RESUMO
Phenotypic and transcriptional profiling of regulatory T (Treg) cells at homeostasis reveals that T cell receptor activation promotes Treg cells with an effector phenotype (eTreg) characterized by the production of interleukin-10 and expression of the inhibitory receptor PD-1. At homeostasis, blockade of the PD-1 pathway results in enhanced eTreg cell activity, whereas during infection with Toxoplasma gondii, early interferon-γ upregulates myeloid cell expression of PD-L1 associated with reduced Treg cell populations. In infected mice, blockade of PD-L1, complete deletion of PD-1 or lineage-specific deletion of PD-1 in Treg cells prevents loss of eTreg cells. These interventions resulted in a reduced ratio of pathogen-specific effector T cells: eTreg cells and increased levels of interleukin-10 that mitigated the development of immunopathology, but which could compromise parasite control. Thus, eTreg cell expression of PD-1 acts as a sensor to rapidly tune the pool of eTreg cells at homeostasis and during inflammatory processes.
Assuntos
Antígeno B7-H1 , Receptor de Morte Celular Programada 1 , Linfócitos T Reguladores , Toxoplasmose Animal , Animais , Antígeno B7-H1/imunologia , Homeostase , Interleucina-10/imunologia , Camundongos , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/imunologia , Toxoplasma/imunologia , Toxoplasmose Animal/imunologiaRESUMO
Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.
Assuntos
Fator de Ligação a CCCTC , Diferenciação Celular , Interferon gama , Interleucina 22 , Interleucinas , Células Th1 , Animais , Fator de Ligação a CCCTC/metabolismo , Fator de Ligação a CCCTC/genética , Células Th1/imunologia , Camundongos , Diferenciação Celular/imunologia , Interferon gama/metabolismo , Sítios de Ligação , Interleucinas/metabolismo , Interleucinas/genética , Elementos Facilitadores Genéticos/genética , Camundongos Endogâmicos C57BL , Cromatina/metabolismo , Toxoplasmose/imunologia , Toxoplasmose/parasitologia , Toxoplasmose/genética , Regulação da Expressão Gênica , Toxoplasma/imunologia , Citocinas/metabolismo , Linhagem da Célula , Células Th17/imunologiaRESUMO
Mammalian autophagy-related 8 (Atg8) homologs consist of LC3 proteins and GABARAPs, all of which are known to be involved in canonical autophagy. In contrast, the roles of Atg8 homologs in noncanonical autophagic processes are not fully understood. Here we show a unique role of GABARAPs, in particular gamma-aminobutyric acid (GABA)-A-receptor-associated protein-like 2 (Gabarapl2; also known as Gate-16), in interferon-γ (IFN-γ)-mediated antimicrobial responses. Cells that lacked GABARAPs but not LC3 proteins and mice that lacked Gate-16 alone were defective in the IFN-γ-induced clearance of vacuolar pathogens such as Toxoplasma. Gate-16 but not LC3b specifically associated with the small GTPase ADP-ribosylation factor 1 (Arf1) to mediate uniform distribution of interferon-inducible GTPases. The lack of GABARAPs reduced Arf1 activation, which led to formation of interferon-inducible GTPase-containing aggregates and hampered recruitment of interferon-inducible GTPases to vacuolar pathogens. Thus, GABARAPs are uniquely required for antimicrobial host defense through cytosolic distribution of interferon-inducible GTPases.
Assuntos
Fator 1 de Ribosilação do ADP/imunologia , Autofagia/imunologia , Proteínas de Transporte/imunologia , Interferon gama/imunologia , Proteínas Associadas aos Microtúbulos/imunologia , Toxoplasma/imunologia , Toxoplasmose/imunologia , Fator 1 de Ribosilação do ADP/metabolismo , Animais , Proteínas Reguladoras de Apoptose , Família da Proteína 8 Relacionada à Autofagia , Sistemas CRISPR-Cas , Proteínas de Transporte/metabolismo , Simulação por Computador , Proteínas do Citoesqueleto/imunologia , Proteínas do Citoesqueleto/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , GTP Fosfo-Hidrolases/imunologia , GTP Fosfo-Hidrolases/metabolismo , Edição de Genes , Immunoblotting , Imunoprecipitação , Interferon gama/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismoRESUMO
Innate immune responses rely on rapid and precise gene regulation mediated by accessibility of regulatory regions to transcription factors (TFs). In natural killer (NK) cells and other innate lymphoid cells, competent enhancers are primed during lineage acquisition, and formation of de novo enhancers characterizes the acquisition of innate memory in activated NK cells and macrophages. Here, we investigated how primed and de novo enhancers coordinate to facilitate high-magnitude gene induction during acute activation. Epigenomic and transcriptomic analyses of regions near highly induced genes (HIGs) in NK cells both in vitro and in a model of Toxoplasma gondii infection revealed de novo chromatin accessibility and enhancer remodeling controlled by signal-regulated TFs STATs. Acute NK cell activation redeployed the lineage-determining TF T-bet to de novo enhancers, independent of DNA-sequence-specific motif recognition. Thus, acute stimulation reshapes enhancer function through the combinatorial usage and repurposing of both lineage-determining and signal-regulated TFs to ensure an effective response.
Assuntos
Elementos Facilitadores Genéticos/genética , Elementos Facilitadores Genéticos/imunologia , Células Matadoras Naturais/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Animais , Cromatina/genética , Cromatina/imunologia , Feminino , Expressão Gênica/genética , Expressão Gênica/imunologia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Toxoplasma/imunologia , Toxoplasmose/genética , Toxoplasmose/imunologiaRESUMO
The differentiation of helper T cells into effector subsets is critical to host protection. Transcription factors of the E-protein and Id families are important arbiters of T cell development, but their role in the differentiation of the TH1 and TFH subsets of helper T cells is not well understood. Here, TH1 cells showed more robust Id2 expression than that of TFH cells, and depletion of Id2 via RNA-mediated interference increased the frequency of TFH cells. Furthermore, TH1 differentiation was blocked by Id2 deficiency, which led to E-protein-dependent accumulation of effector cells with mixed characteristics during viral infection and severely impaired the generation of TH1 cells following infection with Toxoplasma gondii. The TFH cell-defining transcriptional repressor Bcl6 bound the Id2 locus, which provides a mechanism for the bimodal Id2 expression and reciprocal development of TH1 cells and TFH cells.
Assuntos
Infecções por Arenaviridae/imunologia , Diferenciação Celular , Proteína 2 Inibidora de Diferenciação/metabolismo , Vírus da Coriomeningite Linfocítica/imunologia , Células Th1/fisiologia , Toxoplasma/imunologia , Toxoplasmose/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células Cultivadas , Feminino , Centro Germinativo/imunologia , Proteína 2 Inibidora de Diferenciação/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , RNA Interferente Pequeno/genética , Células Th1/parasitologia , Células Th1/virologiaRESUMO
Traditional views of the inflammasome highlight the assembly of pre-existing core components shortly after infection or tissue damage. Emerging work, however, suggests that the inflammasome machinery is also subject to 'tunable' or inducible signals that might accelerate its autocatalytic properties and dictate where inflammasome assembly takes place in the cell. Many of these signals operate downstream of interferon receptors to elicit inflammasome regulators, including a new family of interferon-induced GTPases called 'guanylate-binding proteins' (GBPs). Here we investigate the critical roles of interferon-induced GBPs in directing inflammasome subtype-specific responses and their consequences for cell-autonomous immunity to a wide variety of microbial pathogens. We discuss emerging mechanisms of action and the potential effect of these GBPs on predisposition to sepsis and other infectious or inflammatory diseases.
Assuntos
Proteínas de Ligação ao GTP/imunologia , Inflamassomos/imunologia , Interferons/imunologia , Transdução de Sinais/imunologia , Animais , Resistência à Doença/genética , Resistência à Doença/imunologia , Proteínas de Ligação ao GTP/classificação , Proteínas de Ligação ao GTP/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Infecções/imunologia , Infecções/microbiologia , Infecções/parasitologia , Inflamassomos/genética , Inflamassomos/metabolismo , Interferons/metabolismo , Listeria monocytogenes/imunologia , Listeria monocytogenes/fisiologia , Camundongos , Modelos Imunológicos , Filogenia , Transdução de Sinais/genética , Toxoplasma/imunologia , Toxoplasma/fisiologiaRESUMO
Chronic Toxoplasma gondii infection induces brain-resident CD8+ T cells (bTr), but the protective functions and differentiation cues of these cells remain undefined. Here, we used a mouse model of latent infection by T. gondii leading to effective CD8+ T cell-mediated parasite control. Thanks to antibody depletion approaches, we found that peripheral circulating CD8+ T cells are dispensable for brain parasite control during chronic stage, indicating that CD8+ bTr are able to prevent brain parasite reactivation. We observed that the retention markers CD69, CD49a, and CD103 are sequentially acquired by brain parasite-specific CD8+ T cells throughout infection and that a majority of CD69/CD49a/CD103 triple-positive (TP) CD8+ T cells also express Hobit, a transcription factor associated with tissue residency. This TP subset develops in a CD4+ T cell-dependent manner and is associated with effective parasite control during chronic stage. Conditional invalidation of Transporter associated with Antigen Processing (TAP)-mediated major histocompatibility complex (MHC) class I presentation showed that presentation of parasite antigens by glutamatergic neurons and microglia regulates the differentiation of CD8+ bTr into TP cells. Single-cell transcriptomic analyses revealed that resistance to encephalitis is associated with the expansion of stem-like subsets of CD8+ bTr. In summary, parasite-specific brain-resident CD8+ T cells are a functionally heterogeneous compartment which autonomously ensure parasite control during T. gondii latent infection and which differentiation is shaped by neuronal and microglial MHC I presentation. A more detailed understanding of local T cell-mediated immune surveillance of this common parasite is needed for harnessing brain-resident CD8+ T cells in order to enhance control of chronic brain infections.
Assuntos
Encéfalo , Linfócitos T CD8-Positivos , Diferenciação Celular , Toxoplasma , Toxoplasmose , Animais , Linfócitos T CD8-Positivos/imunologia , Toxoplasma/imunologia , Camundongos , Encéfalo/imunologia , Encéfalo/parasitologia , Diferenciação Celular/imunologia , Toxoplasmose/imunologia , Toxoplasmose/parasitologia , Infecção Latente/imunologia , Infecção Latente/parasitologia , Antígenos CD/metabolismo , Antígenos CD/imunologia , Antígenos CD/genética , Camundongos Endogâmicos C57BL , FemininoRESUMO
Host defense requires the specification of CD4+ helper T (Th) cells into distinct fates, including Th1 cells that preferentially produce interferon-γ (IFN-γ). IFN-γ, a member of a large family of anti-pathogenic and anti-tumor IFNs, induces T-bet, a lineage-defining transcription factor for Th1 cells, which in turn supports IFN-γ production in a feed-forward manner. Herein, we show that a cell-intrinsic role of T-bet influences how T cells perceive their secreted product in the environment. In the absence of T-bet, IFN-γ aberrantly induced a type I IFN transcriptomic program. T-bet preferentially repressed genes and pathways ordinarily activated by type I IFNs to ensure that its transcriptional response did not evoke an aberrant amplification of type I IFN signaling circuitry, otherwise triggered by its own product. Thus, in addition to promoting Th1 effector commitment, T-bet acts as a repressor in differentiated Th1 cells to prevent abberant autocrine type I IFN and downstream signaling.
Assuntos
Comunicação Autócrina , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Proteínas com Domínio T/metabolismo , Células Th1/imunologia , Toxoplasma/imunologia , Toxoplasmose/imunologia , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Humanos , Interferon Tipo I/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Proteínas com Domínio T/genética , Células Th1/microbiologia , Células Th1/virologia , TranscriptomaRESUMO
White adipose tissue bridges body organs and plays a fundamental role in host metabolism. To what extent adipose tissue also contributes to immune surveillance and long-term protective defense remains largely unknown. Here, we have shown that at steady state, white adipose tissue contained abundant memory lymphocyte populations. After infection, white adipose tissue accumulated large numbers of pathogen-specific memory T cells, including tissue-resident cells. Memory T cells in white adipose tissue expressed a distinct metabolic profile, and white adipose tissue from previously infected mice was sufficient to protect uninfected mice from lethal pathogen challenge. Induction of recall responses within white adipose tissue was associated with the collapse of lipid metabolism in favor of antimicrobial responses. Our results suggest that white adipose tissue represents a memory T cell reservoir that provides potent and rapid effector memory responses, positioning this compartment as a potential major contributor to immunological memory.
Assuntos
Tecido Adiposo Branco/transplante , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Toxoplasmose/imunologia , Infecções por Yersinia pseudotuberculosis/imunologia , Tecido Adiposo Branco/imunologia , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD4-Positivos/parasitologia , Linfócitos T CD8-Positivos/microbiologia , Linfócitos T CD8-Positivos/parasitologia , Expressão Gênica , Genes Reporter , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Metabolismo dos Lipídeos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise de Sobrevida , Transplante de Tecidos , Toxoplasma/imunologia , Toxoplasmose/genética , Toxoplasmose/mortalidade , Toxoplasmose/parasitologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Yersinia pseudotuberculosis/imunologia , Infecções por Yersinia pseudotuberculosis/genética , Infecções por Yersinia pseudotuberculosis/microbiologia , Infecções por Yersinia pseudotuberculosis/mortalidadeRESUMO
Activation of Toll-like receptors (TLRs) by pathogens triggers cytokine production and T cell activation, immune defense mechanisms that are linked to immunopathology. Here we show that IFN-γ production by CD4(+) T(H)1 cells during mucosal responses to the protozoan parasite Toxoplasma gondii resulted in dysbiosis and the elimination of Paneth cells. Paneth cell death led to loss of antimicrobial peptides and occurred in conjunction with uncontrolled expansion of the Enterobacteriaceae family of Gram-negative bacteria. The expanded intestinal bacteria were required for the parasite-induced intestinal pathology. The investigation of cell type-specific factors regulating T(H)1 polarization during T. gondii infection identified the T cell-intrinsic TLR pathway as a major regulator of IFN-γ production in CD4(+) T cells responsible for Paneth cell death, dysbiosis and intestinal immunopathology.
Assuntos
Infecções por Enterobacteriaceae/patologia , Enterobacteriaceae/crescimento & desenvolvimento , Celulas de Paneth/patologia , Transdução de Sinais/imunologia , Células Th1/patologia , Toxoplasma/crescimento & desenvolvimento , Toxoplasmose Animal/patologia , Animais , Linfócitos T CD4-Positivos , Morte Celular , Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/complicações , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/microbiologia , Regulação da Expressão Gênica , Interações Hospedeiro-Parasita , Interações Hospedeiro-Patógeno , Interferon gama/genética , Interferon gama/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Ativação Linfocitária , Camundongos , Camundongos Transgênicos , Celulas de Paneth/microbiologia , Celulas de Paneth/parasitologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Células Th1/microbiologia , Células Th1/parasitologia , Toxoplasma/imunologia , Toxoplasmose Animal/complicações , Toxoplasmose Animal/imunologia , Toxoplasmose Animal/parasitologia , alfa-Defensinas/deficiênciaRESUMO
Highly active killer T cells mediate a stable standoff during controlled persistent infections. In this issue of Immunity, Robey and colleagues describe a unique antigen-addicted T cell population bearing characteristics of both effector and memory CD8(+) T cells that provides a continuous supply of potent killer T cells to curb Toxoplasma gondii growth during latency.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Toxoplasma/imunologia , Humanos , Linfócitos T Citotóxicos/imunologiaRESUMO
Highly functional CD8(+) effector T (Teff) cells can persist in large numbers during controlled persistent infections, as exemplified by rare HIV-infected individuals who control the virus. Here we examined the cellular mechanisms that maintain ongoing T effector responses using a mouse model for persistent Toxoplasma gondii infection. In mice expressing the protective MHC-I molecule, H-2L(d), a dominant T effector response against a single parasite antigen was maintained without a contraction phase, correlating with ongoing presentation of the dominant antigen. Large numbers of short-lived Teff cells were continuously produced via a proliferative, antigen-dependent intermediate (Tint) population with a memory-effector hybrid phenotype. During an acute, resolved infection, decreasing antigen load correlated with a sharp drop in the Tint cell population and subsequent loss of the ongoing effector response. Vaccination approaches aimed at the development of Tint populations might prove effective against pathogens that lead to chronic infection.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Subpopulações de Linfócitos/imunologia , Toxoplasma/imunologia , Toxoplasmose/imunologia , Animais , Apresentação de Antígeno , Antígenos de Protozoários/imunologia , Antígenos de Protozoários/metabolismo , Linfócitos T CD8-Positivos/parasitologia , Proliferação de Células , Células Cultivadas , Doença Crônica , Citotoxicidade Imunológica , Antígenos de Histocompatibilidade Classe I/metabolismo , Epitopos Imunodominantes/imunologia , Epitopos Imunodominantes/metabolismo , Memória Imunológica , Subpopulações de Linfócitos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
In a representative sample of female children and adolescents in Germany, Toxoplasma gondii seroprevalence was 6.3% (95% CI 4.7%-8.0%). With each year of life, the chance of being seropositive increased by 1.2, indicating a strong force of infection. Social status and municipality size were found to be associated with seropositivity.
Assuntos
Toxoplasma , Toxoplasmose , Humanos , Feminino , Alemanha/epidemiologia , Toxoplasmose/epidemiologia , Toxoplasmose/parasitologia , Adolescente , Criança , Toxoplasma/imunologia , Estudos Soroepidemiológicos , Pré-Escolar , Fatores de Risco , Lactente , Anticorpos Antiprotozoários/sangueRESUMO
BACKGROUND: Infection with the protozoan parasite Toxoplasma gondii leads to the formation of lifelong cysts in neurons that can have devastating consequences in the immunocompromised. In the immunocompetent individual, anti-parasitic effector mechanisms and a balanced immune response characterized by pro- and anti-inflammatory cytokine production establishes an asymptomatic infection that rarely leads to neurological symptoms. Several mechanisms are known to play a role in this successful immune response in the brain including T cell production of IFNγ and IL-10 and the involvement of CNS resident cells. This limitation of clinical neuropathology during chronic infection suggests a balance between immune response and neuroprotective mechanisms that collectively prevent clinical manifestations of disease. However, how these two vital mechanisms of protection interact during chronic Toxoplasma infection remains poorly understood. MAIN TEXT: This study demonstrates a previously undescribed connection between innate neutrophils found chronically in the brain, termed "chronic brain neutrophils" (CBNeuts), and neuroprotective mechanisms during Toxoplasma infection. Lack of CBNeuts during chronic infection, accomplished via systemic neutrophil depletion, led to enhanced infection and deleterious effects on neuronal regeneration and repair mechanisms in the brain. Phenotypic and transcriptomic analysis of CBNeuts identified them as distinct from peripheral neutrophils and revealed two main subsets of CBNeuts that display heterogeneity towards both classical effector and neuroprotective functions in an age-dependent manner. Further phenotypic profiling defined expression of the neuroprotective molecules NRG-1 andErbB4 by these cells, and the importance of this signaling pathway during chronic infection was demonstrated via NRG-1 treatment studies. CONCLUSIONS: In conclusion, this work identifies CBNeuts as a heterogenous population geared towards both classical immune responses and neuroprotection during chronic Toxoplasma infection and provides the foundation for future mechanistic studies of these cells.
Assuntos
Neutrófilos , Toxoplasmose , Animais , Neutrófilos/imunologia , Neutrófilos/metabolismo , Camundongos , Toxoplasmose/imunologia , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Neurônios/imunologia , Toxoplasma/imunologia , Feminino , Neuroproteção/fisiologia , Masculino , Encéfalo/imunologia , Encéfalo/patologia , Encéfalo/parasitologiaRESUMO
For decades, an immunosorbent agglutination assay (ISAGA) has been considered the gold standard method for the detection of Toxoplasma gondii-specific IgM in infants for the diagnosis of congenital toxoplasmosis (CT). The Toxoplasma IgM ISAGA was consistently reported as having superior sensitivity. Unfortunately, the commercial kit for the detection of Toxoplasma IgM ISAGA will no longer be available in 2024 and alternatives will only be available at a handful of reference laboratories as in-house or laboratory-developed tests. In a recent study, S. Arkhis, C. Rouges, N. Dahane, H. Guegan, et al. (J Clin Microbiol 62:e01222-23, 2024, https://doi.org/10.1128/jcm.01222-23), reported that the performance of the PLATELIA Toxo IgM was comparable to that of the ISAGA method for the diagnosis of CT. A second study revealing similar results supports the PLATELIA Toxo IgM as the new gold standard for the detection of T. gondii-specific IgM in infants. Although the laboratory toolbox for CT diagnosis has been reshuffled successfully, it is by universally implementing all available serological and molecular tools at the earliest possible time during gestation that we can best defend children's brain from the potential harm caused by trans-placentally transmitted T. gondii.
Assuntos
Anticorpos Antiprotozoários , Imunoglobulina M , Toxoplasma , Toxoplasmose Congênita , Humanos , Toxoplasmose Congênita/diagnóstico , Imunoglobulina M/sangue , Toxoplasma/imunologia , Toxoplasma/isolamento & purificação , Anticorpos Antiprotozoários/sangue , Lactente , Sensibilidade e Especificidade , Recém-Nascido , Testes de Aglutinação/métodosRESUMO
T helper 1 (Th1) cell-associated immunity exacerbates ileitis induced by oral Toxoplasma gondii infection. We show here that attenuated ileitis observed in interleukin-22 (IL-22)-deficient mice was associated with reduced production of Th1-cell-promoting IL-18. IL-22 not only augmented the expression of Il18 mRNA and inactive precursor protein (proIL-18) in intestinal epithelial cells after T. gondii or Citrobacter rodentium infection, but also maintained the homeostatic amount of proIL-18 in the ileum. IL-22, however, did not induce the processing to active IL-18, suggesting a two-step regulation of IL-18 in these cells. Although IL-18 exerted pathogenic functions during ileitis triggered by T. gondii, it was required for host defense against C. rodentium. Conversely, IL-18 was required for the expression of IL-22 in innate lymphoid cells (ILCs) upon T. gondii infection. Our results define IL-18 as an IL-22 target gene in epithelial cells and describe a complex mutual regulation of both cytokines during intestinal infection.
Assuntos
Infecções por Enterobacteriaceae/imunologia , Interleucina-18/imunologia , Interleucinas/imunologia , Mucosa Intestinal/imunologia , Toxoplasmose/imunologia , Animais , Células Cultivadas , Citrobacter rodentium/imunologia , Infecções por Enterobacteriaceae/microbiologia , Células Epiteliais/imunologia , Ileíte/imunologia , Ileíte/microbiologia , Ileíte/parasitologia , Íleo/imunologia , Íleo/microbiologia , Íleo/parasitologia , Inflamação/imunologia , Interferon gama/biossíntese , Interleucina-18/biossíntese , Interleucinas/genética , Mucosa Intestinal/microbiologia , Mucosa Intestinal/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Técnicas de Cultura de Órgãos , RNA Mensageiro/biossíntese , Células Th1/imunologia , Toxoplasma/imunologia , Toxoplasmose/parasitologia , Regulação para Cima , Interleucina 22RESUMO
Tissue-infiltrating Ly6C(hi) monocytes play diverse roles in immunity, ranging from pathogen killing to immune regulation. How and where this diversity of function is imposed remains poorly understood. Here we show that during acute gastrointestinal infection, priming of monocytes for regulatory function preceded systemic inflammation and was initiated prior to bone marrow egress. Notably, natural killer (NK) cell-derived IFN-γ promoted a regulatory program in monocyte progenitors during development. Early bone marrow NK cell activation was controlled by systemic interleukin-12 (IL-12) produced by Batf3-dependent dendritic cells (DCs) in the mucosal-associated lymphoid tissue (MALT). This work challenges the paradigm that monocyte function is dominantly imposed by local signals after tissue recruitment, and instead proposes a sequential model of differentiation in which monocytes are pre-emptively educated during development in the bone marrow to promote their tissue-specific function.
Assuntos
Células da Medula Óssea/imunologia , Células Dendríticas/imunologia , Mucosa Intestinal/imunologia , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/imunologia , Toxoplasma/imunologia , Toxoplasmose/imunologia , Animais , Antígenos Ly/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Células da Medula Óssea/parasitologia , Diferenciação Celular , Células Cultivadas , Interferon gama/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Mucosa Intestinal/parasitologia , Células Matadoras Naturais/parasitologia , Leucócitos Mononucleares/parasitologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Imunológicos , Especificidade de Órgãos/imunologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismoRESUMO
BACKGROUND: The highly expressed surface antigen 1 (SAG1)-related sequence (SRS) proteins of T. gondii tachyzoites, as a widespread zoonotic parasite, are critical for host cell invasion and represent promising vaccine targets. In this study, we employed a computer-aided multi-method approach for in silico design and evaluation of TgVax452, an epitope-based candidate vaccine against T. gondii tachyzoite-specific SRS proteins. METHODS: Using immunoinformatics web-based tools, structural modeling, and static/dynamic molecular simulations, we identified and screened B- and T-cell immunodominant epitopes and predicted TgVax452's antigenicity, stability, safety, adjuvanticity, and physico-chemical properties. RESULTS: The designed protein possessed 452 residues, a MW of 44.07 kDa, an alkaline pI (6.7), good stability (33.20), solubility (0.498), and antigenicity (0.9639) with no allergenicity. Comprehensive molecular dynamic (MD) simulation analyses confirmed the stable interaction (average potential energy: 3.3799 × 106 KJ/mol) between the TLR4 agonist residues (RS09 peptide) of the TgVax452 in interaction with human TLR4, potentially activating innate immune responses. Also, a dramatic increase was observed in specific antibodies (IgM and IgG), cytokines (IFN-γ), and lymphocyte responses, based on C-ImmSim outputs. Finally, we optimized TgVax452's codon adaptation and mRNA secondary structure for efficient expression in E. coli BL21 expression machinery. CONCLUSION: Our findings suggest that TgVax452 is a promising candidate vaccine against T. gondii tachyzoite-specific SRS proteins and requires further experimental studies for its potential use in preclinical trials.
Assuntos
Antígenos de Protozoários , Biologia Computacional , Epitopos de Linfócito T , Proteínas de Protozoários , Vacinas Protozoárias , Toxoplasma , Proteínas de Protozoários/imunologia , Proteínas de Protozoários/genética , Proteínas de Protozoários/química , Toxoplasma/imunologia , Toxoplasma/genética , Toxoplasma/química , Vacinas Protozoárias/imunologia , Vacinas Protozoárias/genética , Antígenos de Protozoários/imunologia , Antígenos de Protozoários/genética , Antígenos de Protozoários/química , Animais , Camundongos , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/genética , Feminino , Anticorpos Antiprotozoários/imunologia , Camundongos Endogâmicos BALB C , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito B/genética , Epitopos de Linfócito B/química , Humanos , Simulação de Dinâmica Molecular , Epitopos Imunodominantes/imunologia , Epitopos Imunodominantes/genética , Epitopos Imunodominantes/química , Toxoplasmose/prevenção & controle , Toxoplasmose/imunologia , ImunoinformáticaRESUMO
BACKGROUND: Toxoplasma gondii (T. gondii) is a ubiquitous protozoan parasite on our planet that causes toxoplasmosis. This study evaluated the seroprevalence and related risk factors for T. gondii infection in a population referred to healthcare centers in Meshkin-Shahr, Northwest Iran. METHODS: A total of 400 blood samples were randomly collected from the general population and assessed using the anti-Toxoplasma antibodies, Immunoglobulin G and M (IgG and IgM) Enzyme-linked immunosorbent assay (ELISA) Kits in two steps before and during the coronavirus disease 2019 (COVID-19) pandemic, 2019-2020. The results were analyzed through logistic regression via SPSS 26 software. RESULTS: Before the COVID-19 pandemic, anti-toxoplasma antibodies were detected in 39% of individuals (IgG: 38%, IgM: 0.5%, and IgG-IgM: 0.5%). Among the eleven risk factors evaluated, contact with soil and people awareness were significantly associated with T. gondii infection (p < 0.05). However, factors such as females, 20-39 age groups, junior high schools, housewives, rural areas, raw meat or vegetable consumption, vegetable or fruits washed by water, not detergent, and cat owners did not show a significant relationship with seropositivity (p > 0.05). After the outbreak of the COVID-19 pandemic, the overall seroprevalence for anti-T. gondii antibody increased to 49.7% (IgG: 47.7%, IgM: 0.5%, and IgG and IgM: 1.5%). Among these patients, 26% were positive for COVID-19. Additionally, before the COVID-19 pandemic, 40 samples were negative for anti-T. gondii antibodies but later became positive. The crude and adjusted models suggested that toxoplasmosis may be a possible risk factor for increased susceptibility to COVID-19, with an odds ratio (OR) of 1.28 (95% confidence interval (CI), 0.82-1.99; P < 0.05). Conversely, a non-significant protective effect against latent toxoplasmosis was observed in COVID-19-positive individuals (OR = 0.99; 95% CI, 0.51-1.92; P > 0.05), and COVID-19 positivity did not increase the levels of anti-T. gondii IgG antibodies. CONCLUSIONS: The general population in this region had a moderate seroprevalence of T. gondii. The increased number of COVID-19-positive patients with latent toxoplasmosis highlights the need to pay attention to the early diagnosis and proper treatment of toxoplasmosis in these patients and implement preventive programs in these areas for future possible viral infections.
Assuntos
Anticorpos Antiprotozoários , COVID-19 , Imunoglobulina G , Imunoglobulina M , SARS-CoV-2 , Toxoplasma , Toxoplasmose , Humanos , COVID-19/epidemiologia , COVID-19/imunologia , Irã (Geográfico)/epidemiologia , Estudos Soroepidemiológicos , Toxoplasmose/epidemiologia , Feminino , Masculino , Adulto , Toxoplasma/imunologia , Pessoa de Meia-Idade , Adulto Jovem , Imunoglobulina G/sangue , Fatores de Risco , Imunoglobulina M/sangue , Anticorpos Antiprotozoários/sangue , SARS-CoV-2/imunologia , Adolescente , Idoso , Criança , Prevalência , Ensaio de Imunoadsorção Enzimática , Pré-Escolar , PandemiasRESUMO
There is a need to reconsider the acceptance of organs from donors considered suboptimal, in the absence of data. Toxoplasma antibody-positive donors (TPD) constitute one such group. The objective of our study was to compare graft survival in deceased donor renal transplant (Tx) recipients, stratified by Toxoplasma IgG status, using the Organ Procurement and Transplantation Network (OPTN) database. A log-linear event history regression model for graft failure categorized by Toxoplasma IgG status, adjusting for confounders was applied to first kidney-only Tx recipients from 2018 to 2022. Of the 51,422 Tx, 4,317 (8.4%) were from TPD. Acute rejection and graft failure (5% each) were similar between groups. Crude graft failure was 7.3 failures per 100 person-years for TPD recipients compared to 6.5 failures per 100 person-years for the Toxoplasma-negative group (p 0.008). The crude failure rate ratio was 1.14 with an adjusted hazard rate ratio of 1.04 (95% CI: 0.94, 1.15, p 0.39). In renal Tx recipients, TPD graft recipients have comparable survival to Tx from Toxoplasma-negative recipients. While caution and close monitoring of recipients post-Tx for surveillance of disseminated toxoplasmosis are still warranted, our study suggests that patients can be successfully managed using TPD organs.