Varicella zoster virus (VZV) famously establishes latency in dorsal root (DRG) and cranial nerve (CNG) ganglia after its disseminated primary infection (varicella; chickenpox). VZV can reactivate from latency to cause a localized secondary infection (zoster; shingles). VZV latency, however, is not restricted to DRG/CNG; latent VZV is present in the enteric nervous system (ENS) in virtually everyone who has experienced varicella or received the live attenuated varicella vaccine. VZV reactivates in the ENS (enteric zoster) as it does in DRG/CNG but because enteric neurons lack cutaneous projections, enteric zoster occurs without rash and may be an unsuspected cause of GI disease. A major hindrance to research on VZV has been the absence of a suitable animal model. To overcome this difficulty, we demonstrated that VZV infects, establishes latency, and reactivates in isolated guinea pig enteric neurons; moreover, VZV infects guinea pigs in vivo, establishes latent infection in their DRG/CNG and ENS, and can be reactivated to produce a secondary infection resembling disseminated zoster. VZV can be transported to the ENS from infected epidermis in axons of DRG neurons that project both to the skin and gut but intravenous injection of VZV- infected T lymphocytes establishes latency in almost every ENS and DRG neuron of the animal. It had been thought that latent infection of enteric neurons could be established by cell-free VZV (VZVCF) but not by cell associated VZV (VZVCA). VZV-infected lymphocytes, however, do not secrete VZVCF but they are able transmit infection to neurons in vitro and in vivo that is exclusively latent.
Aim 1 tests hypotheses that: (i) evanescent cell fusion is responsible for transmission of VZV from lymphocytes to neurons; (ii) exosomes derived from VZV-infected lymphocytes introduce stimulator of interferon genes (STING) to neurons; (iii) STING induces a type1 interferon response in neurons that inhibits VZV proliferation and facilitates establishment of latency.
Aim 2 tests hypotheses that: (i) VZV-infected lymphocytes can induce a varicella- like primary infection in guinea pigs if immunosuppression and stress precedes infection; (ii) restriction of VZV latency allows localized reactivations to be confined to gut or skin; (iii) continuous activation of a receptor tyrosine kinase transduction pathway, similar to that in HSV1 reactivation in sympathetic neurons, regulates latent VZV genomes in enteric neurons.
Aim 3 directly tests the hypothesis that salivary VZV DNA in patients with unexplained abdominal pain severe enough to warrant endoscopy and biopsy is a marker of enteric zoster. To validate this idea with a tissue diagnosis, we will analyze VZV DNA in saliva and GI mucosal expression of gE transcripts and protein which would indicate productive VZV infection (enteric zoster) in the bowel. This research makes the first use a novel animal model in which VZV reactivates in vivo and the first application of a non-invasive technique to identify patients that might have enteric zoster.
Relevance to Public Health Varicella zoster virus (VZV) infects nave individuals to cause chickenpox and then becomes latent in nerve cells for the life of its host; however, VZV can reactivate to give rise to a painful secondary disease, shingles, which may be followed by post-herpetic neuralgia, a fearful pathological pain syndrome. VZV also establishes latency in the nervous system of the gut (ENS) and, when VZV reactivates in the ENS, it causes enteric zoster, which occurs without a rash and is difficult to diagnose, even when severe. We have now developed the first animal model (in guinea pig) of VZV latency and reactivation and the first non-invasive method to identify patients with enteric zoster (detection of VZV genes in saliva); these tools will now be employed to determine how latent VZV infection is transmitted to nerve cells, how enteric nerve cells regulate the transition of VZV infection from latency to reactivation and, by analyzing VZV genes in saliva, select patients with enteric zoster to determine the manifestations and consequences of this condition.
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