Antibody Is Critical for the Clearance of Murine Norovirus Infection

Chachu, Karen A.; Strong, David W.; LoBue, Anna D.; Wobus, Christiane E.; Baric, Ralph S.; Virgin, Herbert W.

doi:10.1128/jvi.00141-08

Cited by 87 publications

(84 citation statements)

References 57 publications

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“…Both hypotheses are supported by the finding from this study that daily viral RNA titre is associated with multiple proinflammatory serum cytokines and chemokines. The immune response to NoV has been found to be critical for limiting viral replication and eventually clearing infection [27,34,35]. However, there may also be immune-mediated damage, as seen in other enteric infections [36].…”

Section: Discussionmentioning

confidence: 99%

Norovirus in symptomatic and asymptomatic individuals: cytokines and viral shedding

Newman

Moe

Kirby

et al. 2016

Clinical and Experimental Immunology

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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.

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Section: Discussionmentioning

confidence: 99%

Norovirus in symptomatic and asymptomatic individuals: cytokines and viral shedding

Newman

Moe

Kirby

et al. 2016

Clinical and Experimental Immunology

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“…Chachu et al have shown that virus levels in persistently infected Rag1 Ϫ/Ϫ mice can be reduced by adoptive transfer of total splenocytes from CW3 immune donors. Furthermore, viral control in these studies required the presence of all three components of the adaptive response, i.e., B cells and CD4 and CD8 T cells, as selective depletion of any one of these subsets prior to transfer led to incomplete viral clearance (49,50). The relative importance of specific B or T cell subsets individually to MNV clearance, however, has not been examined.…”

Section: Fig 4 Epitope P1mentioning

confidence: 99%

“…Thus, Rag1 Ϫ/Ϫ mice fail to clear MNV-CW3, while immunocompetent mice clear this same strain within 7 days. In addition, selective depletion of CD4 T cells, CD8 T cells, or B cells from wild-type mice impairs MNV clearance and leads to higher viral titers in the intestine and mesenteric lymph nodes (MLN) (49,50). Furthermore, adoptive transfer of splenocytes from MNV immune wildtype mice was sufficient to clear the same strain from chronically infected Rag1 Ϫ/Ϫ recipients (49).…”

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confidence: 99%

Persistent Enteric Murine Norovirus Infection Is Associated with Functionally Suboptimal Virus-Specific CD8 T Cell Responses

Tomov

Osborne

Dolfi

et al. 2013

J Virol

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“…MNV has also been isolated from wild mice, confirming its widespread distribution (59). Studies with MNV have begun to probe various aspects of the norovirus replication cycle, including entry mechanisms and attachment factors (24,48,49,67), viral protein function (8,19,30,43,64,66), determinants of virulence (7), and host immune responses (14,15,42); however, our understanding of the molecular mechanisms of norovirus genome translation and replication lags far behind that for other RNA viruses.…”

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confidence: 99%

High-Resolution Functional Profiling of the Norovirus Genome

Thorne

Bailey

Goodfellow

2012

J Virol

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Human noroviruses (HuNoV) are a major cause of nonbacterial gastroenteritis worldwide, yet details of the life cycle and replication of HuNoV are relatively unknown due to the lack of an efficient cell culture system. Studies with murine norovirus (MNV), which can be propagated in permissive cells, have begun to probe different aspects of the norovirus life cycle; however, our understanding of the specific functions of the viral proteins lags far behind that of other RNA viruses. Genome-wide functional profiling by insertional mutagenesis can reveal protein domains essential for replication and can lead to generation of tagged viruses, which has not yet been achieved for noroviruses. Here, transposon-mediated insertional mutagenesis was used to create 5 libraries of mutagenized MNV infectious clones, each containing a 15-nucleotide sequence randomly inserted within a defined region of the genome. Infectious virus was recovered from each library and was subsequently passaged in cell culture to determine the effect of each insertion by insertion-specific fluorescent PCR profiling. Genome-wide profiling of over 2,000 insertions revealed essential protein domains and confirmed known functional motifs. As validation, several insertion sites were introduced into a wild-type clone, successfully allowing the recovery of infectious virus. Screening of a number of reporter proteins and epitope tags led to the generation of the first infectious epitope-tagged noroviruses carrying the FLAG epitope tag in either NS4 or VP2. Subsequent work confirmed that epitope-tagged fully infectious noroviruses may be of use in the dissection of the molecular interactions that occur within the viral replication complex. Human norovirus (HuNoV) is the leading cause of nonbacterial gastroenteritis in developed countries, with initial reports also indicating high incidence and mortality in developing countries (47). Due to the low infectious dose, multiple transmission routes, and high stability of HuNoV in the environment (41, 72), outbreaks typically occur in places with close living conditions, such as hospitals. Infections in hospitals alone cost the United Kingdom National Health Service an estimated £115 million and result in 47,000 lost bed days per year, compromising hospital services (39, 53). The majority of HuNoV infections are acute and self-resolving; however, links with conditions such as inflammatory bowel disease (36), infantile seizures (18), and neonatal necrotizing enterocolitis (65, 74) have been established. There are also increasing reports of persistent infections in the elderly and the immunocompromised, such as transplant recipients and some cancer patients (2,13,20,40,55,56).Details of the life cycle and replication of HuNoV are relatively unknown due to the lack of an efficient cell culture system. The discovery of murine norovirus (MNV) in 2003 has since facilitated studies on norovirus replication. Unlike HuNoV, MNV can be propagated in culture, displaying a tropism for macrophage and dendritic cells (75), and ca...

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Antibody Is Critical for the Clearance of Murine Norovirus Infection

Cited by 87 publications

References 57 publications

Norovirus in symptomatic and asymptomatic individuals: cytokines and viral shedding

Norovirus in symptomatic and asymptomatic individuals: cytokines and viral shedding

Persistent Enteric Murine Norovirus Infection Is Associated with Functionally Suboptimal Virus-Specific CD8 T Cell Responses

High-Resolution Functional Profiling of the Norovirus Genome

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