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1.
Front Cell Infect Microbiol ; 11: 643326, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33828999

RESUMO

Secondary bacterial infections enhance the disease burden of influenza infections substantially. Streptococcus pneumoniae (the pneumococcus) plays a major role in the synergism between bacterial and viral pathogens, which is based on complex interactions between the pathogen and the host immune response. Here, we discuss mechanisms that drive the pathogenesis of a secondary pneumococcal infection after an influenza infection with a focus on how pneumococci senses and adapts to the influenza-modified environment. We briefly summarize what is known regarding secondary bacterial infection in relation to COVID-19 and highlight the need to improve our current strategies to prevent and treat viral bacterial coinfections.


Assuntos
COVID-19/complicações , Influenza Humana , Infecções Pneumocócicas/patologia , Sistema Respiratório/patologia , Infecções Respiratórias/microbiologia , Infecções Respiratórias/virologia , Coinfecção , Interações Hospedeiro-Patógeno/imunologia , Humanos , Influenza Humana/complicações , Streptococcus pneumoniae
2.
Proc Natl Acad Sci U S A ; 117(49): 31386-31397, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33229573

RESUMO

Influenza A virus (IAV)-related mortality is often due to secondary bacterial infections, primarily by pneumococci. Here, we study how IAV-modulated changes in the lungs affect bacterial replication in the lower respiratory tract (LRT). Bronchoalveolar lavages (BALs) from coinfected mice showed rapid bacterial proliferation 4 to 6 h after pneumococcal challenge. Metabolomic and quantitative proteomic analyses demonstrated capillary leakage with efflux of nutrients and antioxidants into the alveolar space. Pneumococcal adaptation to IAV-induced inflammation and redox imbalance increased the expression of the pneumococcal chaperone/protease HtrA. Presence of HtrA resulted in bacterial growth advantage in the IAV-infected LRT and protection from complement-mediated opsonophagocytosis due to capsular production. Absence of HtrA led to growth arrest in vitro that was partially restored by antioxidants. Pneumococcal ability to grow in the IAV-infected LRT depends on the nutrient-rich milieu with increased levels of antioxidants such as ascorbic acid and its ability to adapt to and cope with oxidative damage and immune clearance.


Assuntos
Antioxidantes/metabolismo , Capilares/patologia , Influenza Humana/microbiologia , Infecções Pneumocócicas/microbiologia , Sistema Respiratório/microbiologia , Sistema Respiratório/virologia , Streptococcus pneumoniae/crescimento & desenvolvimento , Animais , Proteínas de Bactérias/metabolismo , Glucose/metabolismo , Humanos , Inflamação/complicações , Inflamação/patologia , Camundongos Endogâmicos C57BL , Modelos Biológicos , Chaperonas Moleculares/metabolismo , Infecções por Orthomyxoviridae/microbiologia , Oxirredução , Estresse Oxidativo , Fagocitose , Sistema Respiratório/patologia
3.
Cell Host Microbe ; 27(4): 544-555.e3, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32130952

RESUMO

Streptococcus pneumoniae is a commensal of the human nasopharynx that can also cause severe antibiotic-resistant infections. Antibiotics drive the spread of resistance by inducing S. pneumoniae competence, in which bacteria express the transformation machinery that facilitates uptake of exogenous DNA and horizontal gene transfer (HGT). We performed a high-throughput screen and identified potent inhibitors of S. pneumoniae competence, called COM-blockers. COM-blockers limit competence by inhibiting the proton motive force (PMF), thereby disrupting export of a quorum-sensing peptide that regulates the transformation machinery. Known chemical PMF disruptors and alterations in pH homeostasis similarly inhibit competence. COM-blockers limit transformation of clinical multi-drug-resistant strains and HGT in infected mice. At their active concentrations, COM-blockers do not affect growth, compromise antibiotic activity, or elicit detectable resistance. COM-blockers provide an experimental tool to inhibit competence and other PMF-involved processes and could help reduce the spread of virulence factors and antibiotic resistance in bacteria. VIDEO ABSTRACT.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Transferência Genética Horizontal , Força Próton-Motriz , Streptococcus pneumoniae , Animais , Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Proteínas de Bactérias/efeitos dos fármacos , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Transferência Genética Horizontal/efeitos dos fármacos , Humanos , Camundongos , Percepção de Quorum/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/metabolismo , Fatores de Virulência
4.
Cell Rep ; 20(1): 251-263, 2017 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-28683318

RESUMO

Genome delivery to the proper cellular compartment for transcription and replication is a primary goal of viruses. However, methods for analyzing viral genome localization and differentiating genomes with high identity are lacking, making it difficult to investigate entry-related processes and co-examine heterogeneous RNA viral populations. Here, we present an RNA labeling approach for single-cell analysis of RNA viral replication and co-infection dynamics in situ, which uses the versatility of padlock probes. We applied this method to identify influenza A virus (IAV) infections in cells and lung tissue with single-nucleotide specificity and to classify entry and replication stages by gene segment localization. Extending the classification strategy to co-infections of IAVs with single-nucleotide variations, we found that the dependence on intracellular trafficking places a time restriction on secondary co-infections necessary for genome reassortment. Altogether, these data demonstrate how RNA viral genome labeling can help dissect entry and co-infections.


Assuntos
Genoma Viral , Vírus da Influenza A/fisiologia , RNA Viral/metabolismo , Análise de Célula Única/métodos , Coloração e Rotulagem/métodos , Replicação Viral , Animais , Cães , Células Epiteliais/virologia , Células HEK293 , Humanos , Vírus da Influenza A/genética , Células Madin Darby de Rim Canino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Virais/metabolismo
5.
Cell Host Microbe ; 20(3): 307-317, 2016 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-27593514

RESUMO

Streptococcus pneumoniae is a human-adapted pathogen that encounters terminally sialylated glycoconjugates and free sialic acid (Sia) in the airways. Upon scavenging by the bacterial sialidase NanA, Sias serve as carbon sources for the bacteria. Unlike most animals in which cytidine-monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) converts Sia N-acetylneuraminic acid (Neu5Ac) into N-glycolylneuraminic acid (Neu5Gc), humans have an inactive CMAH, causing an absence of Neu5Gc and excess Neu5Ac. We find that pneumococcal challenge in Cmah(-/-) mice leads to heightened bacterial loads, virulence, and NanA expression. In vitro, NanA is upregulated in response to Neu5Ac compared with Neu5Gc, a process controlled by the two-component response regulator CiaR and requiring Sia uptake by the transporter SatABC. Additionally, compared with Neu5Gc, Neu5Ac increases pneumococcal resistance to antimicrobial reactive oxygen species in a CiaR-dependent manner. Thus, S. pneumoniae senses and responds to Neu5Ac, leading to CiaR activation and increased virulence and potentially explaining the greater susceptibility in humans.


Assuntos
Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Ácido N-Acetilneuramínico/metabolismo , Proteínas Quinases/metabolismo , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/fisiologia , Fatores de Virulência/biossíntese , Animais , Carga Bacteriana , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Oxigenases de Função Mista/deficiência , Pneumonia Pneumocócica/microbiologia
6.
mBio ; 7(2): e00168-16, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26956584

RESUMO

UNLABELLED: A functional immune response is crucial to prevent and limit infections with Streptococcus pneumoniae. Dendritic cells (DCs) play a central role in orchestrating the adaptive and innate immune responses by communicating with other cell types via antigen presentation and secretion of cytokines. In this study, we set out to understand how pneumococci activate human monocyte-derived DCs to produce interleukin-12 (IL-12) p70, an important cytokine during pneumococcal infections. We show that IL-12p70 production requires uptake of bacteria as well as the presence of the adaptor molecule TRIF, which is known to transfer signals of Toll-like receptor 3 (TLR3) or TLR4 from the endosome into the cell. While TLR4 is redundant for IL-12p70 production in DCs, we found that TLR3 is required to induce full IL-12p70 secretion. Influenza A virus (IAV) infection of DCs did not induce IL-12p70 but markedly upregulated TLR3 expression that during coinfection with S. pneumoniae significantly enhanced IL-12p70 secretion. Finally, we show that pneumococcal RNA can act as a bacterial stimulus for TLR3 and that it is a key signal to induce IL-12p70 production during challenge of DCs with pneumococci. IMPORTANCE: Streptococcus pneumoniae, a common colonizer of the nose, is the causative agent of severe and deadly diseases. A well-orchestrated immune response is vital to prevent and limit these diseases. Dendritic cells (DCs) reside in the mucosal linings of the lungs and sample antigens. They are activated by pathogens to present antigens and secrete cytokines. While many studies focus on murine models, we focused our work on human monocyte-derived DCs. We found that pneumococcal RNA is an important stimulus in DCs to activate the endosomal receptor TLR3, a receptor previously not identified to sense pneumococci, and its adaptor molecule TRIF. This leads to secretion of the cytokine interleukin-12 (IL-12). Severe pneumococcal pneumonia occurs closely after influenza A virus (IAV) infection. We show that IAV infection upregulates TLR3 in DCs, which sensitizes the cells to endosomal pneumococcal RNA. This new insight contributes to unlock the interplay between pneumococci, IAV, and humans.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/imunologia , Células Dendríticas/imunologia , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Interleucina-12/imunologia , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Receptor 3 Toll-Like/imunologia , Proteínas Adaptadoras de Transporte Vesicular/genética , Coinfecção/imunologia , Coinfecção/microbiologia , Coinfecção/virologia , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/microbiologia , Células Dendríticas/virologia , Humanos , Vírus da Influenza A/fisiologia , Influenza Humana/genética , Influenza Humana/virologia , Interleucina-12/genética , Monócitos/imunologia , Infecções Pneumocócicas/genética , Infecções Pneumocócicas/microbiologia , RNA Bacteriano/genética , RNA Bacteriano/imunologia , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/fisiologia , Receptor 3 Toll-Like/genética
7.
Open Biol ; 4: 130090, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24430336

RESUMO

Streptococcus pneumoniae is a major human pathogen, and a leading cause of disease and death worldwide. Pneumococcal invasive disease is triggered by initial asymptomatic colonization of the human upper respiratory tract. The pneumococcal serine-rich repeat protein (PsrP) is a lung-specific virulence factor whose functional binding region (BR) binds to keratin-10 (KRT10) and promotes pneumococcal biofilm formation through self-oligomerization. We present the crystal structure of the KRT10-binding domain of PsrP (BR187-385) determined to 2.0 Å resolution. BR187-385 adopts a novel variant of the DEv-IgG fold, typical for microbial surface components recognizing adhesive matrix molecules adhesins, despite very low sequence identity. An extended ß-sheet on one side of the compressed, two-sided barrel presents a basic groove that possibly binds to the acidic helical rod domain of KRT10. Our study also demonstrates the importance of the other side of the barrel, formed by extensive well-ordered loops and stabilized by short ß-strands, for interaction with KRT10.


Assuntos
Proteínas de Bactérias/metabolismo , Queratina-10/química , Modelos Moleculares , Fatores de Virulência/metabolismo , Adesinas Bacterianas/química , Adesinas Bacterianas/metabolismo , Alanina/genética , Alanina/metabolismo , Substituição de Aminoácidos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Cristalografia por Raios X , Humanos , Queratina-10/metabolismo , Ligação Proteica , Dobramento de Proteína , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Eletricidade Estática , Streptococcus pneumoniae/metabolismo , Fatores de Virulência/química , Fatores de Virulência/genética
8.
mBio ; 4(1): e00535-12, 2012 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-23269830

RESUMO

UNLABELLED: Pneumococcal pili have been shown to influence pneumococcal colonization, disease development, and the inflammatory response in mice. The role of the pilus-associated RrgA adhesin in pneumococcal interactions with murine and human macrophages was investigated. Expression of pili with RrgA enhanced the uptake of pneumococci by murine and human macrophages that was abolished by antibodies to complement receptor 3 (CR3) and not seen in CR3-deficient macrophages. Recombinant RrgA, but not pilus subunit RrgC, promoted CR3-mediated phagocytosis of coated beads by murine and human macrophages. Flow cytometry showed that purified CR3 binds pneumococcal cells expressing RrgA, and purified RrgA was shown to interact with CR3 and its I domain. In vivo, RrgA facilitated spread of pneumococci from the upper airways and peritoneal cavity to the bloodstream. Earlier onset of septicemia and more rapidly progressing disease was observed in wild-type mice compared to CR3-deficient mice challenged intranasally or intraperitoneally with pneumococci. Motility assays and time-lapse video microscopy showed that pneumococcal stimulation of macrophage motility required RrgA and CR3. These findings, together with the observed RrgA-dependent increase of intracellular survivors up to 10 h following macrophage infection, suggest that RrgA-CR3-mediated phagocytosis promotes systemic pneumococcal spread from local sites. IMPORTANCE: Streptococcus pneumoniae is a major contributor to morbidity and mortality in infectious diseases globally. Symptomatology is mainly due to pneumococcal interactions with host cells leading to an inflammatory response. However, we still need more knowledge on how pneumococci talk to immune cells and the importance of this interaction. Recently, a novel structure was identified on the pneumococcal surface, an adhesive pilus found in about 30% of clinical pneumococcal isolates. The pilus has been suggested to be important for successful spread of antibiotic-resistant pneumococcal clones globally. Here we sought to identify mechanisms for how the pneumococcal pilin subunit RrgA contributes to disease development by interacting with host immune cells. Our data suggest a new way for how pneumococci may cross talk with phagocytic cells and affect disease progression. An increased understanding of these processes may lead to better strategies for how to treat these common infections.


Assuntos
Proteínas de Fímbrias/imunologia , Proteínas de Fímbrias/metabolismo , Antígeno de Macrófago 1/imunologia , Antígeno de Macrófago 1/metabolismo , Macrófagos/imunologia , Streptococcus pneumoniae/imunologia , Fatores de Virulência/imunologia , Fatores de Virulência/metabolismo , Adesinas Bacterianas/imunologia , Adesinas Bacterianas/metabolismo , Animais , Sangue/microbiologia , Movimento Celular , Feminino , Citometria de Fluxo , Humanos , Macrófagos/microbiologia , Masculino , Camundongos , Cavidade Peritoneal/microbiologia , Fagocitose , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Sistema Respiratório/microbiologia , Streptococcus pneumoniae/patogenicidade , Análise de Sobrevida , Imagem com Lapso de Tempo
9.
RNA Biol ; 9(4): 489-502, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22336758

RESUMO

The RNA chaperone Hfq and its associated small RNAs (sRNAs) regulate a variety of phenotypes in bacteria. In this work, we show that Hfq is a master regulator of biofilm formation in Salmonella enterica serovar Typhimurium. Hfq and two Hfq-dependent sRNAs (ArcZ and SdsR) are required for rdar morphotype expression in S. typhimurium. Hfq controls rdar biofilm formation through the major biofilm regulator CsgD. While csgD mRNA steady-state levels are altered in a sdsR mutant, ArcZ seems to work mainly at the post-transcriptional level. Overexpression of ArcZ complemented rdar morphotype formation of an hfq mutant under plate-grown conditions. Although ArcZ activates rpoS expression, its effect on csgD expression is mainly independent of RpoS. ArcZ does not only regulate rdar morphotype expression, but also the transition between sessility and motility and the timing of type 1 fimbriae vs. curli fimbriae surface-attachment at ambient temperature. Consequently, ArcZ is a major regulator of rdar biofilm development.


Assuntos
Proteínas de Bactérias/fisiologia , Biofilmes , Chaperonas Moleculares/fisiologia , Salmonella typhimurium/fisiologia , Regiões 5' não Traduzidas , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Fímbrias Bacterianas/genética , Fímbrias Bacterianas/metabolismo , Fímbrias Bacterianas/fisiologia , Expressão Gênica , Regulação Bacteriana da Expressão Gênica , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Fenótipo , Pequeno RNA não Traduzido , Salmonella typhimurium/genética , Salmonella typhimurium/metabolismo
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