Elevated serum substance P during simian varicella virus infection in rhesus macaques: implications for chronic inflamma
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Elevated serum substance P during simian varicella virus infection in rhesus macaques: implications for chronic inflammation and adverse cerebrovascular events Andrew N. Bubak 1 & Vicki Traina-Dorge 2 & Christina N. Como 1 & Brittany Feia 1 & Catherine M. Pearce 1 & Laura Doyle-Meyers 2 & Arpita Das 2 & Jayme Looper 3 & Ravi Mahalingam 1 & Maria A. Nagel 1,4 Received: 3 June 2020 / Revised: 24 August 2020 / Accepted: 28 August 2020 # Journal of NeuroVirology, Inc. 2020
Abstract Varicella and zoster, produced by varicella-zoster virus (VZV), are associated with an increased risk of stroke that may be due to persistent inflammation and hypercoagulability. Because substance P is associated with inflammation, hypercoagulability, and atherosclerotic plaque rupture that may contribute to increased stroke risk after VZV infection, we measured serum substance P in simian varicella virus–infected rhesus macaques. We found significantly increased and persistent serum substance P concentrations during varicella and zoster compared with pre-inoculation, supporting the hypothesis that VZV-induced increases in serum substance P may contribute to increased stroke risk associated with VZV infection. Keywords Varicella . Zoster . Stroke . Simian varicella virus . Substance P
Introduction Varicella-zoster virus (VZV) causes varicella during primary infection then establishes life-long latency in ganglionic neurons. Upon immunosuppression and/or age-related immunosenescence, virus can reactivate to produce herpes zoster. Multiple studies show a significantly increased risk of stroke weeks to months after varicella or zoster. Specifically, using electronic health records in the UK, Thomas et al. (2014) found a 4-fold increased risk of stroke in children during the first 6 months after varicella; another study found the median time between varicella and stroke to be 4 months (Science et al. 2014). Similar findings associating * Maria A. Nagel [email protected] 1
Department of Neurology, University of Colorado School of Medicine, 12700 E. 19th Avenue, Mail Stop B182, Aurora, CO 80045, USA
2
Microbiology Division, Tulane National Primate Research Center, Tulane University, Covington, LA 70433, USA
3
Department of Veterinary Clinical Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
4
Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO 80045, USA
increased risk of stroke after varicella were seen in a systemic review and meta-analysis of 41 published reports that assessed the risk of stroke associated with VZV infection; furthermore, zoster was associated with a 1.5-fold increased stroke risk 4 weeks following rash onset, which resolved after 1 year (Forbes et al. 2018). Subgroup analyses suggested that postzoster stroke risk was greater among ophthalmic zoster patients, younger individuals, and others who were not taking antivirals. Another study of VZV vasculopathy patients found that the average time from rash to stroke was 4 months (Nagel et al. 2009
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