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1.
Nat Commun ; 13(1): 2603, 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35546552

RESUMO

Human cytomegalovirus reactivation is a major opportunistic infection after allogeneic haematopoietic stem cell transplantation and has a complex relationship with post-transplant immune reconstitution. Here, we use mass cytometry to define patterns of innate and adaptive immune cell reconstitution at key phases of human cytomegalovirus reactivation in the first 100 days post haematopoietic stem cell transplantation. Human cytomegalovirus reactivation is associated with the development of activated, memory T-cell profiles, with faster effector-memory CD4+ T-cell recovery in patients with low-level versus high-level human cytomegalovirus DNAemia. Mucosal-associated invariant T cell levels at the initial detection of human cytomegalovirus DNAemia are significantly lower in patients who subsequently develop high-level versus low-level human cytomegalovirus reactivation. Our data describe distinct immune signatures that emerged with human cytomegalovirus reactivation after haematopoietic stem cell transplantation, and highlight Mucosal-associated invariant T cell levels at the first detection of reactivation as a marker that may be useful to anticipate the magnitude of human cytomegalovirus DNAemia.


Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Citomegalovirus/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos
4.
Viruses ; 14(2)2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35215877

RESUMO

Human cytomegalovirus (HCMV) can cause severe clinical disease in immunocompromised individuals, such as allograft recipients and infants infected in utero. Neutralizing activity of antibodies, measured as the ability to prevent the entry of cell-free virus, has been correlated with the reduction in HCMV transmission and the severity of HCMV-associated disease. However, in vivo HCMV amplification may occur mainly via cell-to-cell spread. Thus, quantifying the inhibition of cell-to-cell transmission could be important in the evaluation of therapeutic antibodies and/or humoral responses to infection or immunization. Here, we established a quantitative plaque reduction assay, which allowed for the measurement of the capacity of antibodies to limit HCMV spread in vitro. Using an automated fluorescence spot reader, infection progression was assayed by the expansion of viral plaques during the course of infection with various GFP-expressing viruses. We found that in contrast to non-neutralizing monoclonal antibodies (mAbs), neutralizing mAbs against both glycoprotein B and H (gB and gH) could significantly inhibit viral plaque expansion of different HCMV strains and was equally efficient in fibroblasts as in epithelial cells. In contrast, an anti-pentamer mAb was active only in epithelial cells. Taken together, our data demonstrate that specific anti-HCMV mAbs can significantly limit cell-associated virus spread in vitro.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Células Epiteliais/virologia , Fibroblastos/virologia , Anticorpos Monoclonais/imunologia , Linhagem Celular , Células Cultivadas , Humanos , Proteínas do Envelope Viral/imunologia , Ensaio de Placa Viral , Internalização do Vírus
5.
Int J Mol Sci ; 23(3)2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35162953

RESUMO

After solid-organ transplantation, reactivation of the cytomegalovirus (CMV) is often observed in seronegative patients and associated with a high risk of disease and mortality. CMV-specific T cells can prevent CMV reactivation. In a phase 1 trial, CMV-seronegative patients with end-stage renal disease listed for kidney transplantation were subjected to CMV phosphoprotein 65 (CMVpp65) peptide vaccination and further investigated for T-cell responses. To this end, CMV-specific CD8+ T cells were characterized by bulk T-cell-receptor (TCR) repertoire sequencing and combined single-cell RNA and TCR sequencing. In patients mounting an immune response to the vaccine, a common SYE(N)E TCR motif known to bind CMVpp65 was detected. CMV-peptide-vaccination-responder patients had TCR features distinct from those of non-responders. In a non-responder patient, a monoclonal inflammatory T-cell response was detected upon CMV reactivation. The identification of vaccine-induced CMV-reactive TCRs motifs might facilitate the development of cellular therapies for patients wait-listed for kidney transplantation.


Assuntos
Infecções por Citomegalovirus/prevenção & controle , Falência Renal Crônica/terapia , Receptores de Antígenos de Linfócitos T/genética , Proteínas da Matriz Viral/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Ensaios Clínicos Fase I como Assunto , Citomegalovirus/imunologia , Infecções por Citomegalovirus/imunologia , Vacinas contra Citomegalovirus/administração & dosagem , Vacinas contra Citomegalovirus/imunologia , Humanos , Falência Renal Crônica/imunologia , Transplante de Rim , Análise de Sequência de RNA , Imagem Individual de Molécula , Proteínas da Matriz Viral/imunologia
6.
Front Immunol ; 13: 680559, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35154089

RESUMO

Human cytomegalovirus (HCMV) is an ubiquitous herpesvirus that can cause serious morbidity and mortality in immunocompromised or immune-immature individuals. A vaccine that induces immunity to CMV in these target populations is therefore highly needed. Previous attempts to generate efficacious CMV vaccines primarily focused on the induction of humoral immunity by eliciting neutralizing antibodies. Current insights encourage that a protective immune response to HCMV might benefit from the induction of virus-specific T cells. Whether addition of antiviral T cell responses enhances the protection by antibody-eliciting vaccines is however unclear. Here, we assessed this query in mouse CMV (MCMV) infection models by developing synthetic vaccines with humoral immunity potential, and deliberately adding antiviral CD8+ T cells. To induce antibodies against MCMV, we developed a DNA vaccine encoding either full-length, membrane bound glycoprotein B (gB) or a secreted variant lacking the transmembrane and intracellular domain (secreted (s)gB). Intradermal immunization with an increasing dose schedule of sgB and booster immunization provided robust viral-specific IgG responses and viral control. Combined vaccination of the sgB DNA vaccine with synthetic long peptides (SLP)-vaccines encoding MHC class I-restricted CMV epitopes, which elicit exclusively CD8+ T cell responses, significantly enhanced antiviral immunity. Thus, the combination of antibody and CD8+ T cell-eliciting vaccines provides a collaborative improvement of humoral and cellular immunity enabling enhanced protection against CMV.


Assuntos
Anticorpos Antivirais/sangue , Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/prevenção & controle , Vacinas contra Citomegalovirus/imunologia , Citomegalovirus/imunologia , Vacinas de DNA/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Infecções por Citomegalovirus/imunologia , Epitopos/imunologia , Imunidade Celular , Imunidade Humoral , Imunização Secundária/métodos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Organismos Livres de Patógenos Específicos , Vacinação , Vacinas de DNA/administração & dosagem , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia
7.
Proc Natl Acad Sci U S A ; 119(6)2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35105802

RESUMO

Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of viral immune evasion, targeting intrinsic, innate, and adaptive immunity. We have employed two orthogonal multiplexed tandem mass tag-based proteomic screens to identify host proteins down-regulated by viral factors expressed during the latest phases of viral infection. This approach revealed that the HIV-1 restriction factor Schlafen-11 (SLFN11) was degraded by the poorly characterized, late-expressed HCMV protein RL1, via recruitment of the Cullin4-RING E3 Ubiquitin Ligase (CRL4) complex. SLFN11 potently restricted HCMV infection, inhibiting the formation and spread of viral plaques. Overall, we show that a restriction factor previously thought only to inhibit RNA viruses additionally restricts HCMV. We define the mechanism of viral antagonism and also describe an important resource for revealing additional molecules of importance in antiviral innate immunity and viral immune evasion.


Assuntos
Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Evasão da Resposta Imune , Proteínas Nucleares/imunologia , Proteólise , Proteínas do Envelope Viral/imunologia , Citomegalovirus/genética , Infecções por Citomegalovirus/genética , Humanos , Proteínas Nucleares/genética , Complexos Ubiquitina-Proteína Ligase/genética , Complexos Ubiquitina-Proteína Ligase/imunologia , Proteínas do Envelope Viral/genética
8.
Lupus ; 31(2): 256-260, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35041559

RESUMO

BACKGROUND: Management of infectious complications in pregnant women receiving immunosuppressive therapy for systemic lupus erythematosus (SLE) is important. Maternal infection with cytomegalovirus (CMV) often causes congenital CMV infection in the foetus. Thus far, there are only few reports on congenital CMV infection after maternal reactivation in patients with SLE. We report the first case of congenital CMV infection after maternal primary infection in a patient with SLE. CASE PRESENTATION: A 19-year-old Japanese primigravida with SLE received treatment with prednisolone 3 mg/day and azathioprine 75 mg/day at conception. At 7 weeks of gestation, she suddenly developed fever and had decreased white blood cell and platelet counts and elevated aspartate aminotransferase and alanine aminotransferase levels. These clinical findings led to a diagnosis of SLE exacerbation. The prednisolone dose was increased to 15 mg/day, and hydroxychloroquine (200 mg/day) was administered. Consequently, all clinical findings normalised at 12 weeks. At 19 weeks, foetal ultrasound findings revealed oligohydramnios, brain hypoplasia, ventriculomegaly and hyperechogenic bowel. Maternal serological test results indicated increased CMV-specific IgG and IgM levels, low IgG avidity (26%), and positive CMV antigenemia. The foetus was diagnosed with symptomatic congenital CMV infection transmitted from the maternal primary infection. After counselling about the severe prognosis of the foetus, the mother decided to terminate her pregnancy and underwent artificial abortion at 21 weeks. DISCUSSION: The foetus of a mother with SLE who is receiving immunosuppressive therapy may be at increased risk of transmission and aggravation of congenital CMV infection; thus, preventive management and screening for congenital CMV infection during pregnancy are recommended for such patients. Maternal CMV infection shows clinical findings similar to those of SLE exacerbation, and careful differential diagnosis by maternal serological evaluation and foetal ultrasound scans is required.


Assuntos
Infecções por Citomegalovirus , Lúpus Eritematoso Sistêmico , Prednisolona/farmacologia , Complicações Infecciosas na Gravidez , Anticorpos Antivirais/imunologia , Citomegalovirus/genética , Citomegalovirus/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Adulto Jovem
9.
Cell Mol Immunol ; 19(2): 234-244, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34992275

RESUMO

Global pandemics caused by influenza or coronaviruses cause severe disruptions to public health and lead to high morbidity and mortality. There remains a medical need for vaccines against these pathogens. CMV (cytomegalovirus) is a ß-herpesvirus that induces uniquely robust immune responses in which remarkably large populations of antigen-specific CD8+ T cells are maintained for a lifetime. Hence, CMV has been proposed and investigated as a novel vaccine vector for expressing antigenic peptides or proteins to elicit protective cellular immune responses against numerous pathogens. We generated two recombinant murine CMV (MCMV) vaccine vectors expressing hemagglutinin (HA) of influenza A virus (MCMVHA) or the spike protein of severe acute respiratory syndrome coronavirus 2 (MCMVS). A single injection of MCMVs expressing either viral protein induced potent neutralizing antibody responses, which strengthened over time. Importantly, MCMVHA-vaccinated mice were protected from illness following challenge with the influenza virus, and we excluded that this protection was due to the effects of memory T cells. Conclusively, we show here that MCMV vectors induce not only long-term cellular immunity but also humoral responses that provide long-term immune protection against clinically relevant respiratory pathogens.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Imunidade Humoral , Vírus da Influenza A/imunologia , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação/métodos , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/virologia , Chlorocebus aethiops , Citomegalovirus/imunologia , Cães , Feminino , Células HEK293 , Humanos , Imunidade Celular , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/virologia , Células Vero
10.
Science ; 375(6578): 296-301, 2022 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-35025605

RESUMO

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology. We tested the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a cohort comprising more than 10 million young adults on active duty in the US military, 955 of whom were diagnosed with MS during their period of service. Risk of MS increased 32-fold after infection with EBV but was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion. These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/epidemiologia , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/virologia , Idade de Início , Anticorpos Antivirais/sangue , Biomarcadores/sangue , Estudos de Coortes , Citomegalovirus/imunologia , Feminino , Herpesvirus Humano 4/imunologia , Humanos , Estudos Longitudinais , Masculino , Militares , Esclerose Múltipla/etiologia , Proteínas de Neurofilamentos/sangue , Prevalência , Fatores de Risco , Adulto Jovem
11.
J Immunother Cancer ; 10(1)2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35027426

RESUMO

BACKGROUND: Adoptive transfer of CD19-specific chimeric antigen receptor (CD19CAR) T cells can induce dramatic disease regression in patients with B cell malignancies. CD19CAR T cell therapy may be limited by insufficient engraftment and persistence, resulting in tumor relapse. We previously demonstrated a proof of principle that cytomegalovirus (CMV)-specific T cells can be isolated and enriched prior to CD19CAR transduction to produce CMV-CD19CAR T cells, and that these CMV-CD19CAR T cells can be expanded in vivo through CMV vaccination, resulting in better tumor control in a murine model. Here we developed a clinical platform for generating CMV-CD19CAR T cells. METHODS: Peripheral blood mononuclear cells (PBMCs) collected from CMV-seropositive healthy donors were stimulated with a good manufacturing practices-grade PepTivator overlapping CMVpp65 peptide pool and enriched for CMV-responsive interferon γ (IFNγ)+T cells using IFNγ Catchmatrix, within the CliniMACS Prodigy Cytokine Capture System (Miltenyi Biotec). Resulting CMV-specific T cells were transduced with a lentiviral vector encoding a second generation CD19R:CD28:ζ/EGFRt CAR and expanded with interleukin 2 (IL-2) and IL-15 for 15 days before characterization. RESULTS: CMV-specific T cells were enriched from 0.8%±0.5 of input PBMC to 76.3%±11.6 in nine full-scale qualification runs (absolute yield of 4.2±3.3×106 IFNγ+T cells from an input of 1×109 PBMCs). Average CD19CAR transduction efficiency of CMV-specific T cells was 27.0%±14.2 in the final products, which underwent rapid expansion, resulting in a total cell dose of 6.2±0.9 × 106 CD19CAR-tranduced T cells with CMV specificity (ie, functionally bispecific). CMV-CD19CAR T cells were polyclonal, expressed memory markers but had low expression of exhaustion markers, responded to both CD19 and CMVpp65 stimulation with rapid proliferation and exhibited antigen-specific effector functions against both CD19-expressing tumors and CMVpp65 antigen. The final products passed release criteria for clinical use. CONCLUSIONS: We demonstrated the feasibility of our large-scale platform for generating CMV-CD19CAR T cells for clinical application. We plan to initiate a clinical trial at City of Hope using CMV-CD19CAR T cells for patients with intermediate/high-grade B cell non-Hodgkin's lymphoma immediately after autologous hematopoietic cell transplantation followed by vaccination with a novel CMV vaccine based on Modified Vaccinia Ankara (Triplex) 28 days and 56 days post-T cell infusion.


Assuntos
Imunidade Adaptativa/imunologia , Citomegalovirus/imunologia , Leucócitos Mononucleares/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Animais , Proliferação de Células , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade
12.
Cell Immunol ; 371: 104455, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34864514

RESUMO

Cytomegalovirus (CMV) viral load after liver transplantation (LT) is controlled by cell mediated immune responses (CMI). Quantification of CMV-specific T-cells may identify patients who control CMV spontaneously and avoid expensive and potentially toxic antiviral therapies. Prospective post-LT clinical, virological and immunological monitoring was carried out up to 1-year post-LT in a cohort of adult recipients. The CMV-specific T-cell response was characterized using flow cytometry intracellular cytokine staining in 49 LT recipients-R (79.6% R+, 20.4% R-). CMV infection occurred in 24 patients (18 D+/R+ and 6 D+/R-). Only patients with undetectable polyfunctional CMV-specific CD4+ T-cells developed CMV infection. Predictive models showed that polyfunctional CMV-specific CD4+ T-cells pre-existing before LT are protective for CMV reactivation posttransplantation. Quantitation of CD4+ T-cell responses to CMV may be a useful marker for spontaneous control of viral replication to tailor antiviral prophylaxis after LT.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Citomegalovirus/imunologia , Imunidade Celular/imunologia , Transplante de Fígado/efeitos adversos , Infecções por Citomegalovirus/imunologia , Feminino , Humanos , Hospedeiro Imunocomprometido/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Carga Viral , Ativação Viral/imunologia , Replicação Viral/imunologia
13.
Cell Rep ; 37(9): 110071, 2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34852222

RESUMO

The persistence of anti-viral immunity is essential for protection and exhibits profound heterogeneity across individuals. Here, we elucidate the factors that shape maintenance and function of anti-viral T cell immunity in the body by comprehensive profiling of virus-specific T cells across blood, lymphoid organs, and mucosal tissues of organ donors. We use flow cytometry, T cell receptor sequencing, single-cell transcriptomics, and cytokine analysis to profile virus-specific CD8+ T cells recognizing the ubiquitous pathogens influenza and cytomegalovirus. Our results reveal that virus specificity determines overall magnitude, tissue distribution, differentiation, and clonal repertoire of virus-specific T cells. Age and sex influence T cell differentiation and dissemination in tissues, while T cell tissue residence and functionality are highly correlated with the site. Together, our results demonstrate how the covariates of virus, tissue, age, and sex impact the anti-viral immune response, which is important for targeting, monitoring, and predicting immune responses to existing and emerging viruses.


Assuntos
Antivirais/farmacologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Memória Imunológica/imunologia , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Adulto , Fatores Etários , Criança , Pré-Escolar , Citocinas/metabolismo , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/virologia , Feminino , Humanos , Lactente , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Ativação Linfocitária , Masculino , Receptores de Antígenos de Linfócitos T/imunologia , Fatores Sexuais , Análise de Célula Única , Transcriptoma
14.
Iran J Allergy Asthma Immunol ; 20(6): 721-733, 2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34920655

RESUMO

Natural killer (NK) cells are essential for controlling certain viral infections, including cytomegalovirus (CMV). In particular, the importance of NK cells in the context of CMV infection is underscored by the adaptive capabilities of these cells. Evidence suggests that some viruses can directly interfere with NK cell compartments and their activation and lead to shape-shifting the NK cell receptor repertoire. Still, it remains unknown whether the CMV can interact with NK cells without intermediaries. Here, we examined whether the direct effects of CMV lysate alter phenotypical properties of NK cells. To investigate this issue, NK cells were isolated from the blood of CMV seropositive healthy donors by negative magnetic separation. Isolated NK cells were cultured in the presence of CMV lysate and analyzed for the expression of NKG2A, NKG2C, and CD57 by FACS caliber. The results showed that NKG2C expression is significantly upregulated in the presence of CMV lysate compared to without stimulated group (mean increase, 6.65 %; 95% CI, 0.2582 to 13.02; p=0.043; R square: 0.38). Likewise, results have shown a significant decrease in the frequency of NKG2A+CD57- NK cell subsets (p=0.005; 95% CI, -13.49 to -3.151; R square: 0.5957) in the stimulated group compared to without stimulated ones. According to these results, CMV may drive a direct influence on NK cell receptor repertoire, including the expansion of NK cells expressing NKG2C receptor, which is needed for further studies.


Assuntos
Citomegalovirus/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/virologia , Receptores de Células Matadoras Naturais/metabolismo , Adulto , Biomarcadores/metabolismo , Citomegalovirus/patogenicidade , Feminino , Humanos , Células Matadoras Naturais/metabolismo , Masculino , Fenótipo
15.
Front Immunol ; 12: 779961, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34950144

RESUMO

CD4+ T cells are crucial in cytomegalovirus (CMV) infection, but their role in infection remains unclear. The heterogeneity and potential functions of CMVpp65-reactivated CD4+ T cell subsets isolated from human peripheral blood, as well as their potential interactions, were analyzed by single-cell RNA-seq and T cell receptor (TCR) sequencing. Tregs comprised the largest population of these reactivated cells, and analysis of Treg gene expression showed transcripts associated with both inflammatory and inhibitory functions. The detailed phenotypes of CMV-reactivated CD4+ cytotoxic T1 (CD4+ CTL1), CD4+ cytotoxic T2 (CD4+ CTL2), and recently activated CD4+ T (Tra) cells were analyzed in single cells. Assessment of the TCR repertoire of CMV-reactivated CD4+ T cells confirmed the clonal expansion of stimulated CD4+ CTL1 and CD4+ CTL2 cells, which share a large number of TCR repertoires. This study provides clues for resolving the functions of CD4+ T cell subsets and their interactions during CMV infection. The specific cell groups defined in this study can provide resources for understanding T cell responses to CMV infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , RNA-Seq/métodos , Receptores de Antígenos de Linfócitos T/genética , Análise de Célula Única/métodos , Citomegalovirus/imunologia , Genes Codificadores dos Receptores de Linfócitos T , Humanos
16.
Int J Mol Sci ; 22(24)2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34948284

RESUMO

Congenital cytomegalovirus (CMV) infection may cause severe long-term sequelae. Recent studies have demonstrated that early antiviral therapy for infants with symptomatic congenital CMV (cCMV) infection may improve neurological outcomes; thus, accurate identification of newborns at high risk of cCMV infection may contribute to improved outcomes in affected children. However, maternal serological screening for cCMV infection by diagnosing primary infection during pregnancy, which is a popular screening strategy, is inefficient, because the number of cCMV infections with nonprimary causes, including reactivation of or reinfection with CMV, is larger than that of cCMV infections with primary causes. Low levels of neutralizing antibodies against pentameric complex and potent CMV-specific T cell-mediated immune responses are associated with an increased risk of cCMV infection. Conversely, our prospective cohort studies revealed that the presence of maternal fever/flu-like symptoms, threatened miscarriage/premature delivery, or actual premature delivery are risk factors for cCMV infection among both women with normal pregnancies and those with high-risk ones, regardless of whether the infection is primary or nonprimary. This review focused on host immune responses to human CMV and current knowledge of potential biological and clinical factors that are predictive of cCMV infection.


Assuntos
Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/imunologia , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Estudos de Coortes , Citomegalovirus/imunologia , Citomegalovirus/patogenicidade , DNA Viral , Feminino , Humanos , Lactente , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/estatística & dados numéricos , Masculino , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Prognóstico , Estudos Prospectivos , Fatores de Risco
17.
Cells ; 10(12)2021 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-34943824

RESUMO

The incidence and severity of viral complications after cellular therapy are highly variable. Recent publications describe relevant interactions between the human Cytomegalovirus (CMV) and host immunity in recipients of allogeneic hematopoietic cell transplantation (HCT). Although immune monitoring is routinely performed in HCT patients, validated cut-off levels correlating with transplant outcomes such as survival or CMV reactivation are mostly limited to day +100, which is later than the median time for CMV reactivation in the absence of medical prophylaxis. To address this gap in early risk assessment, we applied an unsupervised machine learning technique based on clustering of day +30 CD4+ helper T cell count data, and identified relevant cut-off levels within the diverse spectrum of early CD4+ reconstitution. These clusters were stratified for CMV recipient serostatus to identify early risk groups that predict clinical HCT outcome. Indeed, the new risk groups predicted subsequent clinical events such as NRM, OS, and high CMV peak titers better than the most established predictor, i.e., the positive CMV recipient serostatus (R+). More specifically, patients from the R+/low CD4+ subgroup strongly associated with high CMV peak titers and increased 3-year NRM (subdistribution hazard ratio (SHR) 10.1, 95% CI 1.38-73.8, p = 0.023), while patients from the R-/very high CD4+ subgroup showed comparable NRM risks (SHR 9.57, 95% CI 1.12-81.9, p = 0.039) without such an association. In short, our study established novel cut-off levels for early CD4+ T cells via unsupervised learning and supports the integration of host cellular immunity into clinical risk-assessment after HCT in the context of CMV reactivation.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Citomegalovirus/imunologia , Transplante de Células-Tronco Hematopoéticas , Medição de Risco , Adolescente , Adulto , Idoso , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/terapia , Feminino , Humanos , Incidência , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Transplante Homólogo , Adulto Jovem
18.
Front Immunol ; 12: 732826, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777342

RESUMO

Haploidentical stem cell transplantation (haploSCT) has advanced to a common procedure for treating patients with hematological malignancies and immunodeficiency diseases. However, cure is seriously hampered by cytomegalovirus (CMV) infections and delayed immune reconstitution for the majority of haploidentical transplant recipients compared to HLA-matched stem cell transplantation. Three major approaches, including in vivo T-cell depletion (TCD) using antithymocyte globulin for haploSCT (in vivo TCD-haploSCT), ex vivo TCD using CD34 + positive selection for haploSCT (ex vivo TCD-haploSCT), and T-cell replete haploSCT using posttransplant cyclophosphamide (PTCy-haploSCT), are currently used worldwide. We provide an update on CMV infection and CMV-specific immune recovery in this fast-evolving field. The progress made in cellular immunotherapy of CMV infection after haploSCT is also addressed. Groundwork has been prepared for the creation of personalized avenues to enhance immune reconstitution and decrease the incidence of CMV infection after haploSCT.


Assuntos
Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus/imunologia , Reconstituição Imune , Hospedeiro Imunocomprometido , Depleção Linfocítica , Infecções Oportunistas/prevenção & controle , Transplante de Células-Tronco/efeitos adversos , Condicionamento Pré-Transplante , Animais , Antígenos CD34/imunologia , Soro Antilinfocitário/uso terapêutico , Ciclofosfamida/uso terapêutico , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Haplótipos , Interações Hospedeiro-Patógeno , Humanos , Imunossupressores/uso terapêutico , Depleção Linfocítica/efeitos adversos , Infecções Oportunistas/imunologia , Infecções Oportunistas/virologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Condicionamento Pré-Transplante/efeitos adversos
19.
Pak J Biol Sci ; 24(11): 1169-1174, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34842389

RESUMO

<b>Background and Objective:</b> In recent years, respiratory tract viral infections have caused many pandemics that impact the whole world. To investigate the seropositivity of <i>Toxoplasma gondii</i>, rubella, CMV, HSV-1 and group A <i>Streptococcus</i> in recovered COVID-19 patients and correlate these findings with vitamin D levels. <b>Materials and Methods:</b> A total of 417 COVID-19 patients with diarrhoea were enrolled in this study. Vitamin D and seroprevalence for <i>Toxoplasma gondii</i>, rubella, CMV, HSV-1 and group A <i>Streptococcus</i> were evaluated and correlated. <b>Results:</b> It was found that recent infection in COVID-19 patients with HSV-1, rubella, <i>Toxoplasma</i> and CMV, respectively. IgG was detected indicating the development of adaptive immunity with all microbes. <b>Conclusion:</b> Current study detected a correlation between vitamin D levels and HSV-1 and no correlation between this infection and vitamin D deficiency with the other microbes.


Assuntos
Teste Sorológico para COVID-19 , COVID-19/diagnóstico , Calcifediol/sangue , Herpes Simples/diagnóstico , Herpesvirus Humano 1/imunologia , Imunoglobulina G/sangue , Deficiência de Vitamina D/diagnóstico , Imunidade Adaptativa , Adulto , Biomarcadores/sangue , COVID-19/sangue , COVID-19/epidemiologia , COVID-19/imunologia , Citomegalovirus/imunologia , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/imunologia , Feminino , Herpes Simples/sangue , Herpes Simples/epidemiologia , Herpes Simples/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Rubéola (Sarampo Alemão)/sangue , Rubéola (Sarampo Alemão)/diagnóstico , Rubéola (Sarampo Alemão)/epidemiologia , Rubéola (Sarampo Alemão)/imunologia , Vírus da Rubéola/imunologia , Arábia Saudita/epidemiologia , Estudos Soroepidemiológicos , Infecções Estreptocócicas/sangue , Infecções Estreptocócicas/diagnóstico , Infecções Estreptocócicas/epidemiologia , Infecções Estreptocócicas/imunologia , Streptococcus/imunologia , Toxoplasma/imunologia , Toxoplasmose/sangue , Toxoplasmose/diagnóstico , Toxoplasmose/epidemiologia , Toxoplasmose/imunologia , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/epidemiologia
20.
Front Immunol ; 12: 713763, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34712226

RESUMO

Chronic cytomegalovirus (CMV) infection is a trigger factor for the development of immunosenescence and negatively impacts the immune response to influenza virus vaccination (IVV) in older adults. However, the role of physical exercise training in this context is unknown. Thus, the aim of this study was to investigate whether the regular practice of combined exercise training can improve the specific antibody response to IVV in CMV-seropositive older adults. Eighty older adults were distributed into two groups-non-practitioners (NP, n = 31, age = 74.06 ± 6.4 years) and practitioners of combined exercise training (CET, n = 49, age = 71.7 ± 5.8 years)-for at least 12 months. Both volunteer groups were submitted to IVV and blood samples were collected before (pre) and 30 days after (post) the vaccination. Concerning the specific antibody response to IVV, higher serum levels of specific immunoglobulin A (IgA) were found in the CET group post- than pre-vaccination (p < 0.01), whereas higher levels of specific immunoglobulin M (IgM) were observed both in the NP (p < 0.05) and CET (p < 0.001) groups post-vaccination as compared to the pre-vaccination values. Serum levels of specific immunoglobulin G (IgG) for IVV and CMV, as well as interleukin 6 (IL-6) and IL-10, were similar between the time points evaluated. However, the IL-10/IL-6 ratio post-vaccination was higher (p < 0.05) in the CET group than that before vaccination. Negative correlations were observed between the specific IgG levels for IVV and CMV only in the CET group, both pre- and post-vaccination. In addition, negative correlations were found between IL-10 and specific IgG for CMV in all volunteer groups pre- and post-vaccination, whereas a positive correlation between IL-10 and specific-IgG for IVV pre- and post-vaccination was observed in the CET group. In addition, with the hemagglutination inhibition (HAI) assay, it was found that 32.2% of the NP group and 32.6% of the CET group were responders to IVV and displayed reductions in the CMV serostatus (p < 0.05 and p < 0.001, respectively) and increases in naive and effector CD8+ T cells post-vaccination (p < 0.01). However, only the responders from the CET group showed significant reductions in the ratio of effector to naive CD8+ T cells (p < 0.05) and increased IL-10 levels post-vaccination (p < 0.001). In summary, this study demonstrates that the improvement in the response to IVV in CMV-seropositive older adults was related to an anti-inflammatory status and enhancement of naive CD8+ T cells, particularly associated with regular practice of CET.


Assuntos
Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Memória Imunológica , Vacinas contra Influenza/imunologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/virologia , Exercício Físico , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Masculino , Vacinação
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