Rotavirus non-structural proteins: structure and function

Hu, Liya; Crawford, Sue E.; Hyser, Joseph M.; Estes, Mary K.; Prasad, B. V. Venkataram

doi:10.1016/j.coviro.2012.06.003

Cited by 74 publications

(84 citation statements)

References 78 publications

(50 reference statements)

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“…Moreover, NSP1 seems to interact with the cellular transcription factor interferon regulatory factor 3 (IRF3) and targets it for degradation by the proteasome, thus acting to avoid the host antiviral defense by the blocking INF production [14][15][16][17][18] . However, NSP1 seems not to be necessary for rotavirus replication in vitro and its role is not fully clear 19 .…”

Section: Proteins Involved In Replication Pathogenesis and Immune Rementioning

confidence: 99%

“…Thereafter the ER membrane and NSP4 are removed and VP7 assembles onto the particle 11 . Moreover, NSP4 has been shown to have viroporin properties and to induce release of calcium from ER 19,22,23 . It is not clear how intracellular NSP4 releases calcium from the ER, but this is presumably by a phospholipase C (PLC)--dependent mechanism 22,24 .…”

Section: Proteins Involved In Replication Pathogenesis and Immune Rementioning

confidence: 99%

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Rotavirus Disease Mechanisms Diarrhea, Vomiting and Inflammation : How and Why

Hagbom¹

2015

Linköping University Medical Dissertations

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Rotavirus infections cause diarrhea and vomiting that can lead to severe dehydration. Despite extensive tissue damage and cell death, the inflammatory response is very limited. The focus of this thesis was to study pathophysiological mechanisms behind diarrhea and vomiting during rotavirus infection and also to investigate the mechanism behind the limited inflammatory response. An important discovery in this thesis was that rotavirus infection and the rotavirus toxin NSP4 stimulate release of the neurotransmitter serotonin from intestinal sensory enterochromaffin cells, in vitro and ex vivo. Interestingly, serotonin is known to be a mediator of both diarrhea and vomiting. Moreover, mice pups infected with rotavirus responded with central nervous system (CNS) activation in brain structures associated with vomiting, thus indicating a cross-talk between the gut and brain in rotavirus disease. Our finding that rotavirus infection activates the CNS led us to address the hypothesis that rotavirus infection not only activates the vagus nerve to stimulate vomiting, but also suppresses the inflammatory response via the cholinergic anti-inflammatory pathway, both of which are mediated by activated vagal afferent nerve signals into the brain stem. We found that mice lacking an intact vagus nerve, and mice lacking the α7 nicotine acetylcholine receptor (nAChR), being involved in cytokine suppression from macrophages, responded with a higher inflammatory response. Moreover, stimulated cytokine release from macrophages, by the rotavirus toxin NSP4, could be attenuated by nicotine, an agonist of the α7 nAChR. Thus, it seems most reasonable that the cholinergic anti-inflammatory pathway contributes to the limited inflammatory response during rotavirus infection. Moreover, rotavirus-infected mice displayed increased intestinal motility at the onset of diarrhea, which was not associated with increased intestinal permeability. The increased motility and diarrhea in infant mice could be attenuated by drugs acting on the enteric nervous system, indicating the importance and contribution of nerves in the rotavirus mediated disease. In conclusion, this thesis provides further insight into the pathophysiology of diarrhea and describe for the first time how rotavirus and host cross-talk to induce the vomiting reflex and limit inflammation. Results from these studies strongly support our hypothesis that serotonin and activation of the enteric nervous system and CNS contributes to diarrhea, vomiting and suppression of the inflammatory response in rotavirus disease

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Section: Proteins Involved In Replication Pathogenesis and Immune Rementioning

confidence: 99%

Section: Proteins Involved In Replication Pathogenesis and Immune Rementioning

confidence: 99%

Rotavirus Disease Mechanisms Diarrhea, Vomiting and Inflammation : How and Why

Hagbom¹

2015

Linköping University Medical Dissertations

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“…The 41 kDa band that was observed for S-NSP4 was weak in comparison to the control (pET plasmid alone) in Western blots, probably due to the toxicity of S-NSP4. A possible explanation could be that although the diarrhea-inducing domain (aa 114-135) was removed, still the viroporin domain (aa 47-92) which includes the membrane-destabalizing region (aa 55-69) was present (3), and this may have lead to cytotoxicity. However, this hypothesis, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…The domain functions include diarrhea-induction, which is attributed to amino acids 114-135 in the cytoplasmic tail, and calcium binding. A synthetic peptide corresponding to the diarrhea-inducing domain, was shown to induce diarrhea in neonatal mice in a 100-fold molar excess in comparison to the full-length protein (3,4). However, this suggests that other domains could also influence the diarrhea-induction ability of NSP4 (5).…”

mentioning

confidence: 99%

“…However, this suggests that other domains could also influence the diarrhea-induction ability of NSP4 (5). This so-called diarrhea-inducing region forms part of the oligomerization domain (amino acids 95-137), thus contributes directly to the conformation of the functional domain (C-terminus) of NSP4 (3,6). It has also been suggested that a unique conformation is required for optimal function of rotavirus enterotoxin (7).…”

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confidence: 99%

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