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1.
Microbes Infect ; 25(7): 105142, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37080384

RESUMO

Human Angiotensin-Converting Enzyme 2 (hACE2) is the major receptor enabling host cell invasion by SARS-CoV-2 via interaction with Spike. The murine ACE2 does not interact efficiently with SARS-CoV-2 Spike and therefore the laboratory mouse strains are not permissive to SARS-CoV-2 replication. Here, we generated new hACE2 transgenic mice, which harbor the hACE2 gene under the human keratin 18 promoter, in "HHD-DR1" background. HHD-DR1 mice are fully devoid of murine Major Histocompatibility Complex (MHC) molecules of class-I and -II and express only MHC molecules from Human Leukocyte Antigen (HLA) HLA 02.01, DRA01.01, DRB1.01.01 alleles, widely expressed in human populations. We selected three transgenic strains, with various hACE2 mRNA expression levels and distinctive profiles of lung and/or brain permissiveness to SARS-CoV-2 replication. These new hACE2 transgenic strains display high permissiveness to the replication of SARS-CoV-2 Omicron sub-variants, while the previously available B6.K18-ACE22Prlmn/JAX mice have been reported to be poorly susceptible to infection with Omicron. As a first application, one of these MHC- and ACE2-humanized strains was successfully used to show the efficacy of a lentiviral-based COVID-19 vaccine.


Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Animais , Camundongos , Humanos , Enzima de Conversão de Angiotensina 2/genética , SARS-CoV-2/genética , Vacinas contra COVID-19 , Permissividade , Complexo Principal de Histocompatibilidade , Camundongos Transgênicos
2.
Proc Natl Acad Sci U S A ; 120(4): e2209936120, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36669110

RESUMO

Peptidoglycan, the major structural polymer forming the cell wall of bacteria, is an important mediator of physiological and behavioral effects in mammalian hosts. These effects are frequently linked to its translocation from the intestinal lumen to host tissues. However, the modality and regulation of this translocation across the gut barrier has not been precisely addressed. In this study, we characterized the absorption of peptidoglycan across the intestine and its systemic dissemination. We report that peptidoglycan has a distinct tropism for host organs when absorbed via the gut, most notably by favoring access to the brain. We demonstrate that intestinal translocation of peptidoglycan occurs through a microbiota-induced active process. This process is regulated by the parasympathetic pathway via the muscarinic acetylcholine receptors. Together, this study reveals fundamental parameters concerning the uptake of a major microbiota molecular signal from the steady-state gut.


Assuntos
Microbiota , Peptidoglicano , Animais , Peptidoglicano/metabolismo , Bactérias/metabolismo , Parede Celular/metabolismo , Mamíferos/metabolismo
3.
JCI Insight ; 7(15)2022 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-35737457

RESUMO

Aging is known to be associated with hippocampus-dependent memory decline, but the underlying causes of this age-related memory impairment remain highly debated. Here, we show that fecal microbiota transplantation (FMT) from aged, but not young, animal donors into young mice is sufficient to trigger profound hippocampal alterations, including astrogliosis, decreased adult neurogenesis, decreased novelty-induced neuronal activation, and impairment in hippocampus-dependent memory. Furthermore, similar alterations were reported when mice were subjected to an FMT from aged human donors. To decipher the mechanisms involved in mediating these microbiota-induced effects on brain function, we mapped the vagus nerve-related (VN-related) neuronal activity patterns and report that aged FMT animals showed a reduction in neuronal activity in the ascending-VN output brain structure, whether under basal condition or after VN stimulation. Targeted pharmacogenetic manipulation of VN-ascending neurons demonstrated that the decrease in vagal activity is detrimental to hippocampal functions. In contrast, increasing vagal ascending activity alleviated the adverse effects of aged mouse FMT on hippocampal functions and had a promnesic effect in aged mice. Thus, pharmacogenetic VN stimulation is a potential therapeutic strategy to lessen microbiota-dependent age-associated impairments in hippocampal functions.


Assuntos
Microbioma Gastrointestinal , Adulto , Idoso , Animais , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/fisiologia , Hipocampo/fisiologia , Humanos , Camundongos , Neurogênese , Nervo Vago
4.
Cell Host Microbe ; 30(4): 556-569.e5, 2022 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-35421351

RESUMO

Abundance and diversity of bacteria and their viral predators, bacteriophages (phages), in the digestive tract are associated with human health. Particularly intriguing is the long-term coexistence of these two antagonistic populations. We performed genome-wide RNA sequencing on a human enteroaggregative Escherichia coli isolate to identify genes differentially expressed between in vitro conditions and in murine intestines. We experimentally demonstrated that four of these differentially expressed genes modified the interactions between E. coli and three virulent phages by either increasing or decreasing its susceptibility/resistance pattern and also by interfering with biofilm formation. Therefore, the regulation of bacterial genes expression during the colonization of the digestive tract influences the coexistence of phages and bacteria, highlighting the intricacy of tripartite relationships between phages, bacteria, and the animal host in intestinal homeostasis.


Assuntos
Bacteriófagos , Animais , Bactérias/genética , Bacteriófagos/fisiologia , Escherichia coli/genética , Expressão Gênica , Genes Bacterianos , Camundongos
5.
Cell Host Microbe ; 28(3): 390-401.e5, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32615090

RESUMO

The ecological dynamics underlying the coexistence between antagonistic populations of bacteria and their viruses, bacteriophages (phages), in the mammalian gut microbiota remain poorly understood. We challenged a murine synthetic bacterial community with phages to study the factors allowing phages-bacteria coexistence. Coexistence was not dependent on the development of phage-resistant clones nor on the ability of phages to extend their host range. Instead, our data suggest that phage-inaccessible sites in the mucosa serve as a spatial refuge for bacteria. From there, bacteria disseminate in the gut lumen where they are predated by luminal phages fostering the presence of intestinal phage populations. The heterogeneous biogeography of microbes contributes to the long-term coexistence of phages with phage-susceptible bacteria. This observation could explain the persistence of intestinal phages in humans as well as the low efficiency of oral phage therapy against enteric pathogens in animal models and clinical trials.


Assuntos
Bactérias/crescimento & desenvolvimento , Bactérias/virologia , Bacteriófagos/fisiologia , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/virologia , Trato Gastrointestinal/microbiologia , Mucosa/microbiologia , Animais , Ecossistema , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal , Vida Livre de Germes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Interações Microbianas , Modelos Animais
6.
Nat Microbiol ; 5(1): 34-39, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31819216

RESUMO

The gut commensal segmented filamentous bacterium (SFB) attaches to the ileal epithelium and potently stimulates the host immune system. Using transmission electron microscopy (TEM), we show that mouse and rat SFB are flagellated above the concave tip at the unicellular intracellular offspring (IO) stage and that flagellation occurs prior to full IO differentiation and release of IOs from SFB filaments. This finding adds a missing link to the SFB life cycle.


Assuntos
Bactérias Anaeróbias/crescimento & desenvolvimento , Bactérias Anaeróbias/ultraestrutura , Flagelos/ultraestrutura , Animais , Linhagem Celular , Flagelos/metabolismo , Flagelina/genética , Flagelina/metabolismo , Regulação Bacteriana da Expressão Gênica , Humanos , Íleo/microbiologia , Mucosa Intestinal/microbiologia , Camundongos , Ratos , Receptor 5 Toll-Like/metabolismo
7.
Cell Host Microbe ; 26(5): 691-701.e5, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31726031

RESUMO

Understanding the role of the microbiota components in either preventing or favoring enteric infections is critical. Here, we report the discovery of a Listeria bacteriocin, Lmo2776, which limits Listeria intestinal colonization. Oral infection of conventional mice with a Δlmo2776 mutant leads to a thinner intestinal mucus layer and higher Listeria loads both in the intestinal content and deeper tissues compared to WT Listeria. This latter difference is microbiota dependent, as it is not observed in germ-free mice. Strikingly, it is phenocopied by pre-colonization of germ-free mice before Listeria infection with Prevotella copri, an abundant gut-commensal bacteria, but not with the other commensals tested. We further show that Lmo2776 targets P. copri and reduces its abundance. Together, these data unveil a role for P.copri in exacerbating intestinal infection, highlighting that pathogens such as Listeria may selectively deplete microbiota bacterial species to avoid excessive inflammation.


Assuntos
Antibacterianos/farmacologia , Bacteriocinas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Listeria monocytogenes/metabolismo , Listeriose/prevenção & controle , Prevotella/crescimento & desenvolvimento , Animais , Feminino , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiologia , Vida Livre de Germes , Humanos , Inflamação/prevenção & controle , Listeriose/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Prevotella/efeitos dos fármacos
8.
Immunity ; 50(5): 1276-1288.e5, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-30902637

RESUMO

Microbes colonize all body surfaces at birth and participate in the development of the immune system. In newborn mammals, the intestinal microbiota is first shaped by the dietary and immunological components of milk and then changes upon the introduction of solid food during weaning. Here, we explored the reactivity of the mouse intestinal immune system during the first weeks after birth and into adulthood. At weaning, the intestinal microbiota induced a vigorous immune response-a "weaning reaction"-that was programmed in time. Inhibition of the weaning reaction led to pathological imprinting and increased susceptibility to colitis, allergic inflammation, and cancer later in life. Prevention of this pathological imprinting was associated with the generation of RORγt+ regulatory T cells, which required bacterial and dietary metabolites-short-chain fatty acids and retinoic acid. Thus, the weaning reaction to microbiota is required for immune ontogeny, the perturbation of which leads to increased susceptibility to immunopathologies later in life.


Assuntos
Microbioma Gastrointestinal/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Linfócitos T Reguladores/imunologia , Desmame , Animais , Animais Recém-Nascidos/imunologia , Animais Recém-Nascidos/microbiologia , Ácidos Graxos Voláteis/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Tretinoína/metabolismo
9.
Nat Metab ; 1(11): 1101-1109, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-32694861

RESUMO

Epidemiological data reveal an association between obesity and inflammatory bowel disease (IBD). Furthermore, animal models demonstrate that maternal high-fat diet (HFD) and maternal obesity increase susceptibility to IBD in offspring. Here we report that excess calorie intake by neonatal mice, as a consequence of maternal HFD, forced feeding of neonates or low litter competition, leads to an increase during weaning in intestinal permeability, expression of pro-inflammatory cytokines and hydrogen sulfide production by the microbiota. These intestinal changes engage in mutual positive feedback that imprints increased susceptibility to colitis in adults. The pathological imprinting is prevented by the neutralization of IFN-γ and TNF-α or the production of hydrogen sulfide, or by normalization of intestinal permeability during weaning. We propose that excess calorie intake by neonates leads to multiple causally linked perturbations in the intestine that imprint the individual with long-term susceptibility to IBD.


Assuntos
Colite/etiologia , Suscetibilidade a Doenças , Ingestão de Energia , Exposição Materna , Animais , Animais Recém-Nascidos , Feminino , Homeostase , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Gravidez
10.
Nat Metab ; 1(11): 1169, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32694867

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

11.
Proc Natl Acad Sci U S A ; 115(2): E283-E291, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29279402

RESUMO

Colonization by Streptococcus gallolyticus subsp. gallolyticus (SGG) is strongly associated with the occurrence of colorectal cancer (CRC). However, the factors leading to its successful colonization are unknown, and whether SGG influences the oncogenic process or benefits from the tumor-prone environment to prevail remains an open question. Here, we elucidate crucial steps that explain how CRC favors SGG colonization. By using mice genetically prone to CRC, we show that SGG colonization is 1,000-fold higher in tumor-bearing mice than in normal mice. This selective advantage occurs at the expense of resident intestinal enterococci. An SGG-specific locus encoding a bacteriocin ("gallocin") is shown to kill enterococci in vitro. Importantly, bile acids strongly enhance this bacteriocin activity in vivo, leading to greater SGG colonization. Constitutive activation of the Wnt pathway, one of the earliest signaling alterations in CRC, and the decreased expression of the bile acid apical transporter gene Slc10A2, as an effect of the Apc founding mutation, may thereby sustain intestinal colonization by SGG. We conclude that CRC-specific conditions promote SGG colonization of the gut by replacing commensal enterococci in their niche.


Assuntos
Neoplasias Colorretais/metabolismo , Trato Gastrointestinal/microbiologia , Streptococcus gallolyticus/fisiologia , Adenoma , Animais , Bacteriocinas/genética , Bacteriocinas/metabolismo , Ácidos e Sais Biliares/metabolismo , Regulação da Expressão Gênica , Humanos , Camundongos , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Simportadores/genética , Simportadores/metabolismo
12.
mBio ; 8(5)2017 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-29042502

RESUMO

We identified a crypt-specific core microbiota (CSCM) dominated by strictly aerobic, nonfermentative bacteria in murine cecal and proximal colonic (PC) crypts and hypothesized that, among its possible functions, it may affect epithelial regeneration. In the present work, we isolated representative CSCM strains using selective media based upon our initial 16S rRNA-based molecular identification (i.e., Acinetobacter, Delftia, and Stenotrophomonas). Their tropism for the crypt was confirmed, and their influence on epithelial regeneration was demonstrated in vivo by monocolonization of germfree mice. We also showed that lipopolysaccharide (LPS), through its endotoxin activity, was the dominant bacterial agonist controlling proliferation. The relevant molecular mechanisms were analyzed using colonic crypt-derived organoids exposed to bacterial sonicates or highly purified LPS as agonists. We identified a Toll-like receptor 4 (TLR4)-dependent program affecting crypts at different stages of epithelial differentiation. LPS played a dual role: it repressed cell proliferation through RIPK3-mediated necroptosis of stem cells and cells of the transit-amplifying compartment and concurrently enhanced cell differentiation, particularly the goblet cell lineage.IMPORTANCE The LPS from crypt-specific core microbiota controls intestinal epithelium proliferation through necroptosis of stem cells and enhances cell differentiation, mainly the goblet cell lineage.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/fisiologia , Bactérias Gram-Negativas/metabolismo , Mucosa Intestinal/microbiologia , Lipopolissacarídeos/metabolismo , Células-Tronco/fisiologia , Animais , Apoptose , Células Cultivadas , Colo/microbiologia , Células Epiteliais/efeitos dos fármacos , Microbioma Gastrointestinal , Camundongos , Células-Tronco/efeitos dos fármacos
13.
J Exp Med ; 214(5): 1249-1258, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28385925

RESUMO

Neutrophils have crucial antimicrobial functions but are also thought to contribute to tissue injury upon exposure to bacterial products, such as lipopolysaccharide (LPS). To study the role of neutrophils in LPS-induced endotoxemia, we developed a new mouse model, PMNDTR mice, in which injection of diphtheria toxin induces selective neutrophil ablation. Using this model, we found, surprisingly, that neutrophils serve to protect the host from LPS-induced lethal inflammation. This protective role was observed in conventional and germ-free animal facilities, indicating that it does not depend on a particular microbiological environment. Blockade or genetic deletion of myeloperoxidase (MPO), a key neutrophil enzyme, significantly increased mortality after LPS challenge, and adoptive transfer experiments confirmed that neutrophil-derived MPO contributes importantly to protection from endotoxemia. Our findings imply that, in addition to their well-established antimicrobial properties, neutrophils can contribute to optimal host protection by limiting the extent of endotoxin-induced inflammation in an MPO-dependent manner.


Assuntos
Endotoxemia/imunologia , Lipopolissacarídeos/toxicidade , Neutrófilos/fisiologia , Peroxidase/fisiologia , Animais , Anticorpos/imunologia , Modelos Animais de Doenças , Endotoxemia/mortalidade , Camundongos , Neutrófilos/enzimologia , Sepse/imunologia
14.
Science ; 350(6264): 1079-84, 2015 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-26541610

RESUMO

Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Bacteroides/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Microbioma Gastrointestinal/imunologia , Melanoma/terapia , Neoplasias Cutâneas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antibacterianos/farmacologia , Anticorpos Monoclonais/efeitos adversos , Antígeno CTLA-4/imunologia , Disbiose/imunologia , Transplante de Microbiota Fecal , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Vida Livre de Germes/imunologia , Humanos , Memória Imunológica , Imunoterapia , Intestinos/imunologia , Intestinos/microbiologia , Ipilimumab , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Linfócitos T/imunologia
15.
Science ; 342(6161): 971-6, 2013 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-24264990

RESUMO

Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate antitumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of "pathogenic" T helper 17 (pT(H)17) cells and memory T(H)1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram-positive bacteria showed a reduction in pT(H)17 responses, and their tumors were resistant to cyclophosphamide. Adoptive transfer of pT(H)17 cells partially restored the antitumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response.


Assuntos
Antineoplásicos/uso terapêutico , Translocação Bacteriana/efeitos dos fármacos , Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Intestino Delgado/microbiologia , Microbiota/fisiologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Transferência Adotiva , Animais , Antibacterianos/administração & dosagem , Vida Livre de Germes , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/fisiologia , Memória Imunológica , Tecido Linfoide/imunologia , Tecido Linfoide/microbiologia , Camundongos , Microbiota/efeitos dos fármacos , Células Th17/imunologia , Células Th17/transplante
16.
J Immunol ; 191(2): 583-93, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23776170

RESUMO

We have generated a panel of transgenic mice expressing HLA-A*01:03, -A*24:02, -B*08:01, -B*27:05, -B*35:01, -B*44:02, or -C*07:01 as chimeric monochain molecules (i.e., appropriate HLA α1α2 H chain domains fused with a mouse α3 domain and covalently linked to human ß2-microglobulin). Whereas surface expression of several transgenes was markedly reduced in recipient mice that coexpressed endogenous H-2 class I molecules, substantial surface expression of all human transgenes was observed in mice lacking H-2 class I molecules. In these HLA monochain transgenic/H-2 class I null mice, we observed a quantitative and qualitative restoration of the peripheral CD8(+) T cell repertoire, which exhibited a TCR diversity comparable with C57BL/6 WT mice. Potent epitope-specific, HLA-restricted, IFN-γ-producing CD8(+) T cell responses were generated against known reference T cell epitopes after either peptide or DNA immunization. HLA-wise, these new transgenic strains encompass a large proportion of individuals from all major human races and ethnicities. In combination with the previously created HLA-A*02:01 and -B*07:02 transgenic mice, the novel HLA transgenic mice described in this report should be a versatile preclinical animal model that will speed up the identification and optimization of HLA-restricted CD8(+) T cell epitopes of potential interest in various autoimmune human diseases and in preclinical evaluation of T cell-based vaccines.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Genes MHC Classe I , Animais , Epitopos de Linfócito T/imunologia , Feminino , Antígeno HLA-A1/biossíntese , Antígeno HLA-A1/genética , Antígeno HLA-A24/biossíntese , Antígeno HLA-A24/genética , Antígeno HLA-B27/biossíntese , Antígeno HLA-B27/genética , Antígeno HLA-B35/biossíntese , Antígeno HLA-B35/genética , Antígeno HLA-B44/biossíntese , Antígeno HLA-B44/genética , Antígeno HLA-B8/biossíntese , Antígeno HLA-B8/genética , Antígenos HLA-C/biossíntese , Antígenos HLA-C/genética , Humanos , Interferon gama/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Animais
17.
Nat Immunol ; 12(4): 320-6, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21336274

RESUMO

Lymphoid cells that express the nuclear hormone receptor RORγt are involved in containment of the large intestinal microbiota and defense against pathogens through the production of interleukin 17 (IL-17) and IL-22. They include adaptive IL-17-producing helper T cells (T(H)17 cells), as well as innate lymphoid cells (ILCs) such as lymphoid tissue-inducer (LTi) cells and IL-22-producing NKp46+ cells. Here we show that in contrast to T(H)17 cells, both types of RORγt+ ILCs constitutively produced most of the intestinal IL-22 and that the symbiotic microbiota repressed this function through epithelial expression of IL-25. This function was greater in the absence of adaptive immunity and was fully restored and required after epithelial damage, which demonstrates a central role for RORγt+ ILCs in intestinal homeostasis. Our data identify a finely tuned equilibrium among intestinal symbionts, adaptive immunity and RORγt+ ILCs.


Assuntos
Intestinos/imunologia , Tecido Linfoide/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Transdução de Sinais/imunologia , Imunidade Adaptativa/imunologia , Animais , Antígenos Ly/genética , Antígenos Ly/metabolismo , Feminino , Citometria de Fluxo , Homeostase/imunologia , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/microbiologia , Tecido Linfoide/citologia , Tecido Linfoide/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Simbiose/imunologia , Fatores de Tempo , Interleucina 22
18.
J Immunol ; 186(3): 1531-7, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21178008

RESUMO

Retinoic acid-related orphan receptor (ROR)γt(+) TCRαß(+) cells expressing IL-17, termed Th17 cells, are most abundant in the intestinal lamina propria. Symbiotic microbiota are required for the generation of Th17 cells, but the requirement for microbiota-derived Ag is not documented. In this study, we show that normal numbers of Th17 cells develop in the intestine of mice that express a single TCR in the absence of cognate Ag, whereas the microbiota remains essential for their development. However, such mice, or mice monocolonized with the Th17-inducing segmented filamentous bacteria, fail to induce normal numbers of Foxp3(+) RORγt(+) T cells, the regulatory counterpart of IL-17(+)RORγt(+) T cells. These results demonstrate that a complex microbiota and cognate Ag are required to generate a properly regulated set of RORγt(+) T cells and Th17 cells.


Assuntos
Proliferação de Células , Interleucina-17/biossíntese , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/deficiência , Receptores de Antígenos de Linfócitos T/deficiência , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/microbiologia , Sequência de Aminoácidos , Animais , Contagem de Linfócito CD4 , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Feminino , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/deficiência , Fatores de Transcrição Forkhead/genética , Vida Livre de Germes/genética , Vida Livre de Germes/imunologia , Infecções por Bactérias Gram-Positivas/imunologia , Infecções por Bactérias Gram-Positivas/patologia , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Interleucina-17/genética , Mucosa Intestinal/patologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Dados de Sequência Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/biossíntese , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T Auxiliares-Indutores/patologia
19.
Comp Med ; 59(2): 187-91, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19389312

RESUMO

We report here the characterization of an asymmetric ataxia syndrome (head tilt and circling, with death in the most severe cases) demonstrated by profoundly immunodeficient mice housed at the Institut Curie SPF facility. The immune system of the affected mice had been genetically modified so that they were deficient in both B and T cells. Extensive bacteriologic, parasitic, serologic, and histopathologic analysis of the affected animals and their healthy controls led us to identify Ralstonia pickettii as the causative agent of the ataxic syndrome. The outbreak was managed through a test-and-cull process. Even though they also carried Ralstonia pickettii, immunocompetent mice that were kept in the same facility, did not show any of the signs that were expressed by their immunodeficient counterparts. This case highlights the difficulty of maintaining immunocompetent and immunodeficient mice in the same microbiologic unit and the importance of enlarging the spectrum of health monitoring to opportunistic agents when investigating clinical cases in populations of immunocompromised rodents.


Assuntos
Ataxia/microbiologia , Infecções por Bactérias Gram-Negativas , Hospedeiro Imunocomprometido , Ralstonia pickettii , Animais , Ataxia/imunologia , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/patologia , Infecções por Bactérias Gram-Negativas/fisiopatologia , Síndromes de Imunodeficiência/imunologia , Camundongos , Ralstonia pickettii/imunologia , Ralstonia pickettii/patogenicidade
20.
Nature ; 456(7221): 507-10, 2008 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-18987631

RESUMO

Intestinal homeostasis is critical for efficient energy extraction from food and protection from pathogens. Its disruption can lead to an array of severe illnesses with major impacts on public health, such as inflammatory bowel disease characterized by self-destructive intestinal immunity. However, the mechanisms regulating the equilibrium between the large bacterial flora and the immune system remain unclear. Intestinal lymphoid tissues generate flora-reactive IgA-producing B cells, and include Peyer's patches and mesenteric lymph nodes, as well as numerous isolated lymphoid follicles (ILFs). Here we show that peptidoglycan from Gram-negative bacteria is necessary and sufficient to induce the genesis of ILFs in mice through recognition by the NOD1 (nucleotide-binding oligomerization domain containing 1) innate receptor in epithelial cells, and beta-defensin 3- and CCL20-mediated signalling through the chemokine receptor CCR6. Maturation of ILFs into large B-cell clusters requires subsequent detection of bacteria by toll-like receptors. In the absence of ILFs, the composition of the intestinal bacterial community is profoundly altered. Our results demonstrate that intestinal bacterial commensals and the immune system communicate through an innate detection system to generate adaptive lymphoid tissues and maintain intestinal homeostasis.


Assuntos
Bactérias Gram-Negativas/fisiologia , Homeostase , Intestinos/microbiologia , Intestinos/fisiologia , Tecido Linfoide/imunologia , Proteína Adaptadora de Sinalização NOD1/metabolismo , Animais , Quimiocina CCL20/metabolismo , Quimera , Feminino , Vida Livre de Germes , Bactérias Gram-Negativas/genética , Bactérias Gram-Negativas/imunologia , Bactérias Gram-Negativas/isolamento & purificação , Imunoglobulina A/imunologia , Intestinos/imunologia , Ligantes , Linfonodos/imunologia , Tecido Linfoide/citologia , Masculino , Camundongos , Proteína Adaptadora de Sinalização NOD1/deficiência , Proteína Adaptadora de Sinalização NOD1/genética , Proteína Adaptadora de Sinalização NOD1/imunologia , Peptidoglicano/imunologia , Nódulos Linfáticos Agregados/imunologia , Receptores CCR6/deficiência , Receptores CCR6/genética , Receptores CCR6/metabolismo , beta-Defensinas/metabolismo
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