Cytomegalovirus (CMV) establishes lifelong latency and is linked to immunosenescence in older and immunocompromised individuals. We hypothesize that CMV drives systemic and tissue-specific immune changes that may contribute to cardiovascular disease (CVD). Thoracic aorta, blood and perivascular mediastinal adipose tissue from cardiac surgery patients ( n = 11) were processed within 30–60 min of excision. CMV IgG titres were quantified through ELISA to determine CMV status: CMV(−) ( n = 4) and CMV(+) ( n = 7). Immune profiling was performed using flow cytometry and single-cell RNA sequencing. Analyses included MiloR and differential gene expression. Participants (mean age 69.7 ± 8.4 years) were 80% male and 70% Caucasian. CMV(−) and CMV(+) participants had mean IgG titres of 0.038 and 13.55 IU ml ⁻¹ , respectively. CD8 ⁺ T-cells expressing CD57 ⁺ , GPR56 ⁺ and CX3CR1 ⁺ (CGC) were increased in the blood of CMV(+) participants. In the aorta of CMV(+) participants, CD8 ⁺ T cells and CD4 ⁺ T cells had decreased HLA-C expression and suppressed interferon-α pathways. In contrast, the TNF-α signalling pathway was increased. CMV infection shapes immune responses and in this pilot, we observed suppression of interferon-α signalling and increased TNF-α-associated pathways in the aorta. Larger studies are needed to define how CMV-driven immune remodelling contributes to CVD. This article is part of the discussion meeting issue ‘The indirect effects of cytomegalovirus infection: mechanisms and consequences.’

Cardiovascular disease (CVD) remains the leading cause of death worldwide. Several factors are implicated in the pathogenesis of CVD, and efforts have been made to reduce traditional risks, yet CVD remains a complex burden. Notably, people living with HIV (PLWH) are twice as likely to develop CVD compared to persons without HIV (PWoH). Intensive statin therapy, the first-line treatment to prevent cardiovascular events, is effective at reducing morbidity and mortality. However, statin therapy has not reduced the overall prevalence of CVD. Despite antiretroviral therapy (ART), and new guidelines for statin use, PLWH have persistent elevation of inflammatory markers, which is suggested to be a bigger driver of future cardiovascular events than low-density lipoprotein. Herein, we have summarized the development of atherosclerosis and highlighted mouse models of atherosclerosis in the presence and absence of HIV. Since most mouse strains have several mechanisms that are atheroprotective, researchers have developed mouse models to study CVD using dietary and genetic manipulations. In evaluating the current methodologies for studying HIV-associated atherosclerosis, we have detailed the benefits of integrating multi-omics analyses, genetic manipulations, and immune cell profiling within mouse models. These advanced approaches significantly enhance our capacity to address critical gaps in understanding the immune mechanisms driving CVD, including in the context of HIV.

Exposure to endocrine-disrupting chemicals (EDCs) has been linked to several pathologies in human health, especially those involving the immune system. The vast majority of studies have focused on cells and functions of the adaptive immune system with little investigation of the impact of EDCs on innate immunity. While EDC exposure remains a threat throughout the lifetime of an individual, the most detrimental effects on human health occur during critical stages of development, such as in utero. Fetal development is not only associated with growth and tissue remodeling but also with the establishment of key processes, including those of the immune system. Unfortunately, due to fetal plasticity, developmental exposure to certain EDCs, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), can affect mammalian health well into adulthood by altering fetal programming. Herein, we hypothesize that in utero exposure to TCDD induces developmental reprogramming of the innate immune system that subsequently impacts the adult response to infection. To interrogate our hypothesis, we challenged adult mice with and without a history of in utero TCDD exposure with 1 × 10⁸ CFU Pseudomonas aeruginosa via intraperitoneal injection. Results revealed a significant decrease in the number of innate leukocytes at the site of infection six hours after inoculation in toxicant-exposed mice compared to unexposed mice. The reduction in the number of phagocytes correlated with a reduction in bacterial clearance in toxicant-exposed mice. We also noted a decreased ability of peritoneal immune cells from toxicant-exposed mice to produce chemokines necessary for immune cell recruitment. Taken together, our results indicate that in utero EDC exposure impairs the innate immune response to a bacterial infection in adult offspring, particularly in males.