Pathogenic Exosomes During Herpes Zoster Mediate Increased Vascular Dementia Risk.

Vascular dementia: Vascular dementia is the second most common form of dementia after Alzheimer's disease and is characterized broadly as a loss of blood supply to the brain and compromised blood-brain barrier (BBB) ultimately leading to brain atrophy and cognitive impairment. Cerebrovascular insults such as stroke, myocardial infarctions, inflammation, and hyperactive platelets (thrombosis) are contributors and risk factors for the development of vascular dementia. Recently viruses have been identified as potential risk factors.

Varicella zoster virus (VZV) and vascular dysfunction: VZV is an exclusively human, double-stranded DNA alphaherpesvirus that produces varicella (chickenpox) then establishes latency within sensory and autonomic ganglionic neurons in >95% of adults in the U.S. With aging and immunosuppression, VZV reactivates in at least 1 in 3 individuals to produce herpes zoster (HZ; shingles) and other neurological diseases with or without rash. Despite the availability of two HZ vaccines, more than 1 million Americans develop HZ annually. Lesser known to the general public is the frequency of VZV reactivation without rash (zoster sine herpete). Given that VZV reactivates from ganglionic neurons across the entire neuraxis, essentially all organs and tissues, including the vasculature, are prone to infection and disease without the characteristic and diagnostic HZ rash. In fact, it is predicted that for every 1 case of HZ with rash, 7 individuals will reactivate with VZV without corresponding rash. Furthermore, the group has shown that individuals can still shed active virus in their saliva up to 12 years post-HZ suggesting at least a subset of individuals may have ongoing replication despite no rash; in this study 67% of patients still had active virus in their saliva at least 3 months post-rash. Thus, the burden of VZV disease, particularly duration, is likely grossly underestimated.

HZ is recognized as a stroke risk factor; HZ increases the risk of stroke up to 1 year post-HZ, with risk higher when HZ occurs in the ophthalmic distribution or in individuals <40 years of age. Specifically, data pooled from 9 studies in the U.S., Europe, and Asia show that the relative risk for stroke after HZ was 1.78 (95% CI 1.70-1.88) for the first month following HZ, dropping progressively to 1.20 (95% CI 1.14-1.26) after 1 year. Stroke risk increased by a larger margin during the first month after a HZ ophthalmicus episode: relative risk was 2.05 (95% CI 1.82-2.31); and the stroke risk remained elevated one year after the acute episode. A recent U.S. retrospective study of 23,339 HZ individuals and 46,378 controls, investigators found that during the 8 week aggregate period, HZ individuals were significantly more likely to suffer a stroke: adjusted incidence rate ratios for all patients and patients aged 18 to 49 years were 1.40 (95% CI, 0.93-2.11) and 8.12 (95% CI, 0.93-71.27), respectively (p < 0.05); risk returned to baseline by 1 year. The increased stroke risk in individuals with HZ who are < 50 years of age, compared to all HZ individuals, is remarkable because these individuals do not qualify for the HZ vaccine.

While the mechanisms underlying VZV and vascular disease are not fully elucidated, histological and immunohistochemical studies of VZV-infected arteries, analysis of cerebrospinal fluid (CSF) from VZV vasculopathy patients for cytokines and matrix metalloproteinases (MMPs), and in vitro studies provide some clues to the pathogenesis of disease (reviewed in Nagel and Bubak, 2018). Specifically, upon VZV reactivation, virus travels along nerve fibers that terminate in the outermost adventitial layer of the artery where virus-infected adventitial fibroblasts elicit a robust inflammatory response involving neutrophils early in disease, and T cells and macrophages throughout the entire course of disease. VZV-infected cells, neutrophils, and other infiltrating immune cells produce activated MMPs, which degrade the extracellular matrix potentially leading to weakening of the vessel wall, aneurysm formation, and rupture. Soluble factors secreted by inflammatory cells have also been described to further contribute to vascular smooth muscle death and accumulation of myofibroblasts in the thickened intima, potentially leading to arterial occlusion. However, the "soluble factors" have not been characterized until recently by the investigator group (described below).

Role of exosomes in disease states: Circulating exosomes have emerged as important "soluble factors" that can affect cells remote from their site of origin. Exosomes are small extracellular vesicles (~40-200 nm in diameter) of endosomal origin that carry cargo (proteins, nucleic acids, etc.) from their cells of origin to adjacent or distal cells for communication during normal and pathological states, regulating biological processes and response to disease. For example, exosomes derived from platelets, megakaryocytes, and peripheral blood mononuclear cells (PBMCs) can transfer CXCR4 and CCR5 to cells that lack these receptors, thereby increasing the number of susceptible cells for HIV infection. In other studies, exosomes released from nasopharyngeal carcinoma cells positive for EBV contain the viral latent membrane protein 1 and other viral/cellular factors that manipulate the tumor microenvironment to enhance tumor progression and alleviate immune responses to tumor cells. Furthermore, exosomes (and other extracellular vesicles) derived from: