RESUMEN
Cytomegalovirus (CMV) infection poses risks to newborns, necessitating effective therapies. Given that the damage includes both viral infection of brain cells and immune system-related damage, here we investigate the involvement of cellular prion protein (PrP), which plays vital roles in neuroprotection and immune regulation. Using a murine model, we show the role of PrP in tempering neonatal T cell immunity during CMV infection. PrP-null mice exhibit enhanced viral control through elevated virus-specific CD8 T cell responses, leading to reduced viral titers and pathology. We further unravel the molecular mechanisms by showing CMV-induced upregulation followed by release of PrP via the metalloproteinase ADAM10, impairing CD8 T cell response specifically in neonates. Additionally, we confirm PrP downregulation in human CMV (HCMV)-infected fibroblasts, underscoring the broader relevance of our observations beyond the murine model. Furthermore, our study highlights how PrP, under the stress of viral pathogenesis, reveals its impact on neonatal immune modulation.
Asunto(s)
Animales Recién Nacidos , Linfocitos T CD8-positivos , Infecciones por Citomegalovirus , Citomegalovirus , Ratones Noqueados , Animales , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Citomegalovirus/inmunología , Humanos , Ratones , Linfocitos T CD8-positivos/inmunología , Femenino , Fibroblastos/metabolismo , Fibroblastos/virología , Proteínas Priónicas/metabolismo , Proteínas Priónicas/genética , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Proteína ADAM10/metabolismo , Proteína ADAM10/genéticaRESUMEN
Human cytomegalovirus (HCMV) glycoprotein B (gB) is a class III membrane fusion protein required for viral entry. HCMV vaccine candidates containing gB have demonstrated moderate clinical efficacy, but no HCMV vaccine has been approved. Here, we used structure-based design to identify and characterize amino acid substitutions that stabilize gB in its metastable prefusion conformation. One variant containing two engineered interprotomer disulfide bonds and two cavity-filling substitutions (gB-C7), displayed increased expression and thermostability. A 2.8 Å resolution cryoelectron microscopy structure shows that gB-C7 adopts a prefusion-like conformation, revealing additional structural elements at the membrane-distal apex. Unlike previous observations for several class I viral fusion proteins, mice immunized with postfusion or prefusion-stabilized forms of soluble gB protein displayed similar neutralizing antibody titers, here specifically against an HCMV laboratory strain on fibroblasts. Collectively, these results identify initial strategies to stabilize class III viral fusion proteins and provide tools to probe gB-directed antibody responses.
Asunto(s)
Citomegalovirus , Proteínas del Envoltorio Viral , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/metabolismo , Citomegalovirus/inmunología , Humanos , Animales , Ratones , Microscopía por Crioelectrón , Conformación Proteica , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Internalización del Virus , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Estabilidad Proteica , Vacunas contra Citomegalovirus/inmunología , Sustitución de Aminoácidos , Modelos MolecularesRESUMEN
BACKGROUND: Congenital cytomegalovirus (cCMV) infection can lead to a range of adverse outcomes. The majority of cCMV neonates with clinical symptoms are infected postnatally; however, established cases of intrauterine infection are uncommon, resulting in a paucity of reports on clinical findings and lymphocytes expression in CMV-infected neonates. CASE PRESENTATION: We followed a neonate with cCMV infection from the onset of hospitalization to several months of follow-up. This infant was intrauterine CMV-positive in the amniotic fluid of the mother at 21 weeks' gestation and received intravenous ganciclovir infusion and sequential oral valganciclovir after birth. The typical clinical signs manifested in the nervous system, liver, and peripheral blood and were documented during the hospitalizaion period and up to the follow-up visit. Flow cytometry was employed to examine the expression of T cells, their subsets, and the associated cytokines in peripheral blood samples at various time points. The flow data for the cCMV neonate were compared with those of the controls at each time point. Following treatment, clinical symptoms improved and the infant became CMV negative. However, developmental delays occurred later in life. The proportion of CD8+CD28- Tregs in the peripheral blood of the neonate with congenital CMV infection was higher than that in the controls at the three time points. The expression levels of perforin and granzyme B secreted by γδ T cells (Vδ1 and Vδ2 T cells), increased during the course of hospitalization until follow-up and were higher than those in the controls at the three time points. CONCLUSIONS: Despite the alleviation of clinical symptoms, developmental delay in later life remains inevitable in this intrauterine cCMV neonate. CD8+CD28- Tregs and Vδ1 and Vδ2 T cells secreting perforin and granzyme B may be involved in congenital CMV infection, although this hypothesis requires validation in a larger study. This report may contribute to our understanding of the effect of current treatment and the immune status of intrauterine cCMV-infected neonates.
Asunto(s)
Infecciones por Citomegalovirus , Linfocitos T Reguladores , Humanos , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/tratamiento farmacológico , Recién Nacido , Femenino , Linfocitos T Reguladores/inmunología , Embarazo , Linfocitos T CD8-positivos/inmunología , Antígenos CD28 , Complicaciones Infecciosas del Embarazo , Perforina/metabolismo , Antivirales/uso terapéutico , Masculino , Ganciclovir/uso terapéutico , Granzimas/metabolismoRESUMEN
BACKGROUND/AIM: Wilms' tumors are pediatric renal tumors that generally have a good prognosis and outcomes. Viral illnesses have been linked to development of neoplasms and should be considered as a factor that could modulate overall survival. MATERIALS AND METHODS: We considered recently developed adaptive immune receptor, genomics and bioinformatics approaches to assess the potential impact of cytomegalovirus (CMV) infections in Wilms' tumor. RESULTS: T-cell receptor (TCR) complementarity determining region-3 (CDR3) amino acid sequences from Wilms' tumor specimens represented by the Therapeutically Applicable Research to Generate Effective Treatments dataset were compared with known anti-CMV TCR CDR3s, indicating that cases representing the anti-CMV TCR CDR3s had worse outcomes. Then, a chemical complementarity scoring approach for the Wilms' tumor, TCR CDR3s and a series of CMV antigens further indicated that cases representing a higher chemical complementarity to the CMV antigens had worse outcomes. CONCLUSION: Overall, we present a potentially novel method to assess CMV infections and identify patients who could benefit from therapies that address such infections.
Asunto(s)
Regiones Determinantes de Complementariedad , Citomegalovirus , Neoplasias Renales , Receptores de Antígenos de Linfocitos T , Tumor de Wilms , Humanos , Tumor de Wilms/inmunología , Tumor de Wilms/genética , Regiones Determinantes de Complementariedad/genética , Regiones Determinantes de Complementariedad/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Neoplasias Renales/inmunología , Neoplasias Renales/genética , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Pronóstico , Epítopos/inmunologíaRESUMEN
Human cytomegalovirus (HCMV) infection remains a major complication for solid organ transplant recipients (SOTRs). The aim of this study was to evaluate the role of HCMV-specific T cell immunity measured at the time of the HCMV-DNA peak in predicting the spontaneous clearance of infection. The performance of cytokine flow cytometry using infected dendritic cells (CFC-iDC), infected cell lysate (CFC-iCL) and pp65 peptide pool (CFC-pp65 pool) as stimuli, as well as ELISPOT assays using infected cell lysate (ELISPOT-iCL) and the pp65 peptide pool (ELISPOT-pp65 pool), was analysed. Among the 40 SOTRs enrolled, 16 patients (40%) required antiviral treatment for an HCMV infection (Non-Controllers), while the others spontaneously cleared the infection (Controllers). At the HCMV-DNA peak, the number of HCMV-specific CD4+ T cells detected by the CFC-iDC, CFC-iCL and CFC-pp65 pool assays in Controllers was higher than that detected in Non-Controllers, while no difference was observed in terms of HCMV-specific CD8+ T cell response. The same trend was observed when the HCMV-specific T cell response was measured by ELISPOT-iCL and ELISPOT-pp65 pool. We observed that the CD4+ CFC-pp65 pool assay was the best predictor of self-resolving HCMV infection at the time of the HCVM-DNA peak. The CFC-pp65 pool assay is able to discriminate between CD4+ and CD8+ T cell responses and could be used in daily clinical practice.
Asunto(s)
Infecciones por Citomegalovirus , Citomegalovirus , Receptores de Trasplantes , Humanos , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Citomegalovirus/inmunología , Femenino , Masculino , Persona de Mediana Edad , Adulto , Trasplante de Órganos/efectos adversos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD4-Positivos/inmunología , Anciano , ADN Viral , Células Dendríticas/inmunología , Ensayo de Immunospot Ligado a Enzimas , Pruebas Inmunológicas/métodos , Citocinas/metabolismoRESUMEN
CD8 T cells are the predominant effector cells of adaptive immunity in preventing cytomegalovirus (CMV) multiple-organ disease caused by cytopathogenic tissue infection. The mechanism by which CMV-specific, naïve CD8 T cells become primed and clonally expand is of fundamental importance for our understanding of CMV immune control. For CD8 T-cell priming, two pathways have been identified: direct antigen presentation by infected professional antigen-presenting cells (pAPCs) and antigen cross-presentation by uninfected pAPCs that take up antigenic material derived from infected tissue cells. Studies in mouse models using murine CMV (mCMV) and precluding either pathway genetically or experimentally have shown that, in principle, both pathways can congruently generate the mouse MHC/H-2 class-I-determined epitope-specificity repertoire of the CD8 T-cell response. Recent studies, however, have shown that direct antigen presentation is the canonical pathway when both are accessible. This raised the question of why antigen cross-presentation is ineffective even under conditions of high virus replication thought to provide high amounts of antigenic material for feeding cross-presenting pAPCs. As delivery of antigenic material for cross-presentation is associated with programmed cell death, and as CMVs encode inhibitors of different cell death pathways, we pursued the idea that these inhibitors restrict antigen delivery and thus CD8 T-cell priming by cross-presentation. To test this hypothesis, we compared the CD8 T-cell responses to recombinant mCMVs lacking expression of the apoptosis-inhibiting protein M36 or the necroptosis-inhibiting protein M45 with responses to wild-type mCMV and revertant viruses expressing the respective cell death inhibitors. The data reveal that increased programmed cell death improves CD8 T-cell priming in mice capable of antigen cross-presentation but not in a mutant mouse strain unable to cross-present. These findings strongly support the conclusion that CMV cell death inhibitors restrict the priming of CD8 T cells by antigen cross-presentation.
Asunto(s)
Presentación de Antígeno , Linfocitos T CD8-positivos , Reactividad Cruzada , Infecciones por Citomegalovirus , Animales , Linfocitos T CD8-positivos/inmunología , Ratones , Reactividad Cruzada/inmunología , Presentación de Antígeno/inmunología , Infecciones por Citomegalovirus/inmunología , Muromegalovirus/inmunología , Apoptosis , Citomegalovirus/inmunología , Células Presentadoras de Antígenos/inmunología , Ratones Endogámicos C57BL , Antígenos Virales/inmunologíaRESUMEN
Human cytomegalovirus (HCMV) is the most common congenital infection. Several HCMV vaccines are in development, but none have yet been approved. An understanding of the kinetics of CMV replication and transmission may inform the rational design of vaccines to prevent this infection. The salivary glands (SG) are an important site of sustained CMV replication following primary infection and during viral reactivation from latency. As such, the strength of the immune response in the SG likely influences viral dissemination within and between hosts. To study the relationship between the immune response and viral replication in the SG, and viral dissemination from the SG to other tissues, mice were infected with low doses of murine CMV (MCMV). Following intra-SG inoculation, we characterized the viral and immunological dynamics in the SG, blood, and spleen, and identified organ-specific immune correlates of protection. Using these data, we constructed compartmental mathematical models of MCMV infection. Model fitting to data and analysis indicate the importance of cellular immune responses in different organs and point to a threshold of infection within the SG necessary for the establishment and spread of infection.
Asunto(s)
Muromegalovirus , Glándulas Salivales , Animales , Glándulas Salivales/virología , Glándulas Salivales/inmunología , Ratones , Muromegalovirus/inmunología , Muromegalovirus/fisiología , Replicación Viral/fisiología , Cinética , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/virología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/transmisión , Biología ComputacionalRESUMEN
Cytomegalovirus (CMV) has successfully established a long-lasting latent infection in humans due to its ability to counteract the host antiviral innate immune response. During coevolution with the host, the virus has evolved various evasion techniques to evade the host's innate immune surveillance. At present, there is still no vaccine available for the prevention and treatment of CMV infection, and the interaction between CMV infection and host antiviral innate immunity is still not well understood. However, ongoing studies will offer new insights into how to treat and prevent CMV infection and its related diseases. Here, we update recent studies on how CMV evades antiviral innate immunity, with a focus on how CMV proteins target and disrupt critical adaptors of antiviral innate immune signaling pathways. This review also discusses some classic intrinsic cellular defences that are crucial to the fight against viral invasion. A comprehensive review of the evasion mechanisms of antiviral innate immunity by CMV will help investigators identify new therapeutic targets and develop vaccines against CMV infection.
Asunto(s)
Infecciones por Citomegalovirus , Citomegalovirus , Evasión Inmune , Inmunidad Innata , Humanos , Inmunidad Innata/inmunología , Citomegalovirus/inmunología , Evasión Inmune/inmunología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Transducción de Señal/inmunología , Interacciones Huésped-Patógeno/inmunología , Animales , Proteínas Virales/inmunología , Proteínas Virales/metabolismoRESUMEN
The signal sequences of the human cytomegalovirus (CMV) UL40 protein and its rhesus CMV (RhCMV) counterpart, Rh67, contain a peptide (VMAPRT[L/V][F/I/L/V]L, VL9) that is presented by major histocompatibility complex (MHC) antigen E (MHC-E). The CMV VL9 peptides replace VL9 peptides derived from classical MHC (Ia) signal sequences, which are lost when CMV disrupts antigen processing and presentation and MHC Ia expression. This allows infected cells to maintain MHC-E surface expression and escape killing by Natural Killer cells. We demonstrate that processing of the Rh67 VL9 peptide mirrors that of UL40, despite the lack of sequence conservation between the two proteins. Processing of both VL9 peptides is dependent on cleavage of their signal sequences by the host protease signal peptide peptidase. As previously shown for UL40, up-regulation of MHC-E expression by Rh67 requires only its signal sequence, with sequences upstream of VL9 critical for conferring independence from TAP, the transporter associated with antigen processing. Our results also suggest that the mature UL40 and Rh67 proteins contribute to CMV immune evasion by decreasing surface expression of MHC Ia. Unexpectedly, while the Rh67 VL9 peptide is resistant to the effects of Rh67, UL40 can partially counteract the up-regulation of MHC-E expression mediated by its own VL9 peptide. This suggests differences in the mechanisms by which the two VL9 peptides up-regulate MHC-E, and further work will be required to determine if any such differences have implications for translating a RhCMV-vectored simian immunodeficiency virus (SIV) vaccine to HIV-1 using human CMV as a vector. IMPORTANCE: The protective immune response induced by a rhesus cytomegalovirus (RhCMV)-vectored simian immunodeficiency virus (SIV) vaccine in rhesus macaques depends on the presence of the viral Rh67 gene in the vaccine. The Rh67 protein contains a peptide that allows the RhCMV-infected cells to maintain expression of major histocompatibility complex (MHC) antigen E at the cell surface. We show that production of this peptide, referred to as "VL9," mirrors that of the equivalent peptide present in the human cytomegalovirus (CMV) protein UL40, despite the little sequence similarity between the two CMV proteins. We also show that the mature UL40 and Rh67 proteins, which have no previously described function, also contribute to CMV immune evasion by reducing cell surface expression of MHC proteins important for the immune system to detect infected cells. Despite these similarities, our work also reveals possible differences between Rh67 and UL40, and these may have implications for the use of human CMV as the vector for a potential HIV-1 vaccine.
Asunto(s)
Citomegalovirus , Antígenos de Histocompatibilidad Clase I , Macaca mulatta , Proteínas Virales , Citomegalovirus/inmunología , Humanos , Animales , Proteínas Virales/metabolismo , Proteínas Virales/inmunología , Proteínas Virales/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Antígenos de Histocompatibilidad Clase I/inmunología , Presentación de Antígeno , Señales de Clasificación de Proteína , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Evasión InmuneRESUMEN
CMV drives the accumulation of virus-specific, highly differentiated CD8 memory T cells (memory inflation [MI]). In mice, MI was shown to directly correlate with the CMV infection dose, yet the CMV-associated CD8 MI plateaus over time. It is unclear how MI is regulated with aging. We infected young mice with 102, 104, and 106 PFU of murine CMV and confirmed that MI magnitude was directly proportional to the infectious dose, reaching a setpoint by midlife. By old age, MI subsided, most prominently in mice infected with 106 PFU, and reached statistical parity between groups in 26-mo-old mice. This corresponded to an age-related loss in lymphatic endothelial cells in lymph nodes, recently shown to be sufficient to drive MI in mice. We propose that MI size and persistence over the lifespan is controlled by the size of the lymphatic endothelial cell niche, whose shrinking leads to reduced MI with aging.
Asunto(s)
Linfocitos T CD8-positivos , Memoria Inmunológica , Muromegalovirus , Latencia del Virus , Animales , Ratones , Linfocitos T CD8-positivos/inmunología , Latencia del Virus/inmunología , Memoria Inmunológica/inmunología , Muromegalovirus/inmunología , Envejecimiento/inmunología , Ratones Endogámicos C57BL , Células T de Memoria/inmunología , Infecciones por Citomegalovirus/inmunología , Infecciones por Herpesviridae/inmunología , Células Endoteliales/inmunología , Células Endoteliales/virología , Citomegalovirus/inmunología , Citomegalovirus/fisiología , Ganglios Linfáticos/inmunologíaRESUMEN
This systematic review discusses the use of prophylaxis to prevent cytomegalovirus (CMV) infection in recipients who have undergone hematopoietic cell transplantation. It highlights the need for new approaches to control and prevent CMV infection. The approval of the anti-CMV drug letermovir has made antiviral prophylaxis more popular. CMV-specific T cell-mediated immunity tests are effective in identifying patients who have undergone immune reconstitution and predicting disease progression. Maribavir (MBV) has been approved for the treatment of post-transplant CMV infection/disease in adolescents. Adoptive T-cell therapy and the PepVax CMV vaccine show promise in tackling refractory and resistant CMV. However, the effectiveness of PepVax in reducing CMV viremia/disease was not demonstrated in a phase II trial. Cell-mediated immunity assays are valuable for personalized management plans, but more interventional studies are needed. MBV and adoptive T-cell therapy are promising treatments, and trials for CMV vaccines are ongoing.
Asunto(s)
Antivirales , Infecciones por Citomegalovirus , Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Humanos , Antivirales/administración & dosificación , Citomegalovirus/efectos de los fármacos , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/prevención & control , Infecciones por Citomegalovirus/virología , Vacunas contra Citomegalovirus/administración & dosificación , Vacunas contra Citomegalovirus/inmunología , Diclororribofuranosil Benzoimidazol/administración & dosificación , Diclororribofuranosil Benzoimidazol/análogos & derivados , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Linfocitos T/inmunologíaRESUMEN
The most common congenital viral infection is CMV, which leads to numerous neurologic disabilities. Using a mouse model of congenital CMV, we previously determined that Ag-specific CD8+ T cells traffic to the brain in a CCR9-dependent manner. The mechanism by which these CD8+ T cells acquire a CCR9-dependent "brain-tropic" phenotype remains unclear. In this study, we identify the key factor that imprints brain homing specificity on CD8+ T cells, the source of production, and the location where CCR9 expression is induced. Specifically, we discovered that CCR9 is induced on CD8+ T cells by retinoic acid-producing CD8α+ dendritic cells in the cervical lymph node postinfection. We found that retinoic acid is important for CD8+ T cells to establish tissue residency in the brain. Collectively, our data expand the role of retinoic acid during infection and mechanistically demonstrate how CD8+ T cells are primed to protect the brain during congenital viral infection.
Asunto(s)
Encéfalo , Linfocitos T CD8-positivos , Infecciones por Citomegalovirus , Tretinoina , Animales , Linfocitos T CD8-positivos/inmunología , Tretinoina/metabolismo , Ratones , Infecciones por Citomegalovirus/inmunología , Encéfalo/inmunología , Ratones Endogámicos C57BL , Células Dendríticas/inmunología , Citomegalovirus/inmunología , Modelos Animales de Enfermedad , Movimiento Celular/inmunologíaRESUMEN
Primary cytomegalovirus infection during pregnancy has a high risk of vertical transmission, with severe fetal sequelae mainly associated with first-trimester infections. We conducted a retrospective analysis of 200 IU/kg cytomegalovirus-specific hyperimmune globulin (HIG), used in first-trimester maternal primary infections for congenital infection prevention. The primary outcome was vertical transmission, defined as neonatal viruria or positive amniocentesis if pregnancy was discontinued. HIG, initially administered monthly and since 2019 biweekly, was discontinued in negative amniocentesis cases. Women declining amniocentesis and positive amniocentesis cases with normal sonography were offered monthly HIG until delivery as a treatment strategy. The total transmission rate was 29.9% (32/107; 10 pregnancy terminations with positive amniocentesis, 18 completed pregnancies with positive amniocentesis and 4 declining amniocentesis). Maternal viremia was the only factor associated with fetal transmission (OR 4.62, 95% CI 1.55-13.74). The transmission rate was not significantly different whether HIG was started during the first or second trimester (28.2% vs. 33.3%; p = 0.58), or between monthly and biweekly subgroups (25.7% vs. 37.8%, p = 0.193). Pre-treatment maternal viremia could inform decisions as a predictor of congenital infection.
Asunto(s)
Infecciones por Citomegalovirus , Transmisión Vertical de Enfermedad Infecciosa , Complicaciones Infecciosas del Embarazo , Primer Trimestre del Embarazo , Humanos , Femenino , Embarazo , Infecciones por Citomegalovirus/prevención & control , Infecciones por Citomegalovirus/transmisión , Infecciones por Citomegalovirus/inmunología , Estudios Retrospectivos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Adulto , Complicaciones Infecciosas del Embarazo/prevención & control , Complicaciones Infecciosas del Embarazo/virología , Inmunoglobulinas/administración & dosificación , Inmunoglobulinas/uso terapéutico , Prevención Secundaria/métodos , Recién Nacido , Citomegalovirus/inmunología , Estudios de Cohortes , Amniocentesis , Viremia , Inmunoglobulinas IntravenosasRESUMEN
The QuantiFERON CMV (QCMV) test evaluates specific adaptive immune system activity against CMV by measuring IFN-γ released by activated CD8+ T lymphocytes. We aimed to evaluate the QCMV test as a predictive tool for CMV manifestations and acute or chronic lung allograft rejection (AR and CLAD) in lung transplant (LTx) patients. A total of 73 patients were divided into four groups based on donor and recipient (D/R) serology for CMV and QCMV assay: group A low-risk for CMV infection and disease (D-/R-); group B and C at intermediate-risk (R+), group B with non-reactive QCMV and group C with reactive QCMV; group D at high-risk (D+/R-). Group D patients experienced higher viral replication; no differences were observed among R+ patients of groups B and C. D+/R- patients had a higher number of AR events and group C presented a lower incidence of AR. Prevalence of CLAD at 24 months was higher in group B with a higher risk of CLAD development (OR 6.33). The QCMV test allows us to identify R+ non-reactive QCMV population as the most exposed to onset of CLAD. This population had a higher, although non-significant, susceptibility to AR compared to the R+ population with reactive QCMV.
Asunto(s)
Infecciones por Citomegalovirus , Citomegalovirus , Rechazo de Injerto , Trasplante de Pulmón , Humanos , Trasplante de Pulmón/efectos adversos , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/inmunología , Rechazo de Injerto/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Citomegalovirus/inmunología , Adulto , Anciano , Interferón gamma/sangre , Linfocitos T CD8-positivos/inmunología , Aloinjertos , Ensayos de Liberación de Interferón gamma/métodos , Enfermedad CrónicaRESUMEN
Cytomegalovirus (CMV), a representative member of the Betaherpesvirinae subfamily of herpesviruses, is common in the human population, but immunocompetent individuals are generally asymptomatic when infected with this virus. However, in immunocompromised individuals and immunologically immature fetuses and newborns, CMV can cause a wide range of often long-lasting morbidities and even death. CMV is not only widespread throughout the population but it is also widespread in its hosts, infecting and establishing latency in nearly all tissues and organs. Thus, understanding the pathogenesis of and immune responses to this virus is a prerequisite for developing effective prevention and treatment strategies. Multiple arms of the immune system are engaged to contain the infection, and general concepts of immune control of CMV are now reasonably well understood. Nonetheless, in recent years, tissue-specific immune responses have emerged as an essential factor for resolving CMV infection. As tissues differ in biology and function, so do immune responses to CMV and pathological processes during infection. This review discusses state-of-the-art knowledge of the immune response to CMV infection in tissues, with particular emphasis on several well-studied and most commonly affected organs.
Asunto(s)
Infecciones por Citomegalovirus , Citomegalovirus , Vigilancia Inmunológica , Humanos , Citomegalovirus/inmunología , Citomegalovirus/fisiología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Animales , Especificidad de Órganos/inmunologíaRESUMEN
Previous studies of the immune control of cytomegalovirus infection have primarily focused on analysis of the traditional adaptive T-cell response. Donadeu et al. bring a new perspective through evaluation of multiple adaptive and innate immune subtypes in parallel with cytomegalovirus-specific cell-mediated immunity in a prospective cohort of kidney transplant recipients with findings validated in 2 independent studies. Identification of a natural killer T-cell subtype associated with cell-mediated immunity and freedom from cytomegalovirus infection demonstrates the importance of the coordinated innate and adaptive immune response for effective viral control.
Asunto(s)
Inmunidad Adaptativa , Infecciones por Citomegalovirus , Citomegalovirus , Inmunidad Innata , Trasplante de Riñón , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/prevención & control , Humanos , Trasplante de Riñón/efectos adversos , Citomegalovirus/inmunología , Inmunidad Celular , Células T Asesinas Naturales/inmunologíaRESUMEN
Introduction: Human Cytomegalovirus (HCMV) is a betaherpesvirus that causes severe disease in immunocompromised transplant recipients. Immunotherapy with CD8 T cells specific for HCMV antigens presented on HLA class-I molecules is explored as strategy for long-term relief to such patients, but the antiviral effectiveness of T cell preparations cannot be efficiently predicted by available methods. Methods: We developed an Assay for Rapid Measurement of Antiviral T-cell Activity (ARMATA) by real-time automated fluorescent microscopy and used it to study the ability of CD8 T cells to neutralize HCMV and control its spread. As a proof of principle, we used TCR-transgenic T cells specific for the immunodominant HLA-A02-restricted tegumental phosphoprotein pp65. pp65 expression follows an early/late kinetic, but it is not clear at which stage of the virus cycle it acts as an antigen. We measured control of HCMV infection by T cells as early as 6 hours post infection (hpi). Results: The timing of the antigen recognition indicated that it occurred before the late phase of the virus cycle, but also that virion-associated pp65 was not recognized during virus entry into cells. Monitoring of pp65 gene expression dynamics by reporter fluorescent genes revealed that pp65 was detectable as early as 6 hpi, and that a second and much larger bout of expression occurs in the late phase of the virus cycle by 48 hpi. Since transgenic (Tg)-pp65 specific CD8 T cells were activated even when DNA replication was blocked, our data argue that pp65 acts as an early virus gene for immunological purposes. Discussion: ARMATA does not only allow same day identification of antiviral T-cell activity, but also provides a method to define the timing of antigen recognition in the context of HCMV infection.
Asunto(s)
Linfocitos T CD8-positivos , Infecciones por Citomegalovirus , Citomegalovirus , Fosfoproteínas , Proteínas de la Matriz Viral , Linfocitos T CD8-positivos/inmunología , Citomegalovirus/inmunología , Citomegalovirus/genética , Fosfoproteínas/inmunología , Fosfoproteínas/genética , Humanos , Proteínas de la Matriz Viral/inmunología , Proteínas de la Matriz Viral/genética , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Regulación Viral de la Expresión Génica , Antígenos Virales/inmunología , Antígeno HLA-A2/inmunología , Antígeno HLA-A2/genéticaRESUMEN
M.R2k/b mice are identical to the MA/My parent strain aside from a 5.58-Mb C57L-derived region on chromosome 17 (Cmv5s) that causes increased susceptibility to acute murine CMV (MCMV) infection and the development of significant spleen tissue damage. Spleen pathology begins at the marginal zone (MZ), apparent by 2 d postinfection (dpi), and progresses throughout the red pulp by 4 dpi. To better understand how M.R2k/b mice respond to infection and how Cmv5s contributes to tissue damage in the spleen, we assessed the regulation of myeloid cells and inflammation during acute MCMV infection in MA/My and M.R2k/b mice. We found that Cmv5s drove increased neutrophil accumulation and cell death at the MZ, which corresponded with evidence of localized oxidative stress and increased overall spleen IL-6 and TGF-ß1 early during infection. Further assessment of MCMV infection dynamics at the early MZ revealed infected SIGNR1+ MZ macrophages as the first apparent cell type lost during infection in these mice and the likely target of early neutrophil recruitment. Spleen macrophages were also identified as the mediators of differential spleen IL-6 and TGF-ß1 between MA/My and M.R2k/b mice. Interrogation of MCMV progression past 2 dpi revealed substantial M.R2k/b F480+ red pulp macrophage loss along with buildup of oxidative stress and MZ macrophage debris that was not neutrophil dependent. Together we identify Cmv5s-driven macrophage loss and inflammation during acute MCMV infection corresponding with the spatial and temporal development of spleen tissue damage.
Asunto(s)
Inflamación , Macrófagos , Muromegalovirus , Bazo , Animales , Ratones , Macrófagos/inmunología , Inflamación/inmunología , Muromegalovirus/inmunología , Bazo/inmunología , Bazo/patología , Bazo/virología , Modelos Animales de Enfermedad , Neutrófilos/inmunología , Ratones Endogámicos C57BL , Infecciones por Herpesviridae/inmunología , Enfermedad Aguda , Susceptibilidad a Enfermedades/inmunología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/genética , Predisposición Genética a la EnfermedadRESUMEN
Human cytomegalovirus (HCMV) is accountable for high morbidity in neonates and immunosuppressed individuals. Due to the high genetic variability of HCMV, current prophylactic measures are insufficient. In this study, we employed a pan-genome and reverse vaccinology approach to screen the target for efficient vaccine candidates. Four proteins, envelope glycoprotein M, UL41A, US23, and US28, were shortlisted based on cellular localization, high solubility, antigenicity, and immunogenicity. A total of 29 B-cell and 44 T-cell highly immunogenic and antigenic epitopes with high global population coverage were finalized using immunoinformatics tools and algorithms. Further, the epitopes that were overlapping among the finalized B-cell and T-cell epitopes were linked with suitable linkers to form various combinations of multi-epitopic vaccine constructs. Among 16 vaccine constructs, Vc12 was selected based on physicochemical and structural properties. The docking and molecular simulations of VC12 were performed, which showed its high binding affinity (-23.35 kcal/mol) towards TLR4 due to intermolecular hydrogen bonds, salt bridges, and hydrophobic interactions, and there were only minimal fluctuations. Furthermore, Vc12 eliciting a good response was checked for its expression in Escherichia coli through in silico cloning and codon optimization, suggesting it to be a potent vaccine candidate.
Asunto(s)
Citomegalovirus , Epítopos de Linfocito T , Humanos , Citomegalovirus/inmunología , Citomegalovirus/genética , Epítopos de Linfocito T/inmunología , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/química , Vacunas contra Citomegalovirus/inmunología , Vacunas contra Citomegalovirus/genética , Epítopos de Linfocito B/inmunología , Epítopos de Linfocito B/genética , Epítopos de Linfocito B/química , Vacunología/métodos , Genoma Viral , Infecciones por Citomegalovirus/prevención & control , Infecciones por Citomegalovirus/inmunología , Simulación del Acoplamiento MolecularRESUMEN
OBJECTIVES: Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections in patients with Neuromyelitis optica spectrum disorder (NMOSD) remain unclear. The objective of this study was to investigate CMV and EBV infections in patients with NMOSD. METHODS: Serum immunoglobin (Ig) G antibodies against CMV and EBV were measured in patients with NMOSD and healthy controls (HCs), including anti-CMV, anti-EBV nuclear antigen-1 (EBNA-1), anti-EBV virus capsid antigen (VCA), and anti-EBV early antigen (EA) IgGs. The immune status ratio (ISR) was used to evaluate the serum anti-CMV and anti-EBV IgG levels and ISR â§1.10 was defined as seropositivity. RESULTS: In total, 238 serum samples were collected from 94 patients with NMOSD and 144 HCs, and no significant difference of sex and age between NMOSD and HCs. Comparing to the HCs, patients with NMOSD exhibited significantly higher serum anti-CMV IgG level. In contrast, the serum anti-EBNA1 IgG level was significantly lower in patients with NMOSD than in HCs. The serum anti-VCA and anti-EA IgG levels did not differ between the two groups, but the anti-EA seropositivity was significantly higher in NMOSD group than that in HC group. We did not find associations between serum anti-CMV or anti-EBV IgG levels and NMOSD disease stage, immunotherapy, or disability score. CONCLUSIONS: Our findings indicated that increased CMV infection and EBV recent infection, as well as reduced EBV latency infection were associated with the risk of NMOSD. Prospective cohort studies are needed to verify our findings and clarify the correlation between CMV and EBV infections and clinical characteristics of NMOSD.