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1.
Virology ; 567: 77-86, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35032866

RESUMO

Type-I interferon (IFN-I) signals exert a critical role in disease progression during viral infections. However, the immunomodulatory mechanisms by which IFN-I dictates disease outcomes remain to be fully defined. Here we report that IFN-I signals mediate thymic atrophy in viral infections, with more severe and prolonged loss of thymic output and unique kinetics and subtypes of IFN-α/ß expression in chronic infection compared to acute infection. Loss of thymic output was linked to inhibition of early stages of thymopoiesis (DN1-DN2 transition, and DN3 proliferation) and pronounced apoptosis during the late DP stage. Notably, infection-associated thymic defects were largely abrogated upon ablation of IFNαßR and partially mitigated in the absence of CD8 T cells, thus implicating direct as well as indirect effects of IFN-I on thymocytes. These findings provide mechanistic underpinnings for immunotherapeutic strategies targeting IFN-1 signals to manipulate disease outcomes during chronic infections and cancers.


Assuntos
Atrofia/virologia , Interferon-alfa/imunologia , Interferon beta/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Timócitos/virologia , Timo/virologia , Animais , Atrofia/genética , Atrofia/imunologia , Atrofia/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Doença Crônica , Feminino , Regulação da Expressão Gênica , Humanos , Memória Imunológica , Interferon-alfa/genética , Interferon beta/genética , Linfonodos/imunologia , Linfonodos/patologia , Linfonodos/virologia , Depleção Linfocítica , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/patologia , Vírus da Coriomeningite Linfocítica/patogenicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/imunologia , Transdução de Sinais/imunologia , Análise de Célula Única , Timócitos/imunologia , Timócitos/patologia , Timo/imunologia , Timo/patologia
2.
Signal Transduct Target Ther ; 6(1): 414, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34873151

RESUMO

Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC50 between 1.2 and 4.3 µM, depending on viruses or cells, and selective index (SI) in 15-83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1-9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2-25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.


Assuntos
Antivirais/administração & dosagem , Azidas/administração & dosagem , COVID-19/tratamento farmacológico , Desoxicitidina/análogos & derivados , SARS-CoV-2/metabolismo , Timo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Coronavirus Humano OC43/metabolismo , Desoxicitidina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Timo/metabolismo , Timo/virologia
3.
Front Immunol ; 12: 773146, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956200

RESUMO

Transcription factors (TFs) modulate genes involved in cell-type-specific proliferative and migratory properties, metabolic features, and effector functions. Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important pathogen agents in the porcine industry; however, TFs have been poorly studied during the course of this disease. Therefore, we aimed to evaluate the expressions of the TFs T-bet, GATA3, FOXP3, and Eomesodermin (EOMES) in target organs (the lung, tracheobronchial lymph node, and thymus) and those of different effector cytokines (IFNG, TNFA, and IL10) and the Fas ligand (FASL) during the early phase of infection with PRRSV-1 strains of different virulence. Target organs from mock-, virulent Lena-, and low virulent 3249-infected animals humanely euthanized at 1, 3, 6, 8, and 13 days post-infection (dpi) were collected to analyze the PRRSV viral load, histopathological lesions, and relative quantification through reverse transcription quantitative PCR (RT-qPCR) of the TFs and cytokines. Animals belonging to both infected groups, but mainly those infected with the virulent Lena strain, showed upregulation of the TFs T-bet, EOMES, and FOXP3, together with an increase of the cytokine IFN-γ in target organs at the end of the study (approximately 2 weeks post-infection). These results are suggestive of a stronger polarization to Th1 cells and regulatory T cells (Tregs), but also CD4+ cytotoxic T lymphocytes (CTLs), effector CD8+ T cells, and γδT cells in virulent PRRSV-1-infected animals; however, their biological functionality should be the object of further studies.


Assuntos
Fatores de Transcrição Forkhead/imunologia , Síndrome Respiratória e Reprodutiva Suína/imunologia , Proteínas com Domínio T/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Fator de Transcrição GATA3/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Linfonodos/imunologia , Linfonodos/patologia , Linfonodos/virologia , Síndrome Respiratória e Reprodutiva Suína/patologia , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína , Suínos , Proteínas com Domínio T/genética , Linfócitos T/imunologia , Timo/imunologia , Timo/patologia , Timo/virologia , Carga Viral , Virulência
4.
Dev Comp Immunol ; 122: 104112, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33971216

RESUMO

Chicken Infectious Anaemia (CIA) Virus (CAV) inhibits the function of multiple immune compartments. Mortality due to clinical infection is controlled in broilers by passive immunization derived from vaccinated breeders. Therefore, serological tests are often used in chicks to determine maternally-derived antibodies (MDA). We used a vaccine overdose-induced model of CIA. The model replicated the most common features of the disease. This model was used to determine the role of MDA in the protection of chicks. Hatchlings were tested for anti-CAV titers by ELISA and were sorted into groups based on antibody levels. SPF chicks were used as a no-antibody control. Lower specific antibody levels seemed to facilitate viral entry into the thymus, but viral levels, CD4+ and CD8+ counts, thymus architecture, and haematocrit were preserved by MDA, regardless of its levels. Levels of MDA are not correlated with protection from CIA, but are important for the progression CAV infection.


Assuntos
Anticorpos Antivirais/sangue , Vírus da Anemia da Galinha/imunologia , Galinhas/imunologia , Infecções por Circoviridae/imunologia , Imunidade Materno-Adquirida/imunologia , Vacinas Virais/imunologia , Animais , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Circoviridae/veterinária , Ensaio de Imunoadsorção Enzimática , Feminino , Hematócrito , Imunização Passiva , Doenças das Aves Domésticas/imunologia , Doenças das Aves Domésticas/virologia , Gravidez , Timo/virologia , Vacinação/veterinária , Vacinas Atenuadas/imunologia
5.
Sci Rep ; 11(1): 10270, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33986327

RESUMO

Newcastle disease (ND), caused by virulent Newcastle disease virus (NDV), is a contagious viral disease affecting various birds and poultry worldwide. In this project, differentially expressed (DE) circRNAs, miRNAs and mRNAs were identified by high-throughput RNA sequencing (RNA-Seq) in chicken thymus at 24, 48, 72 or 96 h post LaSota NDV vaccine injection versus pre-inoculation group. The vital terms or pathways enriched by vaccine-influenced genes were tested through KEGG and GO analysis. DE genes implicated in innate immunity were preliminarily screened out through GO, InnateDB and Reactome Pathway databases. The interaction networks of DE innate immune genes were established by STRING website. Considering the high expression of gga-miR-6631-5p across all the four time points, DE circRNAs or mRNAs with the possibility to bind to gga-miR-6631-5p were screened out. Among DE genes that had the probability to interact with gga-miR-6631-5p, 7 genes were found to be related to innate immunity. Furthermore, gga-miR-6631-5p promoted LaSota NDV replication by targeting insulin induced gene 1 (INSIG1) in DF-1 chicken fibroblast cells. Taken together, our data provided the comprehensive information about molecular responses to NDV LaSota vaccine in Chinese Partridge Shank Chickens and elucidated the vital roles of gga-miR-6631-5p/INSIG1 axis in LaSota NDV replication.


Assuntos
Doença de Newcastle/genética , Pequeno RNA não Traduzido/genética , Replicação Viral/genética , Animais , Galinhas/genética , Galinhas/virologia , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Imunidade Inata , MicroRNAs/genética , Doença de Newcastle/virologia , Vírus da Doença de Newcastle/genética , Vírus da Doença de Newcastle/patogenicidade , Doenças das Aves Domésticas/virologia , RNA Circular/genética , RNA Mensageiro/genética , Timo/metabolismo , Timo/virologia , Transcriptoma/genética , Vacinação
6.
Front Immunol ; 12: 671743, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34046040

RESUMO

Virulent porcine reproductive and respiratory syndrome virus (PRRSV) strains, such as the Lena strain, have demonstrated a higher thymus tropism than low virulent strains. Virulent PRRSV strains lead to severe thymus atrophy, which could be related to marked immune dysregulation. Impairment of T-cell functions through immune checkpoints has been postulated as a strategy executed by PRRSV to subvert the immune response, however, its role in the thymus, a primary lymphoid organ, has not been studied yet. Therefore, the goal of this study was to evaluate the expression of selected immune checkpoints (PD1/PDL1, CTLA4, TIM3, LAG3, CD200R1 and IDO1) in the thymus of piglets infected with two different PRRSV-1 strains. Thymus samples from piglets infected with the low virulent 3249 strain, the virulent Lena strain and mock-infected were collected at 1, 3, 6, 8 and 13 days post-infection (dpi) to analyze PRRSV viral load, relative quantification and immunohistochemical staining of immune checkpoints. PD1/PDL1, CTLA4, TIM3, LAG3 and IDO1 immune checkpoints were significantly up-regulated in the thymus of PRRSV infected piglets, especially in those infected with the virulent Lena strain from 6 dpi onwards. This up-regulation was associated with disease progression, high viral load and cell death. Co-expression of these molecules can affect T-cell development, maturation and selection, negatively regulating the host immune response against PRRSV.


Assuntos
Síndrome Respiratória e Reprodutiva Suína/imunologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Timo/imunologia , Timo/virologia , Animais , Síndrome Respiratória e Reprodutiva Suína/virologia , Suínos , Regulação para Cima , Virulência
7.
Cells ; 10(3)2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33808998

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global pandemic of coronavirus disease 2019 (COVID-19) and particularly exhibits severe symptoms and mortality in elderly individuals. Mounting evidence shows that the characteristics of the age-related clinical severity of COVID-19 are attributed to insufficient antiviral immune function and excessive self-damaging immune reaction, involving T cell immunity and associated with pre-existing basal inflammation in the elderly. Age-related changes to T cell immunosenescence is characterized by not only restricted T cell receptor (TCR) repertoire diversity, accumulation of exhausted and/or senescent memory T cells, but also by increased self-reactive T cell- and innate immune cell-induced chronic inflammation, and accumulated and functionally enhanced polyclonal regulatory T (Treg) cells. Many of these changes can be traced back to age-related thymic involution/degeneration. How these changes contribute to differences in COVID-19 disease severity between young and aged patients is an urgent area of investigation. Therefore, we attempt to connect various clues in this field by reviewing and discussing recent research on the role of the thymus and T cells in COVID-19 immunity during aging (a synergistic effect of diminished responses to pathogens and enhanced responses to self) impacting age-related clinical severity of COVID-19. We also address potential combinational strategies to rejuvenate multiple aging-impacted immune system checkpoints by revival of aged thymic function, boosting peripheral T cell responses, and alleviating chronic, basal inflammation to improve the efficiency of anti-SARS-CoV-2 immunity and vaccination in the elderly.


Assuntos
COVID-19/imunologia , Senescência Celular/imunologia , Linfócitos T/imunologia , Timo/imunologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/imunologia , Envelhecimento/patologia , Autoimunidade , COVID-19/tratamento farmacológico , COVID-19/fisiopatologia , Humanos , Inflamação/imunologia , Inflamação/patologia , SARS-CoV-2/imunologia , Timo/efeitos dos fármacos , Timo/fisiopatologia , Timo/virologia
8.
Hum Vaccin Immunother ; 17(3): 638-643, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33064620

RESUMO

The thymus is a largely neglected organ but plays a significant role in the regulation of adaptive immune responses. The effect of aging on the thymus and immune senescence is well established, and the resulting inflammaging is found to be implicated in the development of many chronic diseases including atherosclerosis, hypertension and type 2 diabetes. Both aging and diseases of inflammaging are associated with severe COVID-19 disease, and a dysfunctional thymus may be a predisposing factor. In addition, insults on the thymus during childhood may lead to abnormal thymic function and may explain severe COVID-19 disease among younger individuals; therefore, measurement of thymic function may assist COVID-19 care. Those with poor thymic function may be treated prophylactically with convalescent serum or recombinant antibodies, and they may respond better to high-dose or adjuvanted COVID-19 vaccines. Treatments inducing thymic regeneration may improve patients' overall health and may be incorporated in COVID-19 management.


Assuntos
Anticorpos/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/imunologia , Timo/imunologia , Animais , COVID-19/virologia , Vacinas contra COVID-19/imunologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/virologia , Índice de Gravidade de Doença , Timo/virologia
9.
Can J Microbiol ; 67(1): 23-28, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32640169

RESUMO

Understanding the pathogenesis of certain viral agents is essential for developing new treatments and obtaining a clinical cure. With the onset of the new coronavirus (SARS-CoV-2) pandemic in the beginning of 2020, a rush to conduct studies and develop drugs has led to the publication of articles that seek to address knowledge gaps and contribute to the global scientific research community. There are still no reports on the infectivity or repercussions of SARS-CoV-2 infection on the central lymphoid organ, the thymus, nor on thymocytes or thymic epithelial cells. In this brief review, we present a hypothesis about lymphopenia observed in SARS patients and the probable pathological changes that the thymus may undergo due to this new virus.


Assuntos
COVID-19/complicações , COVID-19/imunologia , Linfopenia/complicações , Timo/virologia , Animais , Humanos , Linfopenia/imunologia , Linfopenia/virologia , Camundongos , Modelos Imunológicos , Pandemias , Timo/imunologia
10.
Front Immunol ; 12: 757379, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35126348

RESUMO

Gamma delta (γδ) T cells play a key role in the innate immune response and serve as the first line of defense against infection and tumors. These cells are defined as tissue-resident lymphocytes in skin, lung, and intestinal mucosa. They are also relatively abundant in the liver; however, little is known about the residency of hepatic γδT cells. By comparing the phenotype of murine γδT cells in liver, spleen, thymus, and small intestine, a CXCR3+CXCR6+ γδT-cell subset with tissue-resident characteristics was found in liver tissue from embryos through adults. Liver sinusoidal endothelial cells mediated retention of CXCR3+CXCR6+ γδT cells through the interactions between CXCR3 and CXCR6 and their chemokines. During acute HBV infection, CXCR3+CXCR6+ γδT cells produced high levels of IFN-γ and adoptive transfer of CXCR3+CXCR6+ γδT cells into acute HBV-infected TCRδ-/- mice leading to lower HBsAg and HBeAg expression. It is suggested that liver resident CXCR3+CXCR6+ γδT cells play a protective role during acute HBV infection. Strategies aimed at expanding and activating liver resident CXCR3+CXCR6+ γδT cells both in vivo or in vitro have great prospects for use in immunotherapy that specifically targets acute HBV infection.


Assuntos
Hepatite B/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores CXCR3/metabolismo , Receptores CXCR6/metabolismo , Linfócitos T/metabolismo , Transferência Adotiva/métodos , Animais , Quimiocinas/metabolismo , Vírus da Hepatite B/patogenicidade , Hepatócitos/metabolismo , Hepatócitos/virologia , Intestino Delgado/metabolismo , Intestino Delgado/virologia , Fígado/metabolismo , Fígado/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Baço/metabolismo , Baço/virologia , Linfócitos T/virologia , Timo/metabolismo , Timo/virologia
11.
Nat Med ; 26(11): 1776-1787, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32868878

RESUMO

An effective strategy to cure HIV will likely require a potent and sustained antiviral T cell response. Here we explored the utility of chimeric antigen receptor (CAR) T cells, expressing the CD4 ectodomain to confer specificity for the HIV envelope, to mitigate HIV-induced pathogenesis in bone marrow, liver, thymus (BLT) humanized mice. CAR T cells expressing the 4-1BB/CD3-ζ endodomain were insufficient to prevent viral rebound and CD4+ T cell loss after the discontinuation of antiretroviral therapy. Through iterative improvements to the CAR T cell product, we developed Dual-CAR T cells that simultaneously expressed both 4-1BB/CD3-ζ and CD28/CD3-ζ endodomains. Dual-CAR T cells exhibited expansion kinetics that exceeded 4-1BB-, CD28- and third-generation costimulated CAR T cells, elicited effector functions equivalent to CD28-costimulated CAR T cells and prevented HIV-induced CD4+ T cell loss despite persistent viremia. Moreover, when Dual-CAR T cells were protected from HIV infection through expression of the C34-CXCR4 fusion inhibitor, these cells significantly reduced acute-phase viremia, as well as accelerated HIV suppression in the presence of antiretroviral therapy and reduced tissue viral burden. Collectively, these studies demonstrate the enhanced therapeutic potency of a novel Dual-CAR T cell product with the potential to effectively treat HIV infection.


Assuntos
Antígenos CD4/imunologia , Infecções por HIV/terapia , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos/imunologia , Animais , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Medula Óssea/imunologia , Medula Óssea/virologia , Complexo CD3/antagonistas & inibidores , Antígenos CD4/administração & dosagem , Regulação da Expressão Gênica/imunologia , Proteína gp41 do Envelope de HIV/antagonistas & inibidores , Proteína gp41 do Envelope de HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/imunologia , HIV-1/patogenicidade , Humanos , Fígado/imunologia , Fígado/virologia , Camundongos , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/imunologia , Domínios Proteicos/imunologia , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/imunologia , Receptores de Antígenos Quiméricos/administração & dosagem , Linfócitos T/imunologia , Timo/imunologia , Timo/virologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/antagonistas & inibidores
12.
J Virol ; 94(21)2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32817213

RESUMO

While feline leukemia virus (FeLV) has been shown to infect felid species other than the endemic domestic cat host, differences in FeLV susceptibility among species has not been evaluated. Previous reports have noted a negative correlation between endogenous FeLV (enFeLV) copy number and exogenous FeLV (exFeLV) infection outcomes in domestic cats. Since felids outside the genus Felis do not harbor enFeLV genomes, we hypothesized absence of enFeLV results in more severe disease consequences in felid species lacking these genomic elements. We infected primary fibroblasts isolated from domestic cats (Felis catus) and pumas (Puma concolor) with FeLV and quantitated proviral and viral antigen loads. Domestic cat enFeLV env and long terminal repeat (LTR) copy numbers were determined for each individual and compared to FeLV viral outcomes. FeLV proviral and antigen levels were also measured in 6 naturally infected domestic cats and 11 naturally infected Florida panthers (P. concolor coryi). We demonstrated that puma fibroblasts are more permissive to FeLV than domestic cat cells, and domestic cat FeLV restriction was highly related to enFeLV-LTR copy number. Terminal tissues from FeLV-infected Florida panthers and domestic cats had similar exFeLV proviral copy numbers, but Florida panther tissues have higher FeLV antigen loads. Our work indicates that enFeLV-LTR elements negatively correlate with exogenous FeLV replication. Further, Puma concolor samples lacking enFeLV are more permissive to FeLV infection than domestic cat samples, suggesting that endogenization can play a beneficial role in mitigating exogenous retroviral infections. Conversely, presence of endogenous retroelements may relate to new host susceptibility during viral spillover events.IMPORTANCE Feline leukemia virus (FeLV) can infect a variety of felid species. Only the primary domestic cat host and related small cat species harbor a related endogenous virus in their genomes. Previous studies noted a negative association between the endogenous virus copy number and exogenous virus infection in domestic cats. This report shows that puma cells, which lack endogenous FeLV, produce more virus more rapidly than domestic cat fibroblasts following cell culture challenge. We document a strong association between domestic cat cell susceptibility and FeLV long terminal repeat (LTR) copy number, similar to observations in natural FeLV infections. Viral replication does not, however, correlate with FeLV env copy number, suggesting that this effect is specific to FeLV-LTR elements. This discovery indicates a protective capacity of the endogenous virus against the exogenous form, either via direct interference or indirectly via gene regulation, and may suggest evolutionary outcomes of retroviral endogenization.


Assuntos
Variações do Número de Cópias de DNA , Produtos do Gene env/genética , Vírus da Leucemia Felina/genética , Vírus da Leucemia Felina/patogenicidade , Leucemia Felina/virologia , Puma/virologia , Animais , Medula Óssea/patologia , Medula Óssea/virologia , Gatos , Feminino , Fibroblastos/patologia , Fibroblastos/virologia , Produtos do Gene env/metabolismo , Especificidade de Hospedeiro , Vírus da Leucemia Felina/metabolismo , Leucemia Felina/patologia , Linfonodos/patologia , Linfonodos/virologia , Masculino , Cultura Primária de Células , Baço/patologia , Baço/virologia , Sequências Repetidas Terminais , Timo/patologia , Timo/virologia , Carga Viral , Replicação Viral/genética
13.
Front Immunol ; 11: 953, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32508833

RESUMO

Background: Visceral leishmaniasis/HIV-co-infected patients (VL/HIV) accounts for around 8% of VL reported cases in Brazil. Relapses of Leishmania infection after anti-leishmanial treatment constitute a great challenge in the clinical practice because of the disease severity and drug resistance. We have shown that non-relapsing-VL/HIV (NR-) evolved with increase of CD4+ T-cell counts and reduction of activated CD4+ and CD8+ T cells after anti-leishmanial treatment. This immune profile was not observed in relapsing-VL/HIV patients (R-), indicating a more severe immunological compromising degree. Elevated activation status may be related to a deficient immune reconstitution and could help to explain the frequent relapses in VL/HIV co-infection. Our aim was to evaluate if this gain of T cells was related to changes in the peripheral TCRVß repertoire and inflammatory status, as well as the possible thymus involvement in the replenishment of these newly formed T lymphocytes. Methods: VL/HIV patients, grouped into non-relapsing (NR- = 6) and relapsing (R- = 12) were evaluated from the active phase up to 12 months post-treatment (mpt). HIV-infected patients (non-VL) and healthy subjects (HS) were included. The TCRVß repertoire was evaluated ex vivo by flow cytometry, whereas the plasmatic cytokine levels were assessed by Luminex assay. To evaluate the thymic output, DNA was extracted from PBMCs for TCR rearrangement excision circles (TREC) quantification by qPCR. Results: VL/HIV cases presented an altered mobilization profile (expansions or retractions) of the TCRVß families when compared to HS independent of the follow-up phase (p < 0.05). TCRVß repertoire on CD4+ T-cells was more homogeneous in the NR-VL/HIV cases, but heterogeneous on CD8+ T-cells, since different Vß-families were mobilized. NR-VL/HIV had the inflammatory pattern reduced after 6 mpt. Importantly, VL/HIV patients showed number of TREC copies lower than controls during all follow-up. An increase of recent thymic emigrants was observed in NR-VL/HIV individuals at 10 mpt compared to R- patients (p < 0.01), who maintained lower TREC contents than the HIV controls. Conclusions: VL/HIV patients that maintain the thymic function, thus generating new T-cells, seem able to replenish the T lymphocyte compartment with effector cells, then enabling parasite control.


Assuntos
Coinfecção , Infecções por HIV/imunologia , Leishmaniose Visceral/imunologia , Ativação Linfocitária , Subpopulações de Linfócitos T/imunologia , Timo/imunologia , Relação CD4-CD8 , Estudos de Casos e Controles , Proliferação de Células , Citocinas/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Humanos , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/metabolismo , Leishmaniose Visceral/parasitologia , Fenótipo , Estudos Prospectivos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Recidiva , Subpopulações de Linfócitos T/parasitologia , Subpopulações de Linfócitos T/virologia , Timo/parasitologia , Timo/virologia , Fatores de Tempo , Resultado do Tratamento
14.
Vet Microbiol ; 243: 108639, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32273018

RESUMO

In the last decade, the outbreaks caused by virulent porcine reproductive and respiratory syndrome virus (PRRSV) strains from both PRRSV-1 and PRRSV-2 have considerably increased. PRRSV is able to modulate the host's immune response through the induction of apoptosis of cells in lymphoid organs like thymus, increasing the susceptibility to secondary infectious agents. The present study aimed to compare the impact of two PRRSV-1 strains, a field low virulent strain (3249 strain) and a virulent strain (Lena strain), in the thymus of infected pigs, focusing on clinical signs, histological analysis, viraemia, thymus viral load and the study of the different routes of apoptosis phenomena by immunohistochemistry. Sera and thymus samples were collected from infected animals with 3249 strain, Lena strain and mock-infected animals at 1, 3, 6, 8 and 13 days post-infection (dpi). Lena-infected animals showed severe clinical disease, high sera and thymus viral loads with evident thymic atrophy since 6 dpi, matching with PRRSV-N protein, TUNEL and cCasp3 expression in the thymic cortex. In both infected groups, there was an increase in the number of cells expressing molecules related to the extrinsic pathway of apoptosis (cCasp8 and Fas) in cortex and medulla, showing an important role in the apoptosis induction produced in thymus of PRRSV-infected piglets. The extensive apoptosis in the thymus through this pathway would lead to a decrease in the number of mature T lymphocytes and the sustained release of viral particles, which may explain the greater severity of the clinical signs observed in Lena-infected pigs.


Assuntos
Apoptose , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Transdução de Sinais , Timo/patologia , Timo/virologia , Animais , Atrofia , Caspase 3/metabolismo , Imuno-Histoquímica , Suínos , Carga Viral , Viremia , Virulência
15.
Front Immunol ; 11: 481, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32300341

RESUMO

The thymus is the main organ of the lymphatic system, in which T cells undergo a rigorous selection to ensure that their receptors (TCRs) will be functional and will not react against the self. Genes encoding for TCR chains are fragmented and must be rearranged by a process of somatic recombination generating TCR rearrangement excision circles (TRECs). We recently documented coxsackievirus B4 (CV-B4) infection of Swiss albino mouse thymus in the course of in utero transmission. In the current study, we intended to evaluate thymic output in this experimental model. For this purpose, pregnant Swiss albino mice were inoculated with CV-B4 at day 10 or 17 of gestation, and thymus and spleen were sampled from offspring at different time points and then subjected to quantification of TREC molecules and Ptk7 gene expression. Results showed a pronounced effect of in utero CV-B4 infection on the thymus with an increase in the cellularity and, consequently, the weight of the organ. sj and DßTREC analysis, by real-time PCR, revealed a significant decrease following CV-B4 infection compared to controls, a decrease which gets worse as time goes by, both in the thymus and in the periphery. Those observations reflect a disturbance in the export of T cells to the periphery and their accumulation within the thymus. The evaluation of Ptk7 transcripts in the thymus, for its part, showed a decrease in expression, especially following an infection at day 10 of gestation, which supports the hypothesis of T cell accumulation in a mature stage in the thymus. The various effects observed correlate either negatively or positively with the viral load in the thymus and spleen. Disruption in thymic export may indeed interfere with T cell maturation. We speculate that this may lead to a premature release of T cells and the possibility of circulating autoreactive or proliferation-impaired T cell clones.


Assuntos
Doenças Autoimunes/imunologia , Infecções por Coxsackievirus/imunologia , Enterovirus/fisiologia , Timo/fisiologia , Útero/imunologia , Animais , Autoimunidade , Diferenciação Celular , Proliferação de Células , Infecções por Coxsackievirus/transmissão , Regulação para Baixo , Enterovirus/patogenicidade , Feminino , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T/genética , Transmissão Vertical de Doenças Infecciosas , Masculino , Camundongos , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Timo/virologia , Útero/virologia , Carga Viral
16.
Proc Natl Acad Sci U S A ; 117(10): 5420-5429, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32094187

RESUMO

Chronic infection provokes alterations in inflammatory and suppressive pathways that potentially affect the function and integrity of multiple tissues, impacting both ongoing immune control and restorative immune therapies. Here we demonstrate that chronic lymphocytic choriomeningitis virus infection rapidly triggers severe thymic depletion, mediated by CD8 T cell-intrinsic type I interferon (IFN) and signal transducer and activator of transcription 2 (Stat2) signaling. Occurring temporal to T cell exhaustion, thymic cellularity reconstituted despite ongoing viral replication, with a rapid secondary thymic depletion following immune restoration by anti-programmed death-ligand 1 (PDL1) blockade. Therapeutic hematopoietic stem cell transplant (HSCT) during chronic infection generated new antiviral CD8 T cells, despite sustained virus replication in the thymus, indicating an impairment in negative selection. Consequently, low amounts of high-affinity self-reactive T cells also escaped the thymus following HSCT during chronic infection. Thus, by altering the stringency and partially impairing negative selection, the host generates new virus-specific T cells to replenish the fight against the chronic infection, but also has the potentially dangerous effect of enabling the escape of self-reactive T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Interferon Tipo I/metabolismo , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/patologia , Vírus da Coriomeningite Linfocítica , Timo/patologia , Timo/virologia , Animais , Atrofia/virologia , Antígeno B7-H1/antagonistas & inibidores , Doença Crônica , Transplante de Células-Tronco Hematopoéticas , Interferon Tipo I/genética , Coriomeningite Linfocítica/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator de Transcrição STAT2/metabolismo , Transdução de Sinais , Replicação Viral
17.
Sci Rep ; 10(1): 1378, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992777

RESUMO

Previous work showed that the thymus can be infected by RNA viruses as HIV and HTLV-1. We thus hypothesized that the thymus might also be infected by the Zika virus (ZIKV). Herein we provide compelling evidence that ZIKV targets human thymic epithelial cells (TEC) in vivo and in vitro. ZIKV-infection enhances keratinization of TEC, with a decrease in proliferation and increase in cell death. Moreover, ZIKV modulates a high amount of coding RNAs with upregulation of genes related to cell adhesion and migration, as well as non-coding genes including miRNAs, circRNAs and lncRNAs. Moreover, we observed enhanced attachment of lymphoblastic T-cells to infected TEC, as well as virus transfer to those cells. Lastly, alterations in thymuses from babies congenitally infected were seen, with the presence of viral envelope protein in TEC. Taken together, our data reveals that the thymus, particularly the thymic epithelium, is a target for the ZIKV with changes in the expression of molecules that are relevant for interactions with developing thymocytes.


Assuntos
Células Epiteliais , Timócitos , Timo , Tropismo Viral , Infecção por Zika virus , Zika virus/fisiologia , Animais , Chlorocebus aethiops , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Células Epiteliais/virologia , Epitélio/metabolismo , Epitélio/patologia , Epitélio/virologia , Humanos , Timócitos/metabolismo , Timócitos/patologia , Timócitos/virologia , Timo/metabolismo , Timo/patologia , Timo/virologia , Células Vero , Infecção por Zika virus/metabolismo , Infecção por Zika virus/patologia
18.
Vet Microbiol ; 241: 108574, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31928707

RESUMO

Duck circovirus (DuCV), an immunosuppressive pathogen, causes serious damage to waterfowls worldwide. A highly efficient vaccine would play a crucial role in preventing DuCV infections in the waterfowl breeding industry. However, to date, there is a dearth of commercial vaccines owing to the lack of a cell culture system for propagating the requisite virus amounts in vitro. In this study, we isolated DuCVs from Muscovy ducks, helped them proliferate using peripheral blood mononuclear cells (PBMCs), and developed an inactivated vaccine. Muscovy ducks vaccinated with the inactivated vaccine had higher neutralizing antibody titers than the control ducks and higher protection in the challenge experiment (as assessed by weight measurement). Moreover, the inactivated vaccine did not cause feather abnormalities, growth repression, and dwarf syndrome; likewise, lesions and lymphocyte apoptosis in the bursa of Fabricius, spleen, and thymus were not observed. Significantly lower virus shedding from the inactivated vaccine was detected up to 42 days post-inoculation. Together, these results suggest that the inactivated DuCV vaccine can induce a high immune response, is relatively safer for Muscovy ducks, and thus it is a protective vaccine candidates against DuCV infection.


Assuntos
Infecções por Circoviridae/veterinária , Circovirus/imunologia , Patos , Doenças das Aves Domésticas/prevenção & controle , Vacinas Virais/normas , Animais , Apoptose , Bolsa de Fabricius/patologia , Bolsa de Fabricius/virologia , Infecções por Circoviridae/prevenção & controle , Circovirus/genética , Circovirus/isolamento & purificação , Circovirus/ultraestrutura , Leucócitos Mononucleares/patologia , Leucócitos Mononucleares/virologia , Microscopia Eletrônica de Transmissão/veterinária , Doenças das Aves Domésticas/virologia , Distribuição Aleatória , Baço/patologia , Baço/virologia , Timo/patologia , Timo/virologia , Vacinas de Produtos Inativados/normas
19.
J Leukoc Biol ; 107(1): 85-94, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31691351

RESUMO

Despite more than three decades of studies and advances in combination antiretroviral therapy (cART) against human immunodeficiency virus (HIV), the mechanisms that precisely determine immune reconstitution failure have not been completely elucidated yet. Thus, this study aimed to investigate the thymic function, immune activation, and cell death by pyroptosis and apoptosis in virologically suppressed HIV-positive patients receiving cART. Immunophenotyping analyses were performed in 57 cART-treated HIV-infected patients with undetectable plasma viral load, who were classified as immunological nonresponders (INR = 29) and immunologic responders (IR = 28). Sociodemographic and clinical data were also assessed from medical records. Twelve healthy volunteers were also included in this study. The INR showed lower pretreatment CD4+ T cell count that remained low even after 1 yr of treatment, lower CD4/CD8 ratio, lower percentage of recent thymic emigrant (RTE) CD4+ T cell (CD45RA+CD31+) and naïve CD4+ T cell (CD45RA+CD62L+), higher levels of effector memory CD4+ T cells (CD45RA-CD62L-), and higher pyroptosis levels of RTE CD4+ T cells (CD31+FLICA-Caspase1+) when compared with IR. Our findings indicate that reduced thymic function and RTE CD4+ T cell death by pyroptosis are the major mechanisms of immunological recovery failure in HIV-infected patients receiving cART.


Assuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Linfócitos T CD4-Positivos/patologia , Infecções por HIV/imunologia , HIV-1/imunologia , Piroptose , Timo/imunologia , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Imunofenotipagem , Masculino , Timo/efeitos dos fármacos , Timo/virologia , Falha de Tratamento , Carga Viral
20.
Trends Microbiol ; 28(3): 212-223, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31744664

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) dramatically affects the thymus and its ability to carry out its normal functions. In particular, infection incapacitates PRRSV-susceptible CD14pos antigen-presenting cells (APCs) in the thymus and throughout the body. PRRSV-induced autophagy in thymic epithelial cells modulates the development of T cells, and PRRSV-induced apoptosis in CD4posCD8pos thymocytes modulates cellular immunity against PRRSV and other pathogens. Pigs are less able to resist and/or eliminate secondary infectious agents due the effect of PRRSV on the thymus, and this susceptibility phenomenon is long recognized as a primary characteristic of PRRSV infection.


Assuntos
Autofagia/imunologia , Síndrome Respiratória e Reprodutiva Suína/patologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Linfócitos T/citologia , Timo/patologia , Animais , Suscetibilidade a Doenças/veterinária , Suscetibilidade a Doenças/virologia , Imunidade Celular/imunologia , Macrófagos/imunologia , Suínos , Linfócitos T/imunologia , Timo/citologia , Timo/virologia
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