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1.
Nat Immunol ; 22(11): 1382-1390, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34663978

RESUMO

Intergenerational inheritance of immune traits linked to epigenetic modifications has been demonstrated in plants and invertebrates. Here we provide evidence for transmission of trained immunity across generations to murine progeny that survived a sublethal systemic infection with Candida albicans or a zymosan challenge. The progeny of trained mice exhibited cellular, developmental, transcriptional and epigenetic changes associated with the bone marrow-resident myeloid effector and progenitor cell compartment. Moreover, the progeny of trained mice showed enhanced responsiveness to endotoxin challenge, alongside improved protection against systemic heterologous Escherichia coli and Listeria monocytogenes infections. Sperm DNA of parental male mice intravenously infected with the fungus C. albicans showed DNA methylation differences linked to immune gene loci. These results provide evidence for inheritance of trained immunity in mammals, enhancing protection against infections.


Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Infecções por Escherichia coli/imunologia , Escherichia coli/imunologia , Hereditariedade , Imunidade Inata/genética , Listeria monocytogenes/imunologia , Listeriose/imunologia , Células Mieloides/imunologia , Animais , Candida albicans/patogenicidade , Candidíase/genética , Candidíase/metabolismo , Candidíase/microbiologia , Células Cultivadas , Metilação de DNA , Modelos Animais de Doenças , Epigênese Genética , Escherichia coli/patogenicidade , Infecções por Escherichia coli/genética , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Interações Hospedeiro-Patógeno , Listeria monocytogenes/patogenicidade , Listeriose/genética , Listeriose/metabolismo , Listeriose/microbiologia , Masculino , Camundongos Transgênicos , Células Mieloides/metabolismo , Células Mieloides/microbiologia , Espermatozoides/imunologia , Espermatozoides/metabolismo , Transcrição Genética
2.
PLoS Pathog ; 17(9): e1009493, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34555127

RESUMO

Listeria monocytogenes is an intracellular bacterium that elicits robust CD8+ T-cell responses. Despite the ongoing development of L. monocytogenes-based platforms as cancer vaccines, our understanding of how L. monocytogenes drives robust CD8+ T-cell responses remains incomplete. One overarching hypothesis is that activation of cytosolic innate pathways is critical for immunity, as strains of L. monocytogenes that are unable to access the cytosol fail to elicit robust CD8+ T-cell responses and in fact inhibit optimal T-cell priming. Counterintuitively, however, activation of known cytosolic pathways, such as the inflammasome and type I IFN, lead to impaired immunity. Conversely, production of prostaglandin E2 (PGE2) downstream of cyclooxygenase-2 (COX-2) is essential for optimal L. monocytogenes T-cell priming. Here, we demonstrate that vacuole-constrained L. monocytogenes elicit reduced PGE2 production compared to wild-type strains in macrophages and dendritic cells ex vivo. In vivo, infection with wild-type L. monocytogenes leads to 10-fold increases in PGE2 production early during infection whereas vacuole-constrained strains fail to induce PGE2 over mock-immunized controls. Mice deficient in COX-2 specifically in Lyz2+ or CD11c+ cells produce less PGE2, suggesting these cell subsets contribute to PGE2 levels in vivo, while depletion of phagocytes with clodronate abolishes PGE2 production completely. Taken together, this work demonstrates that optimal PGE2 production by phagocytes depends on L. monocytogenes access to the cytosol, suggesting that one reason cytosolic access is required to prime CD8+ T-cell responses may be to facilitate production of PGE2.


Assuntos
Células Dendríticas/imunologia , Dinoprostona/biossíntese , Dinoprostona/imunologia , Listeriose/imunologia , Macrófagos/imunologia , Animais , Células Dendríticas/metabolismo , Células Dendríticas/microbiologia , Feminino , Listeria monocytogenes/imunologia , Ativação Linfocitária/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
3.
Nat Commun ; 12(1): 4999, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404769

RESUMO

The type I interferon (IFN) signaling pathway has important functions in resistance to viral infection, with the downstream induction of interferon stimulated genes (ISG) protecting the host from virus entry, replication and spread. Listeria monocytogenes (Lm), a facultative intracellular foodborne pathogen, can exploit the type I IFN response as part of their pathogenic strategy, but the molecular mechanisms involved remain unclear. Here we show that type I IFN suppresses the antibacterial activity of phagocytes to promote systemic Lm infection. Mechanistically, type I IFN suppresses phagosome maturation and proteolysis of Lm virulence factors ActA and LLO, thereby promoting phagosome escape and cell-to-cell spread; the antiviral protein, IFN-induced transmembrane protein 3 (IFITM3), is required for this type I IFN-mediated alteration. Ifitm3-/- mice are resistant to systemic infection by Lm, displaying decreased bacterial spread in tissues, and increased immune cell recruitment and pro-inflammatory cytokine signaling. Together, our findings show how an antiviral mechanism in phagocytes can be exploited by bacterial pathogens, and implicate IFITM3 as a potential antimicrobial therapeutic target.


Assuntos
Antibacterianos/farmacologia , Listeria/efeitos dos fármacos , Listeriose/imunologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Fagócitos/imunologia , Fagócitos/microbiologia , Animais , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Interferon Tipo I/metabolismo , Listeria monocytogenes/imunologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagossomos/imunologia , Células RAW 264.7 , Transcriptoma , Fatores de Virulência , Internalização do Vírus/efeitos dos fármacos
4.
PLoS Pathog ; 17(7): e1009697, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34237114

RESUMO

Listeria monocytogenes (L. monocytogenes) is a food-borne bacterial pathogen. Innate immunity to L. monocytogenes is profoundly affected by type I interferons (IFN-I). Here we investigated host metabolism in L. monocytogenes-infected mice and its potential control by IFN-I. Accordingly, we used animals lacking either the IFN-I receptor (IFNAR) or IRF9, a subunit of ISGF3, the master regulator of IFN-I-induced genes. Transcriptomes and metabolite profiles showed that L. monocytogenes infection induces metabolic rewiring of the liver. This affects various metabolic pathways including fatty acid (FA) metabolism and oxidative phosphorylation and is partially dependent on IFN-I signaling. Livers and macrophages from Ifnar1-/- mice employ increased glutaminolysis in an IRF9-independent manner, possibly to readjust TCA metabolite levels due to reduced FA oxidation. Moreover, FA oxidation inhibition provides protection from L. monocytogenes infection, explaining part of the protection of Irf9-/- and Ifnar1-/- mice. Our findings define a role of IFN-I in metabolic regulation during L. monocytogenes infection. Metabolic differences between Irf9-/- and Ifnar1-/- mice may underlie the different susceptibility of these mice against lethal infection with L. monocytogenes.


Assuntos
Interferon Tipo I/metabolismo , Listeria monocytogenes/metabolismo , Listeriose/metabolismo , Fígado/metabolismo , Animais , Ácidos Graxos/metabolismo , Interferon Tipo I/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Fígado/imunologia , Camundongos , Camundongos Endogâmicos C57BL
5.
Front Immunol ; 12: 667664, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34135896

RESUMO

The yellow mealworm beetle (Tenebrio molitor) has been exploited as an experimental model to unravel the intricacies of cellular and humoral immunity against pathogenic infections. Studies on this insect model have provided valuable insights into the phenotypic plasticity of immune defenses against parasites and pathogens. It has thus been possible to characterize the hemocoelic defenses of T. molitor that rely on the recognition of non-self-components of pathogens by pattern recognition receptors (PRRs). The subsequent signaling cascade activating pathways such as the NF-κB controlled by Toll and IMD pathways lead to the synthesis of antimicrobial peptides (AMPs), onset of hemocyte-driven phagocytosis, and activation of the prophenoloxidase cascade regulating the process of melanization. Nevertheless, the activation of autophagy-mediated defenses of T. molitor against the facultative intracellular gram-positive bacterium Listeria monocytogenes provides clear evidence of the existence of a cross-talk between autophagy and the IMD pathway. Moreover, the identification of several autophagy-related genes (Atgs) in T. molitor transcriptome and expressed sequence tag (EST) databases has contributed to the understanding of the autophagy-signaling cascade triggered by L. monocytogenes challenge. Providing further evidence of the cross-talk hypothesis, TmRelish has been shown to be required not only for regulating the synthesis of AMPs through the PGRP-LE/IMD pathway activation but also for the expression of Atgs in T. molitor larvae following L. monocytogenes challenge. Notably, L. monocytogenes can stimulate the T. molitor innate immune system by producing molecules recognized by the multifunctional PRR (TmPGRP-LE), which stimulates intracellular activation of the IMD pathway and autophagy. Considering the conservation of autophagy components involved in combating intracellular pathogens, it will be interesting to extrapolate a dynamic cross-talk model of immune activation. This review summarizes the most significant findings on the regulation of autophagy in T. molitor during L. monocytogenes infection and on the role of the innate immunity machinery, including the NF-κB pathway, in the control of pathogenic load.


Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Imunidade Inata , Proteínas de Insetos/metabolismo , Listeria monocytogenes/patogenicidade , Listeriose/microbiologia , Macroautofagia , Tenebrio/microbiologia , Animais , Proteínas Relacionadas à Autofagia/genética , Carga Bacteriana , Interações Hospedeiro-Patógeno , Proteínas de Insetos/genética , Listeria monocytogenes/imunologia , Listeriose/genética , Listeriose/imunologia , Listeriose/metabolismo , Transdução de Sinais , Tenebrio/genética , Tenebrio/imunologia , Tenebrio/metabolismo
6.
J Microbiol ; 59(8): 771-781, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34061343

RESUMO

Listeria monocytogenes is a food-borne pathogen responsible for neurolisteriosis, which is potentially lethal in immunocompromised individuals. Microglia are the main target cells for L. monocytogenes in central nervous system (CNS). However, the precise mechanisms by which they trigger neuroinflammatory processes remain unknown. The BV2 microglial cell line and a murine model of L. monocytogenes infection were used for experiments in this study. Listeria monocytogenes induced pyroptosis and nucleotide binding and oligomerization, leucine-rich repeat, pyrin domain-containing 3 (NLRP3) inflammasome activation in BV2. Pharmacological inhibition of the NLRP3 inflammasome attenuated L. monocytogenes-induced pyroptosis. Moreover, inhibition of nuclear factor kappa-B (NF-κB) and extracellular regulated protein kinases (ERK) pathways induced a decrease in caspase1 activation and mature IL-1ß-17 secretion. Our collective findings support critical involvement of the NLRP3 inflammasome in L. monocytogenes-induced neuroinflammation and, to an extent, ROS production. In addition, ERK and NF-κB signaling play an important role in activation of the NLRP3 inflammasome, both in vitro and in vivo.


Assuntos
Inflamassomos/imunologia , Listeria monocytogenes/fisiologia , Listeriose/imunologia , Microglia/microbiologia , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Espécies Reativas de Oxigênio/imunologia , Animais , Humanos , Inflamassomos/genética , Listeria monocytogenes/genética , Listeriose/genética , Listeriose/microbiologia , Listeriose/fisiopatologia , Sistema de Sinalização das MAP Quinases , Camundongos , Microglia/citologia , Microglia/imunologia , NF-kappa B/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Piroptose , Transdução de Sinais
7.
Cell Physiol Biochem ; 55(3): 256-264, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-33984198

RESUMO

BACKGROUND/AIMS: During an immune response, type I interferon (IFN-I) signaling induces a wide range of changes, including those which are required to overcome viral infection and those which suppress cytotoxic T cells to avoid immunopathology. During certain bacterial infections, IFN-I signaling exerts largely detrimental effects. Although the IFN-I family of proteins all share one common receptor, biologic responses to signaling vary depending on IFN-I subtype. Here, we asked if one IFN-I subtype dominates the pro-bacterial effect of IFN-I signaling and found that control of Listeria monocytogenes (L.m.) infection is more strongly suppressed by IFN-ß than IFN-α. METHODS: To study this, we measured bacterial titers in IFNAR-/-, IFN-ß­/­, Stat2-/-, Usp18fl/fl and Usp18fl/fl x CD11c-Cre mice models in addition to IFN-I blocking antibodies. Moreover, we measured interferon stimulated genes in bone marrow derived dendritic cells after treatment with IFN-α4 and IFN-ß. RESULTS: Specifically, we show that genetic deletion of IFN-ß or antibody-mediated IFN-ß neutralization was sufficient to reduce bacterial titers to levels similar to those observed in mice that completely lack IFN-I signaling (IFNAR-/- mice). However, IFN-α blockade failed to significantly reduce L.m. titers, suggesting that IFN-ß is the dominant IFN-I subtype responsible for the pro-bacterial effect of IFN-I. Mechanistically, when focusing on IFN-I signals to dendritic cells, we found that IFN-ß induces ISGs more robustly than IFN-α, including USP18, the protein we previously identified as driving the pro-bacterial effects of IFN-I. Further, we found that this induction was STAT1/STAT2 heterodimer- or STAT2/STAT2 homodimer-dependent, as STAT2-deficient mice were more resistant to L.m. infection. CONCLUSION: In conclusion, IFN-Β is the principal member of the IFN-I family responsible for driving the pro-bacterial effect of IFN-I.


Assuntos
Interferon-alfa/imunologia , Interferon beta/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Animais , Feminino , Interferon-alfa/genética , Interferon beta/genética , Listeriose/genética , Masculino , Camundongos , Camundongos Knockout , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/imunologia
8.
Nat Immunol ; 22(6): 699-710, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34040226

RESUMO

It is increasingly recognized that immune development within mucosal tissues is under the control of environmental factors during early life. However, the cellular mechanisms that underlie such temporally and regionally restrictive governance of these processes are unclear. Here, we uncover an extrathymic pathway of immune development within the colon that is controlled by embryonic but not bone marrow-derived macrophages, which determines the ability of these organs to receive invariant natural killer T (iNKT) cells and allow them to establish local residency. Consequently, early-life perturbations of fetal-derived macrophages result in persistent decreases of mucosal iNKT cells and is associated with later-life susceptibility or resistance to iNKT cell-associated mucosal disorders. These studies uncover a host developmental program orchestrated by ontogenically distinct macrophages that is regulated by microbiota, and they reveal an important postnatal function of macrophages that emerge in fetal life.


Assuntos
Colite/imunologia , Mucosa Intestinal/imunologia , Listeriose/imunologia , Macrófagos/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Animais , Proliferação de Células/genética , Colite/microbiologia , Colite/patologia , Colo/citologia , Colo/embriologia , Colo/imunologia , Colo/patologia , Citocinas/metabolismo , Toxina Diftérica/administração & dosagem , Toxina Diftérica/imunologia , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Microbioma Gastrointestinal/imunologia , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Vida Livre de Germes , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/embriologia , Mucosa Intestinal/patologia , Listeriose/microbiologia , Listeriose/patologia , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , RNA-Seq , Transdução de Sinais/genética , Transdução de Sinais/imunologia
9.
PLoS Pathog ; 17(4): e1009531, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33878120

RESUMO

Most individuals who consume foods contaminated with the bacterial pathogen Listeria monocytogenes (Lm) develop mild symptoms, while others are susceptible to life-threatening systemic infections (listeriosis). Although it is known that the risk of severe disease is increased in certain human populations, including the elderly, it remains unclear why others who consume contaminated food develop listeriosis. Here, we used a murine model to discover that pulmonary coinfections can impair the host's ability to adequately control and eradicate systemic Lm that cross from the intestines to the bloodstream. We found that the resistance of mice to oral Lm infection was dramatically reduced by coinfection with Streptococcus pneumoniae (Spn), a bacterium that colonizes the respiratory tract and can also cause severe infections in the elderly. Exposure to Spn or microbial products, including a recombinant Lm protein (L1S) and lipopolysaccharide (LPS), rendered otherwise resistant hosts susceptible to severe systemic Lm infection. In addition, we show that this increase in susceptibility was dependent on an increase in the production of interleukin-10 (IL-10) from Ncr1+ cells, including natural killer (NK) cells. Lastly, the ability of Ncr1+ cell derived IL-10 to increase disease susceptibility correlated with a dampening of both myeloid cell accumulation and myeloid cell phagocytic capacity in infected tissues. These data suggest that efforts to minimize inflammation in response to an insult at the respiratory mucosa render the host more susceptible to infections by Lm and possibly other pathogens that access the oral mucosa.


Assuntos
Listeria monocytogenes/imunologia , Listeriose/imunologia , Pneumonia/imunologia , Animais , Progressão da Doença , Suscetibilidade a Doenças , Feminino , Interleucina-10/metabolismo , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/fisiologia , Lipopolissacarídeos , Listeria monocytogenes/patogenicidade , Listeriose/complicações , Listeriose/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doenças da Boca/complicações , Doenças da Boca/imunologia , Doenças da Boca/microbiologia , Doenças da Boca/patologia , Pneumonia/complicações , Pneumonia/etiologia , Pneumonia/patologia
10.
Genes (Basel) ; 12(3)2021 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805671

RESUMO

Listeriosis is a food-borne illness caused by Listeria monocytogenes. Ampicillin (AMP) alone or in combination with gentamicin (GEN) is the first-line treatment option. Membrane vesicle (MV) production in L. monocytogenes under antibiotic stress conditions and pathologic roles of these MVs in hosts have not been reported yet. Thus, the aim of this study was to investigate the production of MVs in L. monocytogenes cultured with sub-minimum inhibitory concentrations (MICs) of AMP, GEN, or trimethoprim/sulfamethoxazole (SXT) and determine pathologic effects of these MVs in colon epithelial Caco-2 cells. L. monocytogenes cultured in tryptic soy broth with 1/2 MIC of AMP, GEN, or SXT produced 6.0, 2.9, or 1.5 times more MV particles, respectively, than bacteria cultured without antibiotics. MVs from L. monocytogenes cultured with AMP (MVAMP), GEN (MVGEN), or SXT (MVSXT) were more cytotoxic to Caco-2 cell than MVs obtained from cultivation without antibiotics (MVTSB). MVAMP induced more expression of tumor necrosis factor (TNF)-α gene than MVTSB, MVGEN and MVSXT, whereas MVTSB induced more expression of interleukin (IL)-1ß and IL-8 genes than other MVs. Expression of pro-inflammatory cytokine genes by L. monocytogenes MVs was significantly inhibited by proteinase K treatment of MVs. In conclusion, antibiotic stress can trigger the biogenesis of MVs in L. monocytogenes and MVs produced by L. monocytogenes exposed to sub-MIC of AMP can induce strong pro-inflammatory responses by expressing TNF-α gene in host cells, which may contribute to the pathology of listeriosis.


Assuntos
Antibacterianos/farmacologia , Imunidade Inata/efeitos dos fármacos , Listeria monocytogenes/efeitos dos fármacos , Listeria monocytogenes/imunologia , Proteínas de Bactérias/imunologia , Células CACO-2 , Linhagem Celular Tumoral , Citocinas/imunologia , Humanos , Listeriose/tratamento farmacológico , Listeriose/imunologia , Testes de Sensibilidade Microbiana/métodos , Fatores de Virulência/imunologia
11.
Infect Immun ; 89(7): e0076820, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-33782151

RESUMO

The development of T cell-based subunit protein vaccines against diseases such as tuberculosis and malaria remains a challenge for immunologists. Here, we have identified a nanoemulsion adjuvant, Adjuplex (ADJ), which enhanced dendritic cell (DC) cross-presentation and elicited effective memory T cell-based immunity to Listeria monocytogenes. We further evaluated whether cross-presentation induced by ADJ can be combined with the immunomodulatory effects of Toll-like receptor (TLR) agonists (CpG or glucopyranosyl lipid adjuvant [GLA]) to evoke systemic CD8 T cell-based immunity to L. monocytogenes. Mechanistically, vaccination with ADJ, alone or in combination with CpG or GLA, augmented activation and antigen uptake by CD103+ migratory and CD8α+ resident DCs and upregulated CD69 expression on B and T lymphocytes in vaccine-draining lymph nodes. By engaging basic leucine zipper ATF-like transcription factor 3-dependent cross-presenting DCs, ADJ potently elicited effector CD8 T cells that differentiated into granzyme B-expressing CD27LO effector-like memory CD8 T cells, which provided effective immunity to L. monocytogenes in the spleen and liver. CpG or GLA alone did not elicit effector-like memory CD8 T cells and induced moderate protection in the spleen but not in the liver. Surprisingly, combining CpG or GLA with ADJ reduced the number of ADJ-induced memory CD8 T cells and compromised protective immunity to L. monocytogenes, especially in the liver. Taken together, the data presented in this study provide a glimpse of protective CD8 T cell memory differentiation induced by a nanoemulsion adjuvant and demonstrate the unexpected negative effects of TLR signaling on the magnitude of CD8 T cell memory and protective immunity to L. monocytogenes, a model intracellular pathogen.


Assuntos
Adjuvantes Imunológicos , Linfócitos T CD8-Positivos/imunologia , Interações Hospedeiro-Patógeno/imunologia , Memória Imunológica , Listeria/imunologia , Listeriose/imunologia , Listeriose/microbiologia , Biomarcadores , Linfócitos T CD8-Positivos/metabolismo , Células Dendríticas/imunologia , Imunomodulação , Imunofenotipagem , Listeriose/metabolismo , Transdução de Sinais
12.
Immunity ; 54(4): 829-844.e5, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33705706

RESUMO

Memory T cells are thought to rely on oxidative phosphorylation and short-lived effector T cells on glycolysis. Here, we investigated how T cells arrive at these states during an immune response. To understand the metabolic state of rare, early-activated T cells, we adapted mass cytometry to quantify metabolic regulators at single-cell resolution in parallel with cell signaling, proliferation, and effector function. We interrogated CD8+ T cell activation in vitro and in response to Listeria monocytogenes infection in vivo. This approach revealed a distinct metabolic state in early-activated T cells characterized by maximal expression of glycolytic and oxidative metabolic proteins. Cells in this transient state were most abundant 5 days post-infection before rapidly decreasing metabolic protein expression. Analogous findings were observed in chimeric antigen receptor (CAR) T cells interrogated longitudinally in advanced lymphoma patients. Our study demonstrates the utility of single-cell metabolic analysis by mass cytometry to identify metabolic adaptations of immune cell populations in vivo and provides a resource for investigations of metabolic regulation of immune responses across a variety of applications.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária/imunologia , Transdução de Sinais/imunologia , Animais , Proliferação de Células/fisiologia , Feminino , Glicólise/imunologia , Memória Imunológica/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Listeriose/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação Oxidativa , Receptores de Antígenos Quiméricos/imunologia , Análise de Célula Única/métodos
13.
Dev Cell ; 56(4): 443-460.e11, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33621492

RESUMO

Intracellular pathogens alter their host cells' mechanics to promote dissemination through tissues. Conversely, host cells may respond to the presence of pathogens by altering their mechanics to limit infection. Here, we monitored epithelial cell monolayers infected with intracellular bacterial pathogens, Listeria monocytogenes or Rickettsia parkeri, over days. Under conditions in which these pathogens trigger innate immune signaling through NF-κB and use actin-based motility to spread non-lytically intercellularly, we found that infected cell domains formed three-dimensional mounds. These mounds resulted from uninfected cells moving toward the infection site, collectively squeezing the softer and less contractile infected cells upward and ejecting them from the monolayer. Bacteria in mounds were less able to spread laterally in the monolayer, limiting the growth of the infection focus, while extruded infected cells underwent cell death. Thus, the coordinated forceful action of uninfected cells actively eliminates large domains of infected cells, consistent with this collective cell response representing an innate immunity-driven process.


Assuntos
Competição entre as Células , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Imunidade Inata , Listeria monocytogenes/fisiologia , Listeriose/imunologia , Listeriose/microbiologia , Transdução de Sinais , Actomiosina/metabolismo , Animais , Apoptose , Fenômenos Biomecânicos , Adesão Celular , Linhagem Celular , Simulação por Computador , Cães , Interações Hospedeiro-Patógeno , Humanos , Junções Intercelulares/metabolismo , Terapia a Laser , Listeriose/genética , Células Madin Darby de Rim Canino , NF-kappa B/metabolismo , Imagem com Lapso de Tempo , Transcrição Genética
14.
Toxicol Appl Pharmacol ; 415: 115441, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33556388

RESUMO

The immunotoxicity of zearalenone (ZEA) and deoxynivalenol (DON), two of the most common environmental mycotoxins, has been well investigated. However, due to the complexity of the immune system, especially during bacterial infection, many types of immune cells are involved in invasion resistance and bacterial clearance. Of these, T helper 2 (Th2) cells, which are members of the helper T cell family, assist B cells to activate and differentiate into antibody-secreting cells, participate in humoral immune response, and, ultimately, eliminate pathogens. Thus, it is important to identify the stage at which these toxins affect the immune function, and to clarity the underlying mechanisms. In this study, mice infected with Listeria monocytogenes (Listeria) were used to study the effects of ZEA, DON, and ZEA + DON on Th2 differentiation, Interleukin-4 Receptor (IL-4R) expression, costimulatory molecules expression and cytokine secretion after Listeria infection. Naive CD4+ T cells, isolated from mice, were used to verify the in vivo effects and the associated mechanisms. In vivo experiments showed that these toxins aggravated spleen damage after Listeria infection and reduced the differentiation of Th2 cells by affecting the synthesis of IL-4R of CD4+ T cells. In addition, the level of the costimulatory molecule CD154 decreased. Consistent with this, in vitro studies showed that these toxins inhibited the differentiation of mouse naive CD4+ T cell into Th2 subtype and decreased IL-4R levels. In addition, the levels of costimulatory molecules CD154, CD278 and the Th2 cells secrete cytokines IL-4, IL-6, and IL-10 decreased. Based on our in vivo and in vitro experiments, we suggest that ZEA, DON, and ZEA + DON inhibit the expression of costimulatory molecules on CD4+ T cell, and inhibit the IL-4R-mediated Th2 cell differentiation. This may indicate that the body cannot normally resist or clear the pathogen after mycotoxin poisoning.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Listeria monocytogenes/patogenicidade , Listeriose/induzido quimicamente , Ativação Linfocitária/efeitos dos fármacos , Receptores de Interleucina-4/metabolismo , Baço/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Tricotecenos/toxicidade , Zearalenona/toxicidade , Animais , Ligante de CD40/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Patógeno , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Listeria monocytogenes/imunologia , Listeriose/imunologia , Listeriose/metabolismo , Listeriose/microbiologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Baço/microbiologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/microbiologia
15.
Ecotoxicol Environ Saf ; 213: 112065, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33636464

RESUMO

Listeria monocytogenes widely exists in the natural environment and does great harm, which can cause worldwide public safety problem. Infection with L. monocytogenes can cause rapid death of Kupffer cell (KCs) in liver tissue and liver damage. American ginseng saponins is a natural compound in plants, which has great potential in inhibiting L. monocytogenes infection. Therefore, American ginseng stem-leaf saponins (AGS) and American ginseng heat-transformed saponins (HTS) were used as raw materials to study their bacteriostatic experiments in vivo and in vitro. In this experiment, female Kunming mice were randomly divided into five groups: control group, negative group, AGS group, HTS group (10 mg/kg/day in an equal volume via gastric administration) and penicillin group, each group containing six mice. Profiles AGS and HTS components were evaluated by high-performance liquid chromatography (HPLC) analysis. The bacteriostatic effect of AGS and HTS on L. monocytogenes was evaluated by inhibition zone test, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The bacteriostatic effect of AGS and HTS pretreatment on mice infected with L. monocytogenes were studies by animal experimental. The results showed that the content of polar saponins in AGS was 0.81 ± 0.003 mg/mg, less polar saponins was 0.08 ± 0.02 mg/mg, the content of polar saponins in HTS was 0.10 ± 0.01 mg/mg, less polar saponins was 0.76 ± 0.02 mg/mg. The in vitro bacteriostatic diameter of HTS (16.6 ± 0.8 mm) is large than that of AGS (10.2 ± 1.2 mm). AGS and HTS pretreatment could reduce the colony numbers in the livers of mice infected with Listeria monocytogenes. The levels of alanine aminotransferase (ALT), IL-1ß, IL-6, TNF-α and IFN-γ in the livers of mice in the pretreatment group were significantly lower than those in the negative group. There were obvious leukoplakia, calcification and other liver damage on the liver surface in the negative control group, and obvious inflammatory cell infiltration in HE sections. AGS and HTS pretreatment can reduce liver injury caused by L. monocytogenes and protect the liver. Compared with AGS, HTS has higher content of less polar saponins and better bacteriostatic effect in vitro. The count of bacterial in liver tissue of HTS group was significantly lower, the survival rate was significantly higher than that of AGS group. Less polar saponins had better bacteriostatic effect. Collectively, less polar saponins pretreatment has a protective effect on mice infected with L. monocytogenes, to which alleviated liver damage, improved anti-inflammatory ability and immunity of the body, protected liver may contribute.


Assuntos
Ginsenosídeos/toxicidade , Listeria monocytogenes/efeitos dos fármacos , Animais , Feminino , Listeriose/imunologia , Listeriose/metabolismo , Listeriose/microbiologia , Listeriose/veterinária , Fígado/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Estômago , Fator de Necrose Tumoral alfa
16.
Int J Biol Macromol ; 176: 567-577, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33581203

RESUMO

Listeria monocytogenes is a cause of infectious food-borne disease in humans, characterized by neurological manifestations, abortion, and neonatal septicemia. It is intracellular bacterium, which limits the development of protective inactivated vacines. Adjuvants capable of stimulating cellular immune response are important tools for developing novel vaccines against intracellular bacteria. The aim of this study was to evaluate the vaccine potential of L. monocytogenes inactivated by gamma irradiation (KLM-γ) encapsulated in alginate microcapsules associated or not with chitosan against listeriosis in the murine model. At the fourth day after challenge there was a reduction in bacterial recovery in mice vaccinated with KLM-γ encapsulated with alginate or alginate-chitosan, with lower bacterial loads in the spleen (10 fold) and liver (100 fold) when compared to non-vaccinated mice. In vitro stimulation of splenocytes from mice vaccinated with alginate-chitosan-encapsulated KLM-γ resulted in lymphocyte proliferation, increase of proportion of memory CD4+ and CD8+ T cell and production of IL-10 and IFN-γ. Interestingly, the group vaccinated with alginate-chitosan-encapsulated KLM-γ had increased survival to lethal infection with lower L. monocytogenes-induced hepatic inflammation and necrosis. Therefore, KLM-γ encapsulation with alginate-chitosan proved to have potential for development of novel and safe inactivated vaccine formulations against listeriosis.


Assuntos
Alginatos , Vacinas Bacterianas , Quitosana , Raios gama , Listeria monocytogenes , Listeriose , Alginatos/química , Alginatos/farmacologia , Animais , Vacinas Bacterianas/química , Vacinas Bacterianas/imunologia , Vacinas Bacterianas/farmacologia , Quitosana/química , Quitosana/farmacologia , Modelos Animais de Doenças , Feminino , Listeria monocytogenes/química , Listeria monocytogenes/imunologia , Listeriose/imunologia , Listeriose/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Vacinas de Produtos Inativados/química , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/farmacologia
17.
Science ; 371(6527): 405-410, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33479154

RESUMO

Infection triggers expansion and effector differentiation of T cells specific for microbial antigens in association with metabolic reprograming. We found that the glycolytic enzyme lactate dehydrogenase A (LDHA) is induced in CD8+ T effector cells through phosphoinositide 3-kinase (PI3K) signaling. In turn, ablation of LDHA inhibits PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1, causing defective antimicrobial immunity. LDHA deficiency cripples cellular redox control and diminishes adenosine triphosphate (ATP) production in effector T cells, resulting in attenuated PI3K signaling. Thus, nutrient metabolism and growth factor signaling are highly integrated processes, with glycolytic ATP serving as a rheostat to gauge PI3K-Akt-Foxo1 signaling in the control of T cell immunity. Such a bioenergetic mechanism for the regulation of signaling may explain the Warburg effect.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Glicólise , Lactato Desidrogenase 5/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Animais , Linfócitos T CD8-Positivos/enzimologia , Proteína Forkhead Box O1/metabolismo , Humanos , Lactato Desidrogenase 5/genética , Listeria monocytogenes , Listeriose/enzimologia , Listeriose/imunologia , Camundongos , Camundongos Mutantes , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Efeito Warburg em Oncologia
18.
Foodborne Pathog Dis ; 18(4): 267-275, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33493413

RESUMO

Consumption of raw food, especially smoked fish, meat, soft cheeses, and vegetables, contaminated with Listeria monocytogenes can cause listeriosis, which can be invasive in pregnant women, elderly, and immunocompromised and diabetic patients. Through June to November of 2017, 11 patients developed invasive listeriosis in a small area of northern Italy. In the same period, 15 food samples (ready-to-eat seafood, raw vegetables, cheese samples, and salami) collected during the routine screening programs in the same area were found to be contaminated with L. monocytogenes. We characterized the isolates to determine the relatedness of L. monocytogenes strains isolated from patients and isolates from food samples and food-processing plants. Whole genome sequencing analysis showed that multiple L. monocytogenes strains were circulating in the area and no association was found between clinical and food isolates.


Assuntos
Manipulação de Alimentos/estatística & dados numéricos , Microbiologia de Alimentos/estatística & dados numéricos , Listeria monocytogenes/isolamento & purificação , Listeriose/epidemiologia , Adulto , Idoso , Queijo/microbiologia , Feminino , Humanos , Hospedeiro Imunocomprometido/imunologia , Itália/epidemiologia , Listeria monocytogenes/genética , Listeria monocytogenes/imunologia , Listeriose/imunologia , Masculino , Carne/microbiologia , Pessoa de Meia-Idade , Alimentos Marinhos/microbiologia , Verduras/microbiologia , Sequenciamento Completo do Genoma
19.
J Immunol ; 206(2): 323-328, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33288542

RESUMO

The NOX2 NADPH oxidase (NOX2) produces reactive oxygen species to kill phagosome-confined bacteria. However, we previously showed that Listeria monocytogenes is able to avoid the NOX2 activity in phagosomes and escape to the cytosol. Thus, despite the established role of NOX2 limiting L. monocytogenes infection in mice, the underlying mechanisms of this antibacterial activity remain unclear. In this article, we report that NOX2 controls systemic L. monocytogenes spread through modulation of the type I IFN response, which is known to be exploited by L. monocytogenes during infection. NOX2 deficiency results in increased expression of IFN-stimulated genes in response to type I IFN and leads to 1) promotion of cell-to-cell spread by L. monocytogenes, 2) defective leukocyte recruitment to infection foci, and 3) production of anti-inflammatory effectors IL-10 and thioredoxin 1. Our findings report a novel antimicrobial role for NOX2 through modulation of type I IFN responses to control bacterial dissemination.


Assuntos
Inflamação/imunologia , Interferon Tipo I/metabolismo , Leucócitos/imunologia , Listeria monocytogenes/fisiologia , Listeriose/imunologia , Macrófagos/metabolismo , NADPH Oxidase 2/metabolismo , Animais , Movimento Celular , Células Cultivadas , Interleucina-10/metabolismo , Listeriose/transmissão , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2/genética , Tiorredoxinas
20.
Curr Opin Microbiol ; 59: 95-101, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33307408

RESUMO

Listeria monocytogenes (Lm) is a foodborne bacterial pathogen that causes listeriosis, a severe infection that manifests as bacteremia and meningo-encephalitis mostly in immunocompromised individuals, and maternal-fetal infection. A critical pathogenic determinant of Lm relies on its ability to actively cross the intestinal barrier, disseminate systemically and cross the blood-brain and placental barriers. Here we illustrate how Lm both evades innate immunity, favoring its dissemination in host tissues, and triggers innate immune defenses that participate to its control.


Assuntos
Interações Hospedeiro-Patógeno , Imunidade Inata , Listeria monocytogenes , Listeriose , Barreira Hematoencefálica/microbiologia , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Listeriose/imunologia , Placenta/microbiologia , Gravidez
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