Intermittent cytomegalovirus infection alters neurobiological metabolism and induces cognitive deficits in mice

Harrison, Mark A.A.; Morris, Sara L.; Rudman, Grace A.; Rittenhouse, Daniel J.; Monk, Chandler H.; Sakamuri, Siva S.V.P.; Mehedi Hasan, Md; Shamima Khatun, Mst; Wang, Hanyun; Garfinkel, Lucas P.; Norton, Elizabeth B.; Kim, Sangku; Kolls, Jay K.; Jazwinski, S. Michal; Mostany, Ricardo; Katakam, Prasad V,G.; Engler-Chiurazzi, Elizabeth B.; Zwezdaryk, Kevin J.

doi:10.1016/j.bbi.2023.12.033

Brain, Behavior, and Immunity

2024

DOI: 10.1016/j.bbi.2023.12.033

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Intermittent cytomegalovirus infection alters neurobiological metabolism and induces cognitive deficits in mice

Mark A.A. Harrison,

Sara L. Morris,

Grace A. Rudman

et al.

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2024

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Cited by 5 publications

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Human herpesvirus reactivation and its potential role in the pathogenesis of post-acute sequelae of SARS-CoV-2 infection

Gáspár,

Szabó,

Ceglédi

et al. 2024

GeroScience

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The emergence of SARS-CoV-2 has precipitated a global pandemic with substantial long-term health implications, including the condition known as post-acute sequelae of SARS-CoV-2 infection (PASC), commonly referred to as Long COVID. PASC is marked by persistent symptoms such as fatigue, neurological issues, and autonomic dysfunction that persist for months beyond the acute phase of COVID-19. This review examines the potential role of herpesvirus reactivation, specifically Epstein-Barr virus (EBV) and cytomegalovirus (CMV), in the pathogenesis of PASC. Elevated antibody titers and specific T cell responses suggest recent herpesvirus reactivation in some PASC patients, although viremia is not consistently detected. SARS-CoV-2 exhibits endothelial trophism, directly affecting the vascular endothelium and contributing to microvascular pathologies. These pathologies are significant in PASC, where microvascular dysfunction may underlie various chronic symptoms. Similarly, herpesviruses like CMV also exhibit endothelial trophism, which may exacerbate endothelial damage when reactivated. Evidence suggests that EBV and CMV reactivation could indirectly contribute to the immune dysregulation, immunosenescence, and autoimmune responses observed in PASC. Additionally, EBV may play a role in the genesis of neurological symptoms through creating mitochondrial dysfunction, though direct confirmation remains elusive. The reviewed evidence suggests that while herpesviruses may not play a direct role in the pathogenesis of PASC, their potential indirect effects, especially in the context of endothelial involvement, warrant further investigation.

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Human herpesvirus reactivation and its potential role in the pathogenesis of post-acute sequelae of SARS-CoV-2 infection

Gáspár,

Szabó,

Ceglédi

et al. 2024

GeroScience

View full text Add to dashboard Cite

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MAD—microbial (origin of) Alzheimer’s disease hypothesis: from infection and the antimicrobial response to disruption of key copper-based systems

Min,

Sarlus,

Harris

2024

Front. Neurosci.

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Microbes have been suspected to cause Alzheimer’s disease since at least 1908, but this has generally remained unpopular in comparison to the amyloid hypothesis and the dominance of Aβ and Tau. However, evidence has been accumulating to suggest that these earlier theories are but a manifestation of a common cause that can trigger and interact with all the major molecular players recognized in AD. Aβ, Tau and ApoE, in particular appear to be molecules with normal homeostatic functions but also with alternative antimicrobial functions. Their alternative functions confer the non-immune specialized neuron with some innate intracellular defenses that appear to be re-appropriated from their normal functions in times of need. Indeed, signs of infection of the neurons by biofilm-forming microbial colonies, in synergy with herpes viruses, are evident from the clinical and preclinical studies we discuss. Furthermore, we attempt to provide a mechanistic understanding of the AD landscape by discussing the antimicrobial effect of Aβ, Tau and ApoE and Lactoferrin in AD, and a possible mechanistic link with deficiency of vital copper-based systems. In particular, we focus on mitochondrial oxidative respiration via complex 4 and ceruloplasmin for iron homeostasis, and how this is similar and possibly central to neurodegenerative diseases in general. In the case of AD, we provide evidence for the microbial Alzheimer’s disease (MAD) theory, namely that AD could in fact be caused by a long-term microbial exposure or even long-term infection of the neurons themselves that results in a costly prolonged antimicrobial response that disrupts copper-based systems that govern neurotransmission, iron homeostasis and respiration. Finally, we discuss potential treatment modalities based on this holistic understanding of AD that incorporates the many separate and seemingly conflicting theories. If the MAD theory is correct, then the reduction of microbial exposure through use of broad antimicrobial and anti-inflammatory treatments could potentially alleviate AD although this requires further clinical investigation.

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Does Getting Sick More Often Impact the Way Our Brain Cells Work and How We Learn and Remember?

Engler-Chiurazzi,

Zwezdaryk,

Sweeten

2024

Front. Young Minds

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Everyone catches the flu or a cold from time to time. We designed an experiment to study how being sick more often affects the brain. To do this, we used a piece of a bacteria to make adult male mice experience symptoms of sickness. We gave mice this substance five total times. Mice got better in a few days and had 2-week breaks between exposures. We then measured how the mice learned and remembered new information, and how well their brain cells were working to help them learn. Our experiments indicate that being sick often interferes with communication between brain cells, causing mice to have trouble learning and remembering. Our data can help doctors predict which patients may have memory problems as they grow older. Our study also shows the importance of staying as healthy as possible and taking steps to protect ourselves and others when we do get sick.

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Intermittent cytomegalovirus infection alters neurobiological metabolism and induces cognitive deficits in mice

Cited by 5 publications

References 69 publications

Human herpesvirus reactivation and its potential role in the pathogenesis of post-acute sequelae of SARS-CoV-2 infection

Human herpesvirus reactivation and its potential role in the pathogenesis of post-acute sequelae of SARS-CoV-2 infection

MAD—microbial (origin of) Alzheimer’s disease hypothesis: from infection and the antimicrobial response to disruption of key copper-based systems

Does Getting Sick More Often Impact the Way Our Brain Cells Work and How We Learn and Remember?

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