Norovirus in symptomatic and asymptomatic individuals: cytokines and viral shedding

Abstract

Summary Noroviruses (NoV) are the most common cause of epidemic gastroenteritis world-wide. NoV infections are often asymptomatic, although individuals still shed large amounts of NoV in their stool. Understanding the differences between asymptomatic and symptomatic individuals would help in elucidating mechanisms of NoV pathogenesis. Our goal was to compare the serum cytokine responses and faecal viral RNA titres of asymptomatic and symptomatic NoV-infected individuals. We tested serum samples from infected subjects (n = 26; 19 symptomatic, seven asymptomatic) from two human challenge studies of GI.1 NoV for 16 cytokines. Samples from prechallenge and days 1-4 post-challenge were tested for these cytokines. Cytokine levels were compared to stool NoV RNA titres quantified previously by reverse transcription–polymerase chain reaction (RT–qPCR). While both symptomatic and asymptomatic groups had similar patterns of cytokine responses, the symptomatic group generally exhibited a greater elevation of T helper type 1 (Th1) and Th2 cytokines and IL-8 post-challenge compared to the asymptomatic group (all P < 0·01). Daily viral RNA titre was associated positively with daily IL-6 concentration and negatively with daily IL-12p40 concentration (all P < 0·05). Symptoms were not associated significantly with daily viral RNA titre, duration of viral shedding or cumulative shedding. Symptomatic individuals, compared to asymptomatic, have greater immune system activation, as measured by serum cytokines, but they do not have greater viral burden, as measured by titre and shedding, suggesting that symptoms may be immune-mediated in NoV infection.

Norovirus infection in primary immune deficiency

“…Indeed, even the types of host cell infected by norovirus are not well established—although varying evidence exists for tropism towards mucosal epithelial cells, B cells, and antigen‐presenting cells . Nevertheless, it is clear from human studies that there is rapid and broad immune activation in response to infection in immunocompetent hosts, both systemically and in stool, with subsequent development of antibody responses. Newman et al document a rise in Th1 (eg, IFNγ), proinflammatory (eg, IL‐1β, IL‐6, and IL‐8) and Th2 (eg, IL‐4 and IL‐10) cytokines in serum, while Ko et al predominantly observed increased IL‐2 and IFNγ in faeces …”

Norovirus Regulation by Host and Microbe

“…Outbreaks occur in places where people gather (e.g., cruise ships, day-care centers, hospitals). They are facilitated by the low numbers of virions able to cause infections (i.e., low infectious dose) [15,16], high amounts of viral shedding [17], high environmental stability of HNoV [18], and a relative viral resistance to disinfectants [19]. …”

“…After an average 1.2-day incubation period, HNoV infection induces symptoms including abdominal pain, nausea, vomiting, and diarrhea, which typically resolve within 1–4 days [17,20,21]. However, viral shedding may occur for weeks to months in asymptomatic healthy hosts [22], and years in immunocompromised patients [23].…”

“…The latter have been postulated to serve as a reservoir for future outbreaks [24]. There is no significant correlation between presentation of symptoms and viral burden, duration, or magnitude of NoV shedding, but enhanced cytokine responses correlate with HNoV symptoms and suggest immune mediation [17]. Complications can occur following acute infection and include postinfectious irritable bowel syndrome [25,26], life-threatening dehydration [27], necrotizing enterocolitis [28], and exacerbation of Crohn’s disease [29].…”

“…The immune response and cytokines in particular may also control symptomatology in HNoV infection [17]. Serum T-helper type 1 (Th1), Th2 cytokines , and interleukin-8 (IL-8) were more elevated in symptomatic versus asymptomatic patients, despite equivalent viral titers [17]. However, the underlying genetic causes for these specific immune responses were not explored.…”