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RUSSO, VENERA (2016) THE ROLE OF INTESTINAL IMMUNE SYSTEM IN HERPES SIMPLEX VIRUS TYPE 1–MEDIATED ENTERIC NERVOUS SYSTEM DYSFUNCTIONS. [Tesi di dottorato]

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Abstract (inglese)

Intestinal neuropathies have been described in a variety of functional and inflammatory gastrointestinal disorders. Although the degenerative alterations and neuronal are often associated to a lymphocytic inflammatory infiltrate, the underlying mechanisms remain obscure. Potential etiologic factors are neurotropic viruses, since they are able to specifically infect neurons and cause cell damage through direct or indirect mechanisms. Among the neurotrophic viruses the HSV-1 shows several interesting features. HSV-1 is most commonly known to latently infect the trigeminal ganglion of cranial nerve innervating the face and oral mucosa but latent HSV-1 has also been found in the nodose ganglia innervating the gastrointestinal tract in humans possibly as a consequence of swallowed viral particles.
The working hypothesis of my PhD work was that swallowed HSV-1 can infect the enteric nervous system and locally trigger an immune mediated response damaging neurons.
To assess the ability of α-herpesvirinae (HSV-1, HSV-2, VZV) to infect human ENS we performed a prospective cohort study using human surgical ileocolonic specimens of patients affected by colon carcinoma (CC), Crohn’s disease (CD), ulcerative colitis (UC) and diverticular disease (DD). A total of 121 patients were studies and presence of herpes simplex virus (HSV) types-1 and -2 and varicella-zoster virus (VZV) DNA was examined by RT-PCR in the muscle intestinal layer including the myenteric plexus. The α-herpesviruses DNA was detected in 44,5 % and 52 % of ileum and colon samples, respectively. No significant differences in the viral DNA positivity were observed among the different groups whereas the viral DNA load was significantly higher in samples of patients affected by Crohn’s disease. Moreover, HSV DNA was detected more frequently than VZV DNA, 46% vs 3%, respectively.
In order to mimic the human α-herpesvirinae infection and spread in ENS, my research group has established an original murine model of persistent ENS infection with HSV-1. Using this model we demonstrated that HSV-1 infection resulted in time-dependent intestinal neuromuscular abnormalities, providing the first in vivo evidence for the ability of neurotropic viruses to reach and damage the ENS.
Since significant intestinal motility anomalies and damage of enteric nerves were evident 8 - 10 weeks (W) post intragastric (IG) challenge with HSV-1, I attempted to characterize the adaptive immune response to HSV-1 and whether was causing the neuromuscular abnormalities.
In the longitudinal muscle myenteric plexus (LMMP) I observed an increase in CD3+ lymphocytes starting at 6 W and persisting up to 10 W after viral IG inoculum. At 8 weeks post IG viral inoculum, HSV-1 reactive CD3+CD4+IL4+ and CD3+CD8+INF-γ+ were detected, whereas at 10 W activated CD8+ T-cells infiltrated the LMMP. By immunohistochemistry CD3+ lymphocytes were demonstrated in the myenteric ganglia of HSV-1 infected mice 6-10 W post IG viral challenge.
To verify the involvement of CD8+ and CD4+ T-cells in HSV-1 induced dysmotility we performed depletion experiments by administration of monoclonal antibody. ENS damage and the neuromuscular anomalies were observed only after depletion of CD8 T cells at 8 and 10 W after viral IG inoculum.
To validate the role of lymphocytes in HSV-1 induced ENS dysfunction, CD3+CD4+ and CD+CD8+ cells were isolated from the LMMP of mice 8-10 W after viral IG inoculum, in vitro pulsed with HSV-1, and injected in recipient mice. The effects on isometric muscle tension were determined after one week. Adoptive transfer of CD8+ T cells isolated from LMMP at 8 W post IG HSV-1 inoculum caused significant neuromuscular anomalies (p<0.01 vs control) in recipient mice only if HSV-1 pulsed in vitro. Instead, the adoptive transfer of both CD4+ and CD8+ T cells isolated from 10 W infected mice resulted in dysmotility with or without in vitro exposure to viral antigens in recipient mice.
In conclusion, in this study we showed that α-herpesvirinae DNA is present in a large percentage of patients and the presence of HSV-1 in murine myenteric ganglia triggered a strong and specific immune response able to damage the ENS. We speculate that persistent HSV-1 infection in the ENS, in predisposed individuals, may contribute to alter neuronal functional integrity favouring the onset of bowel disorders.

Abstract (italiano)

Le neuropatie intestinali sono state descritte in una varietà di disturbi gastrointestinali di natura funzionale e infiammatoria. Inoltre le alterazioni neuronali sono spesso state associate alla presenza di un infiltrato infiammatorio linfocitario, ma rimangono ancora oscuri i meccanismi alla base di questi processi. I potenziali fattori eziologici sono rappresentati da virus neurotropi, i quali sono in grado di infettare specificatamente i neuroni e causare danni alle cellule attraverso meccanismi diretti o indiretti. Tra i virus neurotropici, Herpes Simplex Virus type-1 sembra mostrare diverse caratteristiche interessanti. Anche se l’HSV-1 è più comunemente noto per infettare latentemente il ganglio trigemino del nervo cranico che innerva viso e mucosa orale, HSV-1 è stato trovato anche in gangli che innervano il tratto gastrointestinale nell'uomo probabilmente come conseguenza di particelle virali ingerite.
L’attività di ricerca svolta durante il mio periodo di dottorato si basa sull’ipotesi che HSV-1 è capace di infettare il sistema nervoso enterico e innescare localmente una risposta immunitaria in grado di danneggiare i neuroni del tratto gastrointestinale.
Per valutare la capacità della subfamiglia degli α-Herpesviridae (HSV-1, HSV-2, VZV) di infettare il sistema nervoso enterico (SNE) umano, abbiamo effettuato uno studio di coorte prospettico su resezioni ileocoliche chirurgiche di pazienti affetti da carcinoma del colon, morbo di Crohn, colite ulcerosa e malattia diverticolare.
Un totale di 121 pazienti sono stati collezionati e mediante Real Time-PCR è stata valutata la presenza di DNA virale di HSV-1, HSV-2 e varicella-zoster (VZV), nello strato muscolare intestinale che comprende il plesso mienterico. La presenza di α-herpesvirus è stata evidenziata nel 44,5% dei campioni ileali e nel 52% dei campioni estratti da colon. La frequenza di campioni positivi al DNA virale non evidenzia alcuna correlazione significata con specifiche patologie. E’ stato però osservato che i livelli di DNA virale erano significativamente maggiori nei campioni di pazienti affetti da morbo di Crohn. Inoltre, il DNA di HSV è stato rilevato più frequentemente rispetto a VZV, 46% e 3%, rispettivamente.
Al fine di simulare l'infezione da α-herpesvirinae e la conseguente diffusione nel SNE umano, il mio gruppo ha messo a punto un modello murino di infezione persistente di HSV-1 nel SNE. Utilizzando questo modello abbiamo dimostrato che l’infezione intestinale da HSV-1 provoca anomalie neuromuscolari correlate al tempo d’infezione, fornendo per per la prima volta la prova in vivo che i virus neurotropi sono capaci di raggiungere e, conseguentemente, danneggiare il SNE.
In particolare, significative anomalie della motilità intestinale e danni funzionali dei nervi enterici sono stati evidenziati tra le 8 e 10 settimane dopo l’inoculo intragastrico (IG) in topi infettati con HSV-1. Il mio studio si è focalizzato sulla caratterizzazione della risposta immunitaria adattativa durante l’infezione da HSV-1 con lo scopo di chiarire un possibile coinvolgimento delle cellule immuni sulle alterazione neuronali che causano disfunzioni gastrointestinali.
Abbiamo analizzato la presenza d’infiltrato linfocitario nel plesso mienterico (LMMP) di topi infettati con HSV-1 ed è stato osservato un aumento del numero di linfociti CD3+ a partire dalla sesta settimana e persistenti fino alla decima settimana dopo inoculo IG. In particolare all’ottava settimana d’infezione sono stati osservati sia CD3+CD4+IL4+ che CD3+CD8+INF-γ+ specificatamente attivati e reattivi ad HSV-1, mentre alla decima settimana dopo inoculo IG vi era una maggiore presenza di CD3+CD8+INF-γ+. Con saggi d’immunoistochimica, la localizzazione dei linfociti CD3+ è stata confermata al livello dei gangli mienterici in topi inoculati con HSV-1 dalla sesta alla decina settimana post infezione.
Per verificare il coinvolgimento delle cellule T CD8+ e CD4+ nelle dismotilità indotte da HSV-1 sono stati effettuati esperimenti di deplezione tramite somministrazione di anticorpi monoclonali anti-CD4 e anti-CD8. Danni al SNE e anomalie neuromuscolari sono state osservate solo dopo l'esaurimento delle cellule T CD8+ all’ottava e decima dopo inoculo IG.
Per validare ulteriormente il ruolo dei linfociti T reattivi al virus nel danno neuronale, CD3+CD4+ e CD3+CD8+ sono stati isolati dal plesso mienterico di topi infetti da 8 e 10 settimane e, dopo stimolazione in vitro con HSV-1, trapianti in topi sani. Una settimana dopo il trapianto sono stati valutati gli effetti sulla motilità intestinale nei topi trapiantati. Il trasferimento di cellule T CD8+ isolate dal plesso mienterico a 8 settimane hanno causato significative anomalie neuromuscolari (p <0.01 vs controllo) in topi controllo trapianti, solo in seguito a stimolazione in vitro con HSV-1. Invece, alterazioni della motilità sono state riscontrate in seguito al trapianto di entrambe le sottopopolazioni linfocitarie, CD4+ e CD8+ isolati dal plesso mientercio di topi infetti a 10 settimane, con o senza una precedente esposizione in vitro di antigeni virali.
In conclusione, in questo studio abbiamo dimostrato che α-herpesvirinae DNA è presente in una grande percentuale di pazienti e che la presenza di HSV-1 nei gangli mienterici murini innesca una robusta risposta immunitaria specifica in grado di danneggiare il SNE. Noi ipotizziamo che una persistente infezione da HSV-1 nel SNE, in soggetti predisposti, può contribuire ad alterare l'integrità funzionale neuronale favorendo l'insorgenza di disturbi intestinali.

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Tipo di EPrint:Tesi di dottorato
Relatore:Castagliuolo, Ignazio
Dottorato (corsi e scuole):Ciclo 28 > Scuole 28 > BIOMEDICINA > MEDICINA MOLECOLARE
Data di deposito della tesi:28 Gennaio 2016
Anno di Pubblicazione:28 Gennaio 2016
Parole chiave (italiano / inglese):Neuropatie gastrointestinali, HSV-1, enteric nervous system, sistema nervoso enterico, enteric neuropathies.
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/12 Gastroenterologia
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Molecolare
Codice ID:9263
Depositato il:21 Ott 2016 16:50
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