidores de Proteínas Quinases/farmacologia , Salmonella/imunologia , Salmonella/fisiologia , Infecções por Salmonella/imunologia , Infecções por Salmonella/microbiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Células THP-1
6.
Front Immunol ; 12: 599641, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33732233

RESUMO

It remains undefined whether a subset of CD4+ T cells can function as fast-acting cells to control Mycobacterium tuberculosis (Mtb) infection. Here we show that the primary CD4+CD161+ T-cell subset, not CD4+CD161-, in unexposed healthy humans fast acted as unconventional T cells capable of inhibiting intracellular Mtb and BCG growth upon exposure to infected autologous and allogeneic macrophages or lung epithelial A549 cells. Such inhibition coincided with the ability of primary CD4+CD161+ T cells to rapidly express/secrete anti-TB cytokines including IFN-γ, TNF-α, IL-17, and perforin upon exposure to Mtb. Mechanistically, blockades of CD161 pathway, perforin or IFN-γ by blocking mAbs abrogated the ability of CD4+CD161+ T cells to inhibit intracellular mycobacterial growth. Pre-treatment of infected macrophages with inhibitors of autophagy also blocked the CD4+CD161+ T cell-mediated growth inhibition of mycobacteria. Furthermore, adoptive transfer of human CD4+CD161+ T cells conferred protective immunity against mycobacterial infection in SCID mice. Surprisingly, CD4+CD161+ T cells in TB patients exhibited a loss or reduction of their capabilities to produce perforin/IFN-γ and to inhibit intracellular growth of mycobacteria in infected macrophages. These immune dysfunctions were consistent with PD1/Tim3 up-regulation on CD4+CD161+ T cells in active tuberculosis patients, and the blockade of PD1/Tim3 on this subset cells enhanced the inhibition of intracellular mycobacteria survival. Thus, these findings suggest that a fast-acting primary CD4+CD161+T-cell subset in unexposed humans employs the CD161 pathway, perforin, and IFN-γ/autophagy to inhibit the growth of intracellular mycobacteria, thereby distinguishing them from the slow adaptive responses of conventional CD4+ T cells. The presence of fast-acting CD4+CD161+ T-cell that inhibit mycobacterial growth in unexposed humans but not TB patients also implicates the role of these cells in protective immunity against initial Mtb infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , Transdução de Sinais , Tuberculose/imunologia , Tuberculose/metabolismo , Transferência Adotiva , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/microbiologia , Células Epiteliais Alveolares/patologia , Animais , Autofagia/imunologia , Biomarcadores , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Imunofenotipagem , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Masculino , Camundongos , Viabilidade Microbiana/imunologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Tuberculose/microbiologia , Tuberculose/terapia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/metabolismo , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
7.
Infect Immun ; 89(6)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33782153

RESUMO

Nontypeable Haemophilus influenzae (NTHi), a common inhabitant of the human nasopharynx and upper airways, causes opportunistic respiratory tract infections that are frequently recurring and chronic. NTHi utilizes sialic acid from the host to evade antibacterial defenses and persist in mucosal tissues; however, the role of sialic acid scavenged by NTHi during infection is not fully understood. We previously showed that sialylation protects specific epitopes on NTHi lipooligosaccharide (LOS) targeted by bactericidal IgM in normal human serum. Here, we evaluated the importance of immune evasion mediated by LOS sialylation in the mouse respiratory tract using wild-type H. influenzae and an isogenic siaB mutant incapable of sialylating the LOS. Sialylation protected common NTHi glycan structures recognized by human and murine IgM and protected NTHi from complement-mediated killing directed by IgM against these structures. Protection from IgM binding by sialylated LOS correlated with decreased survival of the siaB mutant versus the wild type in the murine lung. Complement depletion with cobra venom factor increased survival of the siaB mutant in the nasopharynx but not in the lungs, suggesting differing roles of sialylation at these sites. Prior infection increased IgM against H. influenzae but not against sialic acid-protected epitopes, consistent with sialic acid-mediated immune evasion during infection. These results provide mechanistic insight into an NTHi evasive strategy against an immune defense conserved across host species, highlighting the potential of the mouse model for development of anti-infective strategies targeting LOS antigens of NTHi.


Assuntos
Anticorpos Antibacterianos/imunologia , Infecções por Haemophilus/imunologia , Infecções por Haemophilus/microbiologia , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/imunologia , Imunoglobulina M/imunologia , Ácido N-Acetilneuramínico/farmacologia , Animais , Modelos Animais de Doenças , Lipopolissacarídeos/imunologia , Camundongos , Viabilidade Microbiana/efeitos dos fármacos , Viabilidade Microbiana/imunologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia
8.
Microbes Infect ; 22(10): 550-557, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730816

RESUMO

The Complement System (CS) plays an important role in the immune response against leptospirosis and can be activated by the Alternative and Lectin Pathways (Innate Immunity) and by the Classical Pathway (Acquired Immunity). Here we analyzed a broad range of nonpathogenic and pathogenic Leptospira strains considering their interaction with each CS pathway. We determined bacterial survival rate and CS protein deposition in the presence of purified proteins, specific component depleted sera and NHS treated with the chelating agents EDTA (inhibits all three activation pathways) or EGTA (inhibits the Classical and Lectin Pathways). We suggest that the Lectin and the Alternative Pathways have an important role to eliminate saprophytic leptospires since i) approximately 50% survival of both saprophytic strains was observed in the presence of MBL-deficient serum; ii) approximately 50% survival of Leptospira biflexa Patoc I was observed in the presence of NHS - EGTA and iii) C1q-depleted serum caused significant bacterial lysis. In all serovars investigated the deposition of C5-C9 proteins on saprophytic Leptospira strains was more pronounced when compared to pathogenic species confirming previous studies in the literature. No difference on C3 deposition was observed between nonpathogenic and pathogenic strains. In conclusion, Leptospira strains interact to different degrees with CS proteins, especially those necessary to form MAC, indicating that some strains and specific ligands could favor the binding of certain CS proteins.


Assuntos
Ativação do Complemento , Leptospira/imunologia , Leptospirose/imunologia , Proteínas do Sistema Complemento/imunologia , Humanos , Evasão da Resposta Imune , Leptospira/patogenicidade , Viabilidade Microbiana/imunologia
9.
Infect Immun ; 88(7)2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32152198

RESUMO

Neutrophils kill invading microbes and therefore represent the first line of defense of the innate immune response. Activated neutrophils assemble NADPH oxidase to convert substantial amounts of molecular oxygen into superoxide, which, after dismutation into peroxide, serves as the substrate for the generation of the potent antimicrobial hypochlorous acid (HOCl) in the phagosomal space. In this minireview, we explore the most recent insights into physiological consequences of HOCl stress. Not surprisingly, Gram-negative bacteria have evolved diverse posttranslational defense mechanisms to protect their proteins, the main targets of HOCl, from HOCl-mediated damage. We discuss the idea that oxidation of conserved cysteine residues and partial unfolding of its structure convert the heat shock protein Hsp33 into a highly active chaperone holdase that binds unfolded proteins and prevents their aggregation. We examine two novel members of the Escherichia coli chaperone holdase family, RidA and CnoX, whose thiol-independent activation mechanism differs from that of Hsp33 and requires N-chlorination of positively charged amino acids during HOCl exposure. Furthermore, we summarize the latest findings with respect to another bacterial defense strategy employed in response to HOCl stress, which involves the accumulation of the universally conserved biopolymer inorganic polyphosphate. We then discuss sophisticated adaptive strategies that bacteria have developed to enhance their survival during HOCl stress. Understanding bacterial defense and survival strategies against one of the most powerful neutrophilic oxidants may provide novel insights into treatment options that potentially compromise the ability of pathogens to resist HOCl stress and therefore may increase the efficacy of the innate immune response.


Assuntos
Bactérias/metabolismo , Infecções Bacterianas/metabolismo , Infecções Bacterianas/microbiologia , Mecanismos de Defesa , Ácido Hipocloroso/metabolismo , Neutrófilos/metabolismo , Oxidantes/metabolismo , Bactérias/imunologia , Infecções Bacterianas/imunologia , Fenômenos Fisiológicos Bacterianos , Humanos , Viabilidade Microbiana/imunologia , Chaperonas Moleculares/metabolismo , Neutrófilos/imunologia , Oxirredução , Estresse Oxidativo , Ligação Proteica , Explosão Respiratória , Relação Estrutura-Atividade
10.
Immunol Lett ; 221: 39-48, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32092360

RESUMO

NADPH oxidase 2 is a superoxide-generating enzymatic complex based on the catalytic subunit gp91phox that is also known as Nox2. Initially identified in neutrophils, NADPH oxidase 2 was long considered responsible only for the killing of phagocytized microorganisms. However, advances in knowledge about redox signalling and the discovery of Nox2 expression in different cell types, including macrophages, endothelial cells (ECs), dendritic cells (DCs), B and T lymphocytes, have changed this paradigm. For instance, Nox2 expressed in macrophages and neutrophils limits the transcription of cytokines and toll-like receptors (TLRs) induced by lipopolysaccharide (LPS), whereas DC Nox2 facilitates antigen cross-presentation to T cells. More recently, our group observed that Nox2 inhibits the suppressive ability of regulatory T cells (Tregs) by limiting NF-κB and FoxP3 activation. In this review, we discuss non-canonical microbicidal functions and redox-signalling-associated roles of Nox2 in different cell types, emphasizing its roles in the innate and adaptive immune system.


Assuntos
Bactérias/imunologia , Infecções Bacterianas/imunologia , Infecções Bacterianas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Imunomodulação , NADPH Oxidase 2/metabolismo , Animais , Formação de Anticorpos , Apresentação do Antígeno/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Infecções Bacterianas/microbiologia , Quimiotaxia/imunologia , Células Endoteliais/metabolismo , Ativação Enzimática , Humanos , Leucócitos/imunologia , Leucócitos/metabolismo , Viabilidade Microbiana/imunologia , NADPH Oxidase 2/química , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade
11.
PLoS Pathog ; 16(2): e1008362, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32097448

RESUMO

The transmissibility and pandemic potential of influenza viruses depends on their ability to efficiently replicate and be released from an infected host, retain viability as they pass through the environment, and then initiate infection in the next host. There is a significant gap in knowledge about viral properties that enable survival of influenza viruses between hosts, due to a lack of experimental methods to reliably isolate viable virus from the air. Using a novel technique, we isolate and characterise infectious virus from droplets emitted by 2009 pandemic H1N1-infected ferrets. We demonstrate that infectious virus is predominantly released early after infection. A virus containing a mutation destabilising the haemagglutinin (HA) surface protein displayed reduced survival in air. Infectious virus recovered from droplets exhaled by ferrets inoculated with this virus contained mutations that conferred restabilisation of HA, indicating the importance of influenza HA stability for between-host survival. Using this unique approach can improve knowledge about the determinants and mechanisms of influenza transmissibility and ultimately could be applied to studies of airborne virus exhaled from infected people.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vírus da Influenza A Subtipo H1N1/metabolismo , Ar/análise , Microbiologia do Ar , Animais , Linhagem Celular , Transmissão de Doença Infecciosa , Furões/virologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Hemaglutininas/imunologia , Hemaglutininas/metabolismo , Humanos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Influenza Humana/virologia , Viabilidade Microbiana/imunologia , Infecções por Orthomyxoviridae/virologia
12.
Infect Immun ; 88(7)2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-31988177

RESUMO

Streptococcus agalactiae (group B Streptococcus [GBS]) is an important cause of invasive infection in newborns, maternal women, and older individuals with underlying chronic illnesses. GBS has many mechanisms to adapt and survive in its host, and these mechanisms are often controlled via two-component signal transduction systems. In GBS, more than 20 distinct two-component systems (TCSs) have been classified to date, consisting of canonical TCSs as well as orphan and atypical sensors and regulators. These signal transducing systems are necessary for metabolic regulation, resistance to antibiotics and antimicrobials, pathogenesis, and adhesion to the mucosal surfaces to colonize the host. This minireview discusses the structures of these TCSs in GBS as well as how selected systems regulate essential cellular processes such as survival and colonization. GBS contains almost double the number of TCSs compared to the closely related Streptococcus pyogenes and Streptococcus pneumoniae, and while research on GBS TCSs has been increasing in recent years, no comprehensive reviews of these TCSs exist, making this review especially relevant.


Assuntos
Fenômenos Fisiológicos Bacterianos , Regulação Bacteriana da Expressão Gênica , Transdução de Sinais , Infecções Estreptocócicas/microbiologia , Streptococcus agalactiae/fisiologia , Aderência Bacteriana , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Viabilidade Microbiana/imunologia , Membrana Mucosa/imunologia , Membrana Mucosa/metabolismo , Membrana Mucosa/microbiologia , Virulência
13.
Microb Pathog ; 138: 103797, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31614194

RESUMO

Staphylococcus aureus (S. aureus) is an important pathogen causing various limited or systemic infections. Methicillin resistant S. aureus (MRSA) in particular presents a major clinical and public health problem. Toxic shock syndrome toxin-1 (TSST-1) encoded by the gene tst is an important virulence factor of tst positive S. aureus, leading to multi-organ malfunction. However, the mechanism of TSST-1 in pathogenesis is only partly clear. In this study, we investigated the prevalence of the tst gene in clinical isolates of S. aureus. Then, animal experiments were performed to further evaluate the influence of the presence of the tst gene associated Staphylococcus aureus Pathogenicity Island (SaPI) on body weight, serum cytokine concentrations and the bacterial load in different organs. In addition, macrophages were used to analyze the secretion of cytokines in vitro and bacterial survival in the cytoplasm. Finally, pathological analysis was carried out to evaluate organ tissue impairment. The results demonstrated that the prevalence of tst gene was approximately 17.8% of the bacterial strains examined. BALB/c mice infected with tst gene associated SaPI positive isolates exhibited a severe loss of body weight and a high bacterial load in the liver, heart, kidney and spleen. Pathological analysis demonstrated that tissue impairment was more severe after infection with tst gene associated SaPI positive isolates. Moreover, the secretion of IL-6, IL-2 and IL17A by macrophages infected with tst gene associated SaPI positive isolates clearly increased. Notably, IL-6 secretion in BALB/c mice infected with tst gene associated SaPI positive isolates was higher than that in BALB/c mice infected with negative ones. Together, these results indicated that the tst gene associated SaPI may play a critical role in the pathological process of infection via a direct and persistent toxic function, and by promoting the secretion of inflammatory cytokines that indirectly induce immune suppression.


Assuntos
Toxinas Bacterianas/genética , Citocinas/biossíntese , Enterotoxinas/genética , Mediadores da Inflamação/metabolismo , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Superantígenos/genética , Fatores de Virulência/genética , Animais , Linhagem Celular , Modelos Animais de Doenças , Feminino , Humanos , Imunomodulação , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Staphylococcus aureus Resistente à Meticilina/genética , Camundongos , Viabilidade Microbiana/imunologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/patogenicidade , Virulência/genética
14.
Int Immunopharmacol ; 81: 106026, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31759863

RESUMO

Diet is one of the factors contributing to symptom of Helicobacter pylori (H. pylori) infection. Trimethylamine N-oxide (TMAO), a diet-related microbial metabolite, is associated with inflammatory and metabolic diseases. The aim of this study is to investigate the effects of TMAO intake on inflammation and gut microbiota composition in H. pylori-infected mice via 16S rRNA sequencing and biochemical analyses. The in vitro experiments showed that TMAO not only increased the expression of growth- and metabolism-associated genes and the urease activity of H. pylori, but increased the production of virulence factors. Moreover, TMAO intake increased the production of inflammatory markers and reduced the richness and diversity of the gut microbiota in H. pylori-infected mice. Further analysis showed that TMAO increased the relative abundance of Escherichia_Shigella in H. pylori-infected mice, which had positive correlation with the levels of LPS, CRP, and CXCL1. Collectively, our results suggest that TMAO may aggravate H. pylori-induced inflammation by increasing the viability and virulence of H. pylori and may aggravate inflammation in association with the gut microbiota in H. pylori-infected mice. This study may provide a novel insight into the mechanism for the effect of diet-derived metabolites such as TMAO on H. pylori-induced disease development.


Assuntos
Comportamento Alimentar/fisiologia , Gastrite/imunologia , Microbioma Gastrointestinal/imunologia , Infecções por Helicobacter/imunologia , Helicobacter pylori/patogenicidade , Metilaminas/imunologia , Animais , Linhagem Celular , DNA Bacteriano/isolamento & purificação , Modelos Animais de Doenças , Escherichia/imunologia , Escherichia/isolamento & purificação , Feminino , Mucosa Gástrica/citologia , Mucosa Gástrica/imunologia , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Gastrite/microbiologia , Gastrite/patologia , Microbioma Gastrointestinal/genética , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/imunologia , Humanos , Camundongos , Viabilidade Microbiana/imunologia , RNA Ribossômico 16S/genética , Shigella/imunologia , Shigella/isolamento & purificação , Virulência/imunologia
15.
Nat Commun ; 10(1): 5526, 2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31797922

RESUMO

Type I CRISPR-Cas systems are abundant and widespread adaptive immune systems in bacteria and can greatly enhance bacterial survival in the face of phage infection. Upon phage infection, some CRISPR-Cas immune responses result in bacterial dormancy or slowed growth, which suggests the outcomes for infected cells may vary between systems. Here we demonstrate that type I CRISPR immunity of Pectobacterium atrosepticum leads to suppression of two unrelated virulent phages, ɸTE and ɸM1. Immunity results in an abortive infection response, where infected cells do not survive, but viral propagation is severely decreased, resulting in population protection due to the reduced phage epidemic. Our findings challenge the view of CRISPR-Cas as a system that protects the individual cell and supports growing evidence of abortive infection by some types of CRISPR-Cas systems.


Assuntos
Bactérias/imunologia , Bacteriófagos/imunologia , Sistemas CRISPR-Cas/imunologia , Pectobacterium/imunologia , Bactérias/genética , Bactérias/virologia , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Infecções Bacterianas/virologia , Bacteriófagos/genética , Bacteriófagos/fisiologia , Sistemas CRISPR-Cas/genética , Viabilidade Microbiana/genética , Viabilidade Microbiana/imunologia , Pectobacterium/genética , Pectobacterium/virologia , Replicação Viral/genética , Replicação Viral/imunologia
16.
Sci Rep ; 9(1): 16267, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31700127

RESUMO

Invasion and persistence of bacteria within host cells requires that they adapt to life in an intracellular environment. This adaptation induces bacterial stress through events such as phagocytosis and enhanced nutrient-restriction. During stress, bacteria synthesize a family of proteins known as heat shock proteins (HSPs) to facilitate adaptation and survival. Previously, we determined the Staphylococcus aureus HSP ClpC temporally alters bacterial metabolism and persistence. This led us to hypothesize that ClpC might alter intracellular survival. Inactivation of clpC in S. aureus strain DSM20231 significantly enhanced long-term intracellular survival in human epithelial (HaCaT) and endothelial (EA.hy926) cell lines, without markedly affecting adhesion or invasion. This phenotype was similar across a genetically diverse collection of S. aureus isolates, and was influenced by the toxin/antitoxin encoding locus mazEF. Importantly, MazEF alters mRNA synthesis and/or stability of S. aureus virulence determinants, indicating ClpC may act through the mRNA modulatory activity of MazEF. Transcriptional analyses of total RNAs isolated from intracellular DSM20231 and isogenic clpC mutant cells identified alterations in transcription of α-toxin (hla), protein A (spa), and RNAIII, consistent with the hypothesis that ClpC negatively affects the intracellular survival of S. aureus in non-professional phagocytic cells, via modulation of MazEF and Agr.


Assuntos
Proteínas de Bactérias/genética , Proteínas de Choque Térmico/genética , Interações Hospedeiro-Patógeno , Fagócitos/imunologia , Fagócitos/microbiologia , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/fisiologia , Aderência Bacteriana , Proteínas de Bactérias/metabolismo , Citotoxicidade Imunológica , Proteínas de Choque Térmico/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Viabilidade Microbiana/imunologia , Mutação , Fagócitos/metabolismo , Infecções Estafilocócicas/microbiologia , Ativação Transcricional , Virulência
17.
Front Immunol ; 10: 2296, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632394

RESUMO

Altered microbiota has been associated with a number of diseases, including inflammatory bowel diseases, diabetes, and cancer. This dysregulation is thought to relate the host inflammatory response to enteric pathogens. Macrophages play a key role in host response to microbes and are involved in bacterial killing and clearance. This process is partially mediated through the potassium efflux-dependent, cytosolic, PYCARD-containing inflammasome protein complex. Surprisingly, we discovered an alternative mechanism for bacterial killing, independent of the NLRP3 inflammasome/PYCARD. Using the NLRP3 inflammasome-deficient Raw 264.7 and PYCARD-deficient J77 macrophages, which both lack PYCARD, we found that the potassium efflux activator nigericin enhances bacterial killing. Macrophage response to nigericin was examined by RT gene profiling and subsequent qPCR, which demonstrated altered expression of a series of genes involved in the IL-18 bacterial killing pathway. Based on our results we propose a model of bacterial killing, unrelated to NLRP3 inflammasome activation in macrophage cells. Improving understanding of the molecular pathways driving bacterial clearance within macrophage cells will aid in the development of novel immune-targeted therapeutics in a number of diseases.


Assuntos
Antibacterianos/farmacologia , Bactérias/imunologia , Citotoxicidade Imunológica/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Nigericina/farmacologia , Animais , Bactérias/crescimento & desenvolvimento , Interações Hospedeiro-Patógeno , Imunidade Inata , Inflamassomos/metabolismo , Macrófagos/microbiologia , Camundongos , Viabilidade Microbiana/imunologia , Modelos Biológicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
18.
Comp Immunol Microbiol Infect Dis ; 66: 101329, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31437687

RESUMO

The Eurasian wild boar (Sus scrofa) is a reservoir for tuberculosis (TB) in which vaccination is a valuable tool for control. We evaluated the protection and immune response achieved by homologous and heterologous regimes administering BCG and heat-inactivated Mycobacterium bovis (IV). Twenty-one wild boar piglets were randomly allocated in five groups: Control, homologous BCG, homologous IV, heterologous IV-BCG, heterologous BCG-IV. Significant 67% and 66% total lesion score reductions were detected in homologous IV (IVx2) and heterologous IV-BCG groups when compared with Control group (F4,16 = 6.393, p = 0.003; Bonferroni Control vs IVx2 p = 0.026, Tukey Control vs IV-BCG p = 0.021). No significant differences were found for homologous BCG (although a 48% reduction in total lesion score was recorded) and BCG-IV (3% reduction). Heterologous regimes did not improve protection over homologous regimes in the wild boar model and showed variable results from no protection to similar protection as homologous regimes. Therefore, homologous regimes remain the best option to vaccinate wild boar against TB. Moreover, vaccine sequence dramatically influenced the outcome underlining the relevance of studying the effects of prior sensitization in the outcome of vaccination.


Assuntos
Vacina BCG/uso terapêutico , Esquemas de Imunização , Sus scrofa/imunologia , Tuberculose/veterinária , Vacinação/veterinária , Animais , Anticorpos Antibacterianos/sangue , Vacina BCG/administração & dosagem , Citocinas/imunologia , Masculino , Viabilidade Microbiana/imunologia , Mycobacterium bovis , Distribuição Aleatória , Suínos , Tuberculose/prevenção & controle , Vacinas de Produtos Inativados/uso terapêutico
19.
Rev. cuba. med. trop ; 71(2): e399, mayo.-ago. 2019. graf
Artigo em Espanhol | LILACS, CUMED | ID: biblio-1093565

RESUMO

Introducción: Legionella pneumophila se sitúa entre los principales agentes causales de neumonía adquirida en la comunidad y de origen nosocomial. La inhalación de aerosoles potencialmente contaminados con la bacteria, producto de la colonización de redes y otros sistemas que utilizan agua, representa un peligro para la salud de los individuos expuestos. Objetivo: evaluar la viabilidad de L. pneumophila en muestras de agua almacenadas en diferentes intervalos de tiempo para el diagnóstico por cultivo microbiológico de Legionella spp. Métodos: Se contaminaron artificialmente muestras de agua con dos cepas de L. pneumophila de serogrupos diferentes y la conformación de una mezcla de ellas, para un total de 15 muestras. Los frascos contaminados fueron procesados a las 24 h, 72 h, 7 días, 14 días y 21 días. Se realizó cultivo microbiológico según ISO 11731: 2004 y PNO 03-013: 2015. Resultados: Se demostró viabilidad de la bacteria en muestras almacenadas hasta 21 días. El método de concentración por filtración resultó tener los mayores recobrados del microorganismo. Conclusiones: El tiempo de almacenamiento de las muestras afecta la viabilidad de L. pneumophila. Sienta las bases para estudios posteriores de robustez del diagnóstico de L. pneumophila como parte del servicio que presta el Centro de Investigaciones Científicas de la Defensa Civil en los programas de prevención y control Legionella spp. en instalaciones de interés turístico e industrial(AU)


Introduction: Legionella pneumophila is one of the main causative agents of community- and hospital-acquired pneumonia. Inhalation of sprays potentially contaminated with the bacterium, due to the colonization of networks and other systems using water, is a hazard to the health of exposed individuals. Objective: Evaluate the viability of L. pneumophila in samples of water stored at various time intervals for the microbiological culture diagnosis of Legionella spp. Methods: Water samples were artificially contaminated with two strains of L. pneumophila from different serogroups and a mixture of them, for a total of 15 samples. The contaminated vessels were processed at 24 h, 72 h, 7 d, 14 d and 21 d. Microbiological culture was performed in compliance with ISO 11731: 2004 and PNO 03-013: 2015. Results: The bacterium was found to be viable in samples stored up to 21 days. The filtration concentration method obtained the greatest amount of the microorganism. Conclusions: Storage time of the samples affects the viability of L. pneumophila. The study lays the foundations for further research about the validity of L. pneumophila diagnosis as part of the service offered by the Civil Defense Scientific Research Center in Legionella spp. prevention and control programs for tourist and industrial facilities(AU)


Assuntos
Humanos , Doença dos Legionários/imunologia , Amostras de Água , Viabilidade Microbiana/imunologia , Pneumonia/microbiologia , Comunicação
20.
PLoS Pathog ; 15(6): e1007879, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31199852

RESUMO

Burkholderia pseudomallei is a gram-negative, facultative intracellular bacterium, which causes a disease known as melioidosis. Professional phagocytes represent a crucial first line of innate defense against invading pathogens. Uptake of pathogens by these cells involves the formation of a phagosome that matures by fusing with early and late endocytic vesicles, resulting in killing of ingested microbes. Host Rab GTPases are central regulators of vesicular trafficking following pathogen phagocytosis. However, it is unclear how Rab GTPases interact with B. pseudomallei to regulate the transport and maturation of bacterial-containing phagosomes. Here, we showed that the host Rab32 plays an important role in mediating antimicrobial activity by promoting phagosome maturation at an early phase of infection with B. pseudomallei. And we demonstrated that the expression level of Rab32 is increased through the downregulation of the synthesis of miR-30b/30c in B. pseudomallei infected macrophages. Subsequently, we showed that B. pseudomallei resides temporarily in Rab32-positive compartments with late endocytic features. And Rab32 enhances phagosome acidification and promotes the fusion of B. pseudomallei-containing phagosomes with lysosomes to activate cathepsin D, resulting in restricted intracellular growth of B. pseudomallei. Additionally, Rab32 mediates phagosome maturation depending on its guanosine triphosphate/guanosine diphosphate (GTP/GDP) binding state. Finally, we report the previously unrecognized role of miR-30b/30c in regulating B. pseudomallei-containing phagosome maturation by targeting Rab32 in macrophages. Altogether, we provide a novel insight into the host immune-regulated cellular pathway against B. pseudomallei infection is partially dependent on Rab32 trafficking pathway, which regulates phagosome maturation and enhances the killing of this bacterium in macrophages.


Assuntos
Burkholderia pseudomallei/imunologia , Melioidose/imunologia , MicroRNAs/imunologia , Fagossomos/imunologia , Proteínas rab de Ligação ao GTP/imunologia , Animais , Burkholderia pseudomallei/patogenicidade , Melioidose/patologia , Camundongos , Viabilidade Microbiana/imunologia , Fagossomos/microbiologia , Fagossomos/patologia , Células RAW 264.7
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