Immune senescence: relative contributions of age and cytomegalovirus infection.
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ABSTRACT:
SUBMITTER: Mekker A
PROVIDER: S-EPMC3420944 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The relationship between human cytomegalovirus (HCMV) infections and accelerated immune senescence is controversial. Whereas some studies reported a CMV-associated impaired capacity to control heterologous infections at old age, other studies could not confirm this. We hypothesized that these discrepancies might relate to the variability in the infectious dose of CMV occurring in real life. Here, we investigated the influence of persistent CMV infection on immune perturbations and specifically addressed the role of the infectious dose on the contribution of CMV to accelerated immune senescence. We show in experimental mouse models that the degree of mouse CMV (MCMV)-specific memory CD8+ T cell accumulation and the phenotypic T cell profile are directly influenced by the infectious dose, and data on HCMV-specific T cells indicate a similar connection. Detailed cluster analysis of the memory CD8+ T cell development showed that high-dose infection causes a differentiation pathway that progresses faster throughout the life span of the host, suggesting a virus-host balance that is influenced by aging and infectious dose. Importantly, short-term MCMV infection in adult mice is not disadvantageous for heterologous superinfection with lymphocytic choriomeningitis virus (LCMV). However, following long-term CMV infection the strength of the CD8+ T cell immunity to LCMV superinfection was affected by the initial CMV infectious dose, wherein a high infectious dose was found to be a prerequisite for impaired heterologous immunity. Altogether our results underscore the importance of stratification based on the size and differentiation of the CMV-specific memory T cell pools for the impact on immune senescence, and indicate that reduction of the latent/lytic viral load can be beneficial to diminish CMV-associated immune senescence.
| S-EPMC5768196 | biostudies-literature
Project description:Oncogene-induced senescence acts as a barrier against tumour formation and has been implicated as the mechanism preventing the transformation of benign melanocytic lesions that frequently harbour oncogenic B-RAF or N-RAS mutations. In the present study we systematically assessed the relative importance of the tumour suppressor proteins p53, p21(Waf1), pRb and p16(INK4a) in mediating oncogene-induced senescence in human melanocytes. We now show that oncogenic N-RAS induced senescence in melanocytes is associated with DNA damage, a potent DNA damage response and the activation of both the p16(INK4a)/pRb and p53/p21(Waf1) tumour suppressor pathways. Surprisingly neither the pharmacological inhibition of the DNA damage response pathway nor silencing of p53 expression had any detectable impact on oncogene-induced senescence in human melanocytes. Our data indicate that the pRb pathway is the dominant effector of senescence in these cells, as its specific inactivation delays the onset of senescence and weakens oncogene-induced proliferative arrest. Furthermore, we show that although both p16(INK4a) and p21(Waf1) are upregulated in response to N-RAS(Q61K), the activities of these CDK inhibitors are clearly distinct and only the loss of p16(INK4a) weakens senescence. We propose that the ability of p16(INK4a) to inhibit the cyclin D-dependent kinases and DNA replication, functions not shared by p21(Waf1), contribute to its role in senescence. Thus, in melanocytes with oncogenic signalling only p16(INK4a) can fully engage the pRb pathway to alter chromatin structure and silence the genes that are required for proliferation.
| S-EPMC2806033 | biostudies-literature
Project description:Aging reflects long-term decline in physiological function and integrity. Changes arise at a variable pace governed by time-dependent and -independent mechanisms that are themselves complex, interdependent and variable. Molecular decay produces inferior cells that eventually dominate over healthy counterparts in tissues they comprise. In a form of biological entropy, progression from molecular through cellular to tissue level degeneration culminates in organ disease or dysfunction, affecting systemic health. To better understand time-independent contributors and their potential modulation, common biophysical bases for key molecular and cellular changes underlying age-related physiological deterioration must be delineated. This review addresses the potential contribution of cytomegalovirus (CMV)-driven T cell proliferation to cellular senescence and immunosenescence. We first describe molecular processes imposing cell cycle arrest, the foundation of cellular senescence, then focus on the unique distribution, phenotype and function of CMV-specific CD8+ T cells in the context of cellular senescence and "inflammaging". Their features position CMV infection as a pathogenic accelerant of immune cell proliferation underlying immune senescence. In human immunodeficiency virus (HIV) infection, where increased inflammation and exaggerated anti-CMV immune responses accelerate immune senescence, CMV infection has emerged as a major factor in unhealthy aging. Thus, we speculate on mechanistic links between CMV-specific CD8+ T-cell expansion, immune senescence and prevalence of age-related disorders in HIV infection.
| S-EPMC7140628 | biostudies-literature
Project description:Aging confers increased susceptibility to common pathogens including influenza A virus. Despite shared vulnerability to infection with advancing age in humans and rodents, the relatively long time required for immune senescence to take hold practically restricts the use of naturally aged mice to investigate aging-induced immunological shifts. Here, we show accelerated aging Lmna(Dhe) mice with spontaneous mutation in the nuclear scaffolding protein, lamin A, replicate infection susceptibility, and substantial immune cell shifts that occur with advancing age. Naturally aged (≥ 20 month) and 2- to 3-month-old Lmna(Dhe) mice share near identically increased influenza A susceptibility compared with age-matched Lmna(WT) control mice. Increased mortality and higher viral burden after influenza infection in Lmna(Dhe) mice parallel reduced accumulation of lung alveolar macrophage cells, systemic expansion of immune suppressive Foxp3⁺ regulatory T cells, and skewed immune dominance among viral-specific CD8⁺T cells similar to the immunological phenotype of naturally aged mice. Thus, aging-induced infection susceptibility and immune senescence are replicated in accelerated aging Lmna(Dhe) mice.
| S-EPMC4693468 | biostudies-literature
Project description:Human Cytomegalovirus (HCMV) infection is widespread and can result in severe sequelae in susceptible populations. Primary HCMV infection of naïve individuals results in life-long latency characterized by frequent and sporadic reactivations. HCMV infection elicits a robust antibody response, including neutralizing antibodies that can block the infection of susceptible cells in vitro and in vivo. Thus, antibody products and vaccines hold great promise for the prevention and treatment of HCMV, but to date, most attempts to demonstrate their safety and efficacy in clinical trials have been unsuccessful. In this review we summarize publicly available data on these products and highlight new developments and approaches that could assist in successful translation of HCMV immunotherapies.
| S-EPMC8395925 | biostudies-literature
Project description:Cytomegalovirus (CMV) is a β-herpesvirus present in a latent form in most people worldwide. In immunosuppressed individuals, CMV can reactivate and cause serious clinical complications, but the effect of the latent state on healthy people remains elusive. We undertook a systems approach to understand the differences between seropositive and negative subjects and measured hundreds of immune system components from blood samples including cytokines and chemokines, immune cell phenotyping, gene expression, ex vivo cell responses to cytokine stimuli, and the antibody response to seasonal influenza vaccination. As expected, we found decreased responses to vaccination and an overall down-regulation of immune components in aged individuals regardless of CMV status. In contrast, CMV-seropositive young adults exhibited enhanced antibody responses to influenza vaccination, increased CD8(+) T cell sensitivity, and elevated levels of circulating interferon-γ compared to seronegative individuals. Experiments with young mice infected with murine CMV also showed significant protection from an influenza virus challenge compared with uninfected animals, although this effect declined with time. These data show that CMV and its murine equivalent can have a beneficial effect on the immune response of young, healthy individuals, which may explain the ubiquity of CMV infection in humans and many other species.
| S-EPMC4505610 | biostudies-literature
Project description:Porcine cytomegalovirus (PCMV) is a member of the genus Cytomegalovirus, subfamily Betaherpesvirinae, and family Herpesvirus. PCMV is a major immunosuppressive virus that mainly suppress the immune function of T lymphocytes and macrophages. PCMV is widely distributed all over the world, but there are not significantly different serotypes found. Moreover, the molecular mechanisms of host anti-PCMV infection and the molecular immunosuppressive mechanisms of PCMV is still not well charaterized. To understand the PCMV potential impact on the function of immune organs, we performed microarray assay to analyze the transcriptome of porcine immune organs after PCMV infection. We identified 5582 differential expression genes by PCMV infection in microarray. There are 2161 upregulated genes and 3421 down-regulated by PCMV infection genes compare to the uninfected control group. We confirmed 13 differentially expressed immune-related genes by quantitative real-time RT-PCR (qPCR). Gene ontology, gene interaction networks and KEGG pathway analysis uncovered the differentially expressed genes interaction regulatory network. These findings indicated that PCMV regulates multiple functional pathways, including immune system process, cellular process, metabolic process, networks of cytokine-cytokine receptor interaction, TGF-beta signaling pathway, lymphocytes receptor signaling pathway and TNF signaling pathway. Our study is the first comprehensive attempt to explore the host transcriptional response to PCMV infection in porcine immune systems. It provided new insights into the immunosuppressive molecular mechanisms and pathogenesis of PCMV. This previously unrecognized endogenous antiviral mechanism has implications for development of host-directed strategies to the prevention and treatment of immunosuppressive viral diseases. 2 samples were analysed. PCMV infected porcine immune organs; control porcine organs. piglets were divided into two groups of five pigs each, and maintained under controlled temperature and humidity. Each pig in the first group was inoculated with 5 ml of 109 PFU/ml PCMV SC strain by intramuscular and intranasal injection, and the other five pigs were injected with 5 ml of RPMI-1640 nutrient solution (Thermo Fisher Scientific, Waltham, UK) as the control. The sera, lymph nodes, spleens, and thymuses of the infected and control pigs were collected at 14 dpi
2014-07-12 | E-GEOD-59115 | biostudies-arrayexpress
Project description:BackgroundImmune checkpoint inhibitors (ICIs), used for the treatment of solid and hematologic malignancies, come with the risk of immune-related adverse events (irAEs). Opportunistic infections (e.g., cytomegalovirus [CMV]) mimic irAE symptoms and are understudied in this population. We aimed to describe the incidence, characteristics, treatment and outcomes of CMV infection in ICI-treated patients.MethodsWe conducted a single-center retrospective review of all adult patients who were CMV-positive after ICI therapy between 06/2011 and 05/2020. A CMV-positive non-ICI cohort was matched to the ICI group based on age, sex and cancer type. Variables of interest were collected through electronic medical records.ResultsThe study population comprised 192 patients overall. CMV infection incidence was 7.7% in ICI patients and 12.9% in non-ICI patients (P<0.001). Rates of infection clearance (83% vs. 50%, P=0.002) and recurrence (20% vs. 3%, P=0.037) were higher in ICI patients with hematologic vs. solid tumors, despite similar treatments. All-cause mortality was higher in solid rather than hematologic malignancies in ICI patients (83% vs. 54%, P=0.009); CMV-related mortality was low (3-4%) in both groups.ConclusionsCMV infection occurred in about 7.7% of the ICI-treated cancer population. The infection can be disseminated in multiple organs and has a wide spectrum of clinical symptoms. ICI-treated patients with a hematologic malignancy had higher viral clearance and recurrence than those with solid tumors. In this study, CMV itself did not lead to high mortality in cancer patients. Further study is needed to investigate the role of CMV infection in patients' irAEs and cancer outcome.
| S-EPMC9399572 | biostudies-literature
Project description:Transposon-based insertional mutagenesis screens have assessed how disruption of numerous human cytomegalovirus (HCMV) open reading frames (ORFs) impacts in vitro viral replication. Insertional mutagenesis of the HCMV UL30 gene was previously found to substantially inhibit production of viral progeny. However, there are a number of putative UL30-associated ORFs, and it is unclear how they impact viral replication. Here, we report on the contributions of the eight UL30-associated ORFs to infection. We find that deletion of the canonically annotated UL30 ORF substantially reduces production of infectious virus at both high and low multiplicities of infection (MOI). This deletion likely has complex effects on viral replication, as we find that it reduces the expression of neighboring non-UL30-associated ORFs. Mutation of the initiating methionine of the canonical UL30 ORF indicated that it is dispensable for high- and low-MOI infection in the highly passaged AD169 strain, although it is important for low-MOI infection in the less-passaged TB40/E strain. Comutation of eight methionines in the UL30 region results in a low-MOI viral replication defect, as does mutation of the TATA box responsible for the most abundant UL30 transcript, which is found to be necessary for the accumulation of multiple UL30-associated protein isoforms during infection. In total, our data indicate the importance of the UL30-associated ORFs during low-MOI HCMV infection and further highlight the difficulty associated with the functional interrogation of broadly disruptive mutations: e.g., large deletions or transposon insertions.IMPORTANCE Viral genes and their products are the critical determinants of viral infection. Human cytomegalovirus (HCMV) encodes many gene products whose roles during viral infection have not been assessed. Elucidation of the contributions that various HCMV gene products make to infection provides insight into the infectious program, which could potentially be used to limit HCMV-associated morbidity, a major issue during congenital infection and in immunosuppressed populations. Here, we explored the role of HCMV's UL30-associated gene products and found that they are important for HCMV replication. Future work elucidating the mechanisms through which they contribute to viral infection could highlight novel avenues for therapeutic intervention.
| S-EPMC8104089 | biostudies-literature
Project description:IntroductionAnaemia in women during pregnancy and child bearing age is one of the most common global health problems. Reasons are numerous, but in many cases only minimal attempts are made to elucidate the underlying causes. In this study we aim to identify aetiology of anaemia in women of child bearing age and to determine the relative contributions, effects and interactions of α- and β-thalassaemia in a region of the world where thalassaemia is endemic.MethodsA cross sectional study was conducted at the Colombo North Teaching Hospital of Sri Lanka. The patient database of deliveries between January 2015 and September 2016 at University Obstetrics Unit was screened to identify women with anaemia during pregnancy and 253 anaemic females were randomly re-called for the study. Data were collected using an interviewer-administered questionnaire and haematological investigations were done to identify aetiologies.ResultsOut of the 253 females who were anaemic during pregnancy and were re-called, 8 were excluded due to being currently pregnant. Of the remaining 245 females, 117(47.8%) remained anaemic and another 22(9.0%) had non-anaemic microcytosis. Of anaemic females, 28(24.8%) were iron deficient, 40(35.4%) had low-normal serum ferritin without fulfilling the criteria for iron deficiency,18(15.3%) had β-haemoglobinopathy trait and 20(17.0%) had α-thalassaemia trait. Of females who had non-anaemic microcytosis, 14(66.0%) had α-thalassaemia trait. In 4 females, both α- and β-thalassaemia trait coexist. These females had higher levels of haemoglobin (p = 0.06), MCV (p<0.05) and MCH (p<0.01) compared to individuals with only β-thalassaemia trait. A significantly higher proportion of premature births (p<0.01) and lower mean birth weights (p<0.05) were observed in patients with α-thalassaemia trait.ConclusionsNearly one third of anaemic females in child bearing age had thalassaemia trait of which α-thalassemia contributes to a majority. Both α- and β-thalassaemia trait can co-exist and have ameliorating effects on red cell indices in heterozygous states. α-Thalassaemia trait was significantly associated with premature births and low birth weight. It is of paramount importance to investigate the causes of anaemia in women of child bearing age and during pregnancy in addition to providing universal iron supplementation.
| S-EPMC6214573 | biostudies-literature