How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

Aiello, Allison E.; Chiu, Yen‐Ling; Frasca, Daniela

doi:10.1007/s11357-017-9983-9

Cited by 56 publications

(42 citation statements)

References 101 publications

(106 reference statements)

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“…However, evidence to support this hypothesis remains controversial 109 . Some studies have found that human CMV infection in older individuals is associated with increased cardiovascular and all-cause mortality, negative immune risk profile, inflammageing, and lower antibody responses to influenza 125–129 . However, evidence that the association between CMV infection and CVD and mortality is mediated by inflammageing is scant at best 109,130 .…”

Section: Risk Factors and Causes Of Inflammageingmentioning

confidence: 99%

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

2018

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Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty — which affect clinical manifestations, prognosis, and response to treatment — and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials.

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Section: Risk Factors and Causes Of Inflammageingmentioning

confidence: 99%

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

2018

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“…Mechanistically, it remains unclear whether CMV specifically contributes to the “diseases of aging” (CVD, AD, frailty, etc. ), or whether these correlations in human studies are due to another factor that simultaneously predisposes the host for these diseases and for CMV infection [26]. …”

Section: Aging With Persistent Herpesvirus Infections and The Speciamentioning

confidence: 99%

Known unknowns: how might the persistent herpesvirome shape immunity and aging?

Nikolich‐Žugich

Goodrum

Knox

et al. 2017

Current Opinion in Immunology

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The microbial community that colonizes all living organisms is gaining appreciation for its contributions to both physiologic and pathogenic processes. The virome, a subset of the overall microbiome, large and diverse, including viruses that persistently inhabit host cells, endogenous viral elements genomically or epigenomically integrated into cells, and viruses that infect the other (bacterial, protozoan, fungal, archaeal) microbiome phylla. These viruses live in the organism for its life, and therefore are to be considered part of the aging process experienced by the organism. This review considers the impact of the persistent latent virome on immune aging. Specific attention will be devoted to the role of herpesviruses, and within them, the cytomegalovirus, as the key modulators of immune aging.

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“…been linked to increased fragility and mortality in elderly populations (3)(4)(5)(6). HCMV cellular tropism is diverse and includes epithelial, endothelial, fibroblast, and most immune cell types (7).…”

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confidence: 99%

Human Cytomegalovirus Alters Host Cell Mitochondrial Function during Acute Infection

Combs

Norton

Saifudeen

et al. 2020

J Virol

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Human cytomegalovirus (HCMV) is a large DNA herpesvirus that is highly prevalent in the human population. HCMV can result in severe direct and indirect pathologies under immunosuppressed conditions and is the leading cause of birth defects related to infectious disease. Currently, the effect of HCMV infection on host cell metabolism as an increase in glycolysis during infection has been defined. We have observed that oxidative phosphorylation is also increased. We have identified morphological and functional changes to host mitochondria during HCMV infection. The mitochondrial network undergoes fission events after HCMV infection. Interestingly, the network does not undergo fusion. At the same time, mitochondrial mass and membrane potential increase. The electron transport chain (ETC) functions at an elevated rate, resulting in the release of increased reactive oxygen species. Surprisingly, despite the stress applied to the host mitochondria, the network is capable of responding to and meeting the increased bioenergetic and biosynthetic demands placed on it. When mitochondrial DNA is depleted from the cells, we observed severe impairment of viral replication. Mitochondrial DNA encodes many of the ETC components. These findings suggest that the host cell ETC is essential to HCMV replication. Our studies suggest the host cell mitochondria may be a therapeutic target. IMPORTANCE Human cytomegalovirus (HCMV) is a herpesvirus present in up to 85% of some populations. Like all herpesviruses, HCMV infection is for life. No vaccine is currently available, neutralizing antibody therapies are ineffective, and current antivirals have limited long-term efficacy due to side effects and potential for viral mutation and resistance. The significance of this research is in understanding how HCMV manipulates the host mitochondria to support bioenergetic and biosynthetic requirements for replication. Despite a large genome, HCMV relies exclusively on host cells for metabolic functions. By understanding the dependency of HCMV on the mitochondria, we could exploit these requirements and develop novel antivirals.

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How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

Cited by 56 publications

References 101 publications

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

Known unknowns: how might the persistent herpesvirome shape immunity and aging?

Human Cytomegalovirus Alters Host Cell Mitochondrial Function during Acute Infection

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