NIH Reporter #4R01AG085406-03

Pathogenic exosomes during herpes zoster mediate increased vascular dementia risk

This award funds research on how exosomes from herpes zoster patients contribute to increased risk of vascular dementia by promoting vascular inflammation and thrombosis, aiming to improve clinical practices and vaccination efforts.

Description

Project Summary: Vascular dementia is the second most common cause of dementia. Therapies aim to control risk factors (e.g. hypertension, hyperlipidemia, and diabetes mellitus) to prevent development or worsening of disease. Recent studies show that viral infections are potentially modifiable risk factors for dementia. Amongst all pathogens, varicella zoster virus (VZV) is the most likely contributor to vascular dementia. VZV is a neurotropic DNA virus that is latent in >95% of Americans and reactivates to produce herpes zoster (shingles) in 50% by 85 years of age. Despite the availability of zoster vaccines, there are still >1 million cases of zoster annually. Recent studies reveal zoster increases dementia risk and treatment (vaccines, antivirals) reduces risk. Importantly, a recent FinnGen and U.K. biobank study showed VZV was specifically associated with an increased risk of vascular dementia. VZV likely contributes to vascular dementia risk through its ability to produce vascular pathology leading to ischemic or hemorrhagic stroke (VZV vasculopathy). VZV directly infects cerebral arteries and causes vasculitis, as well as induces a prothrombotic state triggering cerebral thrombosis. Plasma exosomes from acute zoster patients contain elevated prothrombotic and proinflammatory proteins including thrombospondin-1, caveolae-associated protein 2, coagulation factors V and XIIIA1, calmodulin 1, and transthyretin. These exosomes induce IL-6 and IL-8 secretion supporting a proinflammatory and prothrombotic state. They persist for at least 3 months post-zoster. The hypothesis is that circulating exosomes promote vasculitis and thrombosis, increasing vascular dysfunction risk. The study will analyze exosome content and mechanisms of vascular dysfunction.

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