Gene Birth, Death, Modification, Poaching, Crippling, Dimorphism and Culling: The Challenge for Genomics

This brief survey covers the main events in the evolution of eukaryotic genes in broad brush style. It concentrates on regulatory DNA, an area that has been relatively neglected, and where we believe that the present case-by-case analysis is likely to be supplemented by more general, genomics-based methods. It is biased towards immunology, in part because the immune system relies heavily on polymorphism of regulatory DNA to provide flexibility and in part because of our own field of interest. It gives a central place to recent work that has shown how analysis of electronic genomes can be used to trace gene duplication and its consequences. It mentions cellular systems that offer models for the study of evolution of regulatory DNA on a small scale. It alludes to the unanswered question of how genomes adjust their overall size

Gender differences and age-specific associations between Body Mass Index and other cardiovascular risk factors in CMV infected and uninfected people

Recent studies have highlighted Body Mass Index (BMI) as an important parameter associated with cardiovascular risk and cancer. Here we have explored the relationship between BMI and other cardiovascular risk factors such as white blood count (WBC) and mean arterial blood pressure (MAP) in young (20-35 years) and older (60-85 years) healthy donors stratified by gender and CMV IgG serostatus. We found a positive correlation between BMI and WBC in young women, which was significant in CMV+ women. Interestingly, there was a non-significant opposite trend in young men. In older women the positive trend was preserved in the presence of CMVinfection, but no clear trend was seen in older men. Gender differences were also observed by opposite trends regarding an association between MAP and WBC (positive in young women, negative in young men). These associations were not observed at older ages. However, in CMV+ older men, there was a significant association between MAP and WBC as well as neutrophil count (NC). CRP values were only available in older participants, and interestingly, correlated with WBC and NC only in women, and more closely in CMVwomen. This study reveals that the correlations between common inflammatory markers/cardiovascular risk factors depend on age, gender, and CMV infection status in a complex fashion. Our findings support the need to evaluate risk factors independently in men and women and to take into account CMV infection status. More focused studies will be required to shed light on these novel findings

A Novel Cytomegalovirus-Induced Regulatory-Type T-Cell Subset Increases in Size During Older Life and Links Virus-Specific Immunity to Vascular Pathology

Background. Cytomegalovirus (CMV) infection directly targets vascular endothelium and smooth muscle and at older ages is associated with accelerated vascular pathology and mortality. CMV-specific cellular immunity might directly contribute to this process. Methods. Conventional ex vivo activation–induced T-cell responses to 19 dominant CMV antigens, along with CMV-specific inducible regulatory-type CD4+ T cells (iTregs), were measured in healthy older people, using a novel protocol that included classic Treg markers alongside the activation marker CD134. Measurements were correlated with diastolic, systolic, and mean arterial blood pressure, a surrogate marker for arterial stiffness. Results. CMV-specific iTregs recognized the same antigens as conventional CD4+ T cells and were significantly more frequent at older ages. They suppressed antigen-specific and nonspecific proliferation and in large part expressed Foxp3. Frequencies of CMV-specific iTregs and CD8+ T cells (summated response) were significantly associated with diastolic and mean arterial pressures. Confounders, including age, body mass index, smoking, antihypertensive medication use, or C-reactive protein levels, did not explain these observations. Conclusions. A novel CMV-induced regulatory-type CD4+ T-cell subset is readily detectable in CMV-infected people and, like the aggregate CD8+ T-cell response to the most dominant CMV antigens, is quantitatively associated with arterial stiffness in older life. Whereas CD8+ effector T cells might directly cause vascular injury, iTregs may attenuate this response

Natural killer cells attenuate cytomegalovirus-induced hearing loss in mice

<div><p>Congenital cytomegalovirus (CMV) infection is the most common non-hereditary cause of sensorineural hearing loss (SNHL) yet the mechanisms of hearing loss remain obscure. Natural Killer (NK) cells play a critical role in regulating murine CMV infection via NK cell recognition of the Ly49H cell surface receptor of the viral-encoded m157 ligand expressed at the infected cell surface. This Ly49H NK receptor/m157 ligand interaction has been found to mediate host resistance to CMV in the spleen, and lung, but is much less effective in the liver, so it is not known if this interaction is important in the context of SNHL. Using a murine model for CMV-induced labyrinthitis, we have demonstrated that the Ly49H/m157 interaction mediates host resistance in the temporal bone. BALB/c mice, which lack functional Ly49H, inoculated with mCMV at post-natal day 3 developed profound hearing loss and significant outer hair cell loss by 28 days of life. In contrast, C57BL/6 mice, competent for the Ly49H/m157 interaction, had minimal hearing loss and attenuated outer hair cell loss with the same mCMV dose. Administration of Ly49H blocking antibody or inoculation with a mCMV viral strain deleted for the m157 gene rendered the previously resistant C57BL/6 mouse strain susceptible to hearing loss to a similar extent as the BALB/c mouse strain indicating a direct role of the Ly49H/m157 interaction in mCMV-dependent hearing loss. Additionally, NK cell recruitment to sites of infection was evident in the temporal bone of inoculated susceptible mouse strains. These results demonstrate participation of NK cells in protection from CMV-induced labyrinthitis and SNHL in mice.</p></div

Socio-economic inequalities in C-reactive protein and fibrinogen across the adult age span: Findings from Understanding Society

Systemic inflammation has been proposed as a physiological process linking socio-economic position (SEP) to health. We examined how SEP inequalities in inflammation -assessed using C-reactive protein (CRP) and fibrinogen- varied across the adult age span. Current (household income) and distal (education) markers of SEP were used. Data from 7,943 participants (aged 25+) of Understanding Society (wave 2, 1/2010-3/2012) were employed. We found that SEP inequalities in inflammation followed heterogeneous patterns by age, which differed by the inflammatory marker examined rather than by SEP measures. SEP inequalities in CRP emerged in 30s, increased up to mid-50s or early 60 s when they peaked and then decreased with age. SEP inequalities in fibrinogen decreased with age. Body mass index (BMI), smoking, physical activity and healthy diet explained part, but not all, of the SEP inequalities in inflammation; in general, BMI exerted the largest attenuation. Cumulative advantage theories and those considering age as a leveler for the accumulation of health and economic advantages across the life-span should be dynamically integrated to better understand the observed heterogeneity in SEP differences in health across the lifespan. The attenuating roles of health-related lifestyle indicators suggest that targeting health promotion policies may help reduce SEP inequalities in health

DNA immunisation with plasmids expressing hCGβ-chimeras.

Human chorionic gonadotropin has been used as an anti-fertility vaccine and as a target for cancer immunotherapy. We have explored the use of DNA immunization with the aim of improving the immunogenicity of this hormone. Stimulating the muscle with electric pulses following intramuscular injection of plasmids expressing hCG resulted in higher levels of human chorionic gonadotropin (hCG)-specific antibodies, which could be further enhanced following a protein boost with hCG mixed with adjuvant. DNA vaccines encoding amembrane attached or a secreted form of hCG produced similar—albeit relatively modest—antibody responses. Providing hCG with additional T cell help by vaccinating with a plasmid encoding a hCG-hFc fusion protein did not further increase the antibody levels in the immunized animals. However, immunization of mice with a construct encodinghCG fused to C3d3 produced significantly lower antibody levels relative to mice immunized with the hCG-alone expression plasmid, even though the hCG-C3d3 chimera was expected to facilitate cross-linking of the antigen-specific B-cell receptor and CR2 thereby lowering the threshold of activation. Thus the limiting factor determining the antibody levels following hCG immunization, at least for DNA immunization, is related to the amount of protein available rather than the form of protein produced or lack of T cell epitopes

The role of CMV-specific immunity in the association between CMV infection and vascular complications in older age

Human Cytomegalovirus (HCMV) is a beta-herpesvirus which establishes persistent infections. HCMV is thought to have infected over half of all adults worldwide with a seroprevalence between 60–99% worldwide. CMV establishes a lifelong persistent latent infection, which may sporadically reactivate. The aim of this study is to determine the contribution, if any, of CMV infection to vascular changes manifested as increased blood pressure along with decreased vascular compliance in 60–90 year olds. Due to the high prevalence of CMV in the elderly, this question is of significant importance. If it is confirmed that CMV contributes to vascular changes, it would be prudent to develop antiviral strategies to slow these vascular changes and increase the quality of life of patients. Carotid to femoral pulse wave velocity (PWV) is a gold standard, non-invasive method of assessing arterial stiffness. Arterial stiffness is a useful parameter for investigating cardiovascular risk. Arterial stiffness will be measured along with virological and immunological parameters of CMV infection. Peripheral blood mononuclear cells(PBMCs) isolated from blood obtained from volunteers will be stimulated with peptide mixes of various CMV peptides. The responses will be assessed by using flow cytometry to investigate the production of TNF-alpha, IL-2 and IFN-gamma. In addition, various populations of cells in whole blood will be phenotyped by flow cytometry. We expect to clearly confirm or refute a contribution of CMV infection to vascular changes. We also hope to build and maintain a cohort for further investigations into immunosenescence and CMV infection

The role of CMV-specific immunity in the association between CMV infection and vascular complications in older age

Human Cytomegalovirus (HCMV) is a beta-herpesvirus which establishes persistent infections. HCMV is thought to have infected over half of all adults worldwide with a seroprevalence between 60–99% worldwide. CMV establishes a lifelong persistent latent infection, which may sporadically reactivate. The aim of this study is to determine the contribution, if any, of CMV infection to vascular changes manifested as increased blood pressure along with decreased vascular compliance in 60–90 year olds. Due to the high prevalence of CMV in the elderly, this question is of significant importance. If it is confirmed that CMV contributes to vascular changes, it would be prudent to develop antiviral strategies to slow these vascular changes and increase the quality of life of patients. Carotid to femoral pulse wave velocity (PWV) is a gold standard, non-invasive method of assessing arterial stiffness. Arterial stiffness is a useful parameter for investigating cardiovascular risk. Arterial stiffness will be measured along with virological and immunological parameters of CMV infection. Peripheral blood mononuclear cells(PBMCs) isolated from blood obtained from volunteers will be stimulated with peptide mixes of various CMV peptides. The responses will be assessed by using flow cytometry to investigate the production of TNF-alpha, IL-2 and IFN-gamma. In addition, various populations of cells in whole blood will be phenotyped by flow cytometry. We expect to clearly confirm or refute a contribution of CMV infection to vascular changes. We also hope to build and maintain a cohort for further investigations into immunosenescence and CMV infection