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Rotavirus
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Lijuan Yuan, Tammy Bui, Ashwin Ramesh
A unique aspect of rotavirus-induced diarrhea is the role of nonstructural protein, NSP4, which acts as an enterotoxin. NSP4 is produced by infected enterocytes,67,99,143,147,148 and peptides are secreted into the intestinal lumen to further affect neighboring cells.149 NSP4 appears to have multiple effects on enterocytes that collectively contribute to intestinal fluid loss and secretion.
Rotavirus
Published in Dongyou Liu, Laboratory Models for Foodborne Infections, 2017
Neonatal mice at 5–7 days of age can develop diarrhea after inoculation with high doses of a heterologous rotavirus, including human, simian, or bovine rotaviruses,74 but virus shedding is not consistently detected75 and virus replication is not required for the development of diarrhea. Neonatal mice inoculated with recombinant NSP4 develop diarrhea comparable to that after challenge with live virus, suggesting the enterotoxigenic properties of rotavirus NSP4.76,77
Viral infections
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Sarah Elizabeth Blutt, Mary K. Estes, Satya Dandekar, Phillip D. Smith
Rotaviruses enhance and exploit Ca2+ signaling as a key cellular target to regulate replication, morphogenesis, and pathogenesis (Figure 28.3). Thus, rotavirus infection results in at least threefold increases in intracellular calcium [Ca2+]i and up to 10-fold increases in uptake of Ca2+ into cells. Ca2+ also plays an important role in virion assembly and disassembly processes. Ca2+ maintains the integrity of the rotavirus outer capsid layer; VP7 is a Ca2+-binding protein; and Ca2+ chelation is a mechanism that activates the endogenous RNA polymerase. NSP5 also is a Ca2+-binding protein, and viroplasm formation requires Ca2+. Rotavirus morphogenesis is dependent on the presence of sufficient levels of [Ca2+]i. In the absence of Ca2+, virus morphogenesis is terminated at the double-layered particle step, and VP7 is excluded from hetero-oligomeric complexes made of NSP4 and VP4 that participate in the budding of double-layered particles into the ER. Furthermore, Ca2+ depletion of the ER by the sarco-/endoplasmic reticulum Ca2+-ATPase pump inhibitor thapsigargin inhibits VP7 and NSP4 glycosylation and virus maturation. NSP4 is the only rotavirus protein that mobilizes [Ca2+]i in cells by functioning as a viroporin in the ER membrane. Release of [Ca2+]i from the ER alters plasma membrane permeability and compensatory entry of extracellular Ca2+ into cells. Changes in calcium homeostasis also alter other cellular functions that affect pathogenesis.
The potential role of interventions impacting on gut-microbiota in epilepsy
Published in Expert Review of Clinical Pharmacology, 2020
Luigi F Iannone, Maria Gómez-Eguílaz, Rita Citaro, Emilio Russo
The aim of the other study [87] was to verify the relationship between rotavirus infection and neonatal seizures, and to determine significant factors potentially associated with seizures and with the white matter injury (WMI) pattern seen in rotavirus infections. The authors design a prospective study in which included 228 neonates who were admitted in neonatal intensive care units in their hospital with rotavirus antigens test and seizures. They found that rotavirus infection is an independent risk factor for neonatal seizures, and it was associated with WMI. Immediate administration of probiotics (Saccharomyces boulardii and only one took Lactobacillus casei) after birth (for a non-specified reason) reduces rotavirus-associated neonatal seizures by 10-fold (OR 0.09; p < 0.001). They proposed that S. boulardii reduces seizures through inhibition of rotavirus structural protein 4 (NSP4) or by anti-inflammatory effect. NSP4 is a viral enterotoxin, who is associated with neurological injury produced by rotavirus. S. boulardii also has shown beneficial effects in various infections by its immunomodulatory effects. The interpretation of this study is limited by the lack of several information; details on prebiotic administration are missing as well as the reason of the administration. Indeed, probiotic administration may have an impact on the gut microbiota of these neonates however this is not demonstrated/studied in the published article. Therefore, the unjustified use of probiotics in neonates cannot be supported.
Targeting Chikungunya virus by computational approaches: from viral biology to the development of therapeutic strategies
Published in Expert Opinion on Therapeutic Targets, 2020
Vitor Won-Held Rabelo, Izabel Christina Nunes de Palmer Paixão, Paula Alvarez Abreu
Finally, CHIKV nsP4 is the viral RNA-dependent RNA polymerase (RdRp) and presents two domains: a large RdRp domain at C-termini which possesses RdRp and adenylyltransferase (TATase) activities; and a partially disordered domain at N-termini that likely interacts with other nsPs in replicase complex and also is essential for virus replication [51,54]. Not long ago, a truncated construct of nsP4 was expressed in a yield suitable for biochemical and structural tests by removing the first 118 amino acid residues and, yet, this construct exhibited RdRp and TATase activities. To improve the understanding regarding this construct structure-function relationship, a homology model was built and showed a similar overall 3D structure as observed for other RdRp proteins from positive-sense single-stranded RNA viruses. The nsP4 architecture was comparable to a hand (fingers, palm, and thumb regions) where the tunnel-shaped RNA binding site was located at the central region of the protein. Besides, hydrogen/deuterium exchange coupled to mass spectrometry studies indicated high flexible regions (e.g. A2106-Y2185) comprising finger regions, probably involved in the correct positioning of the RNA strand in its binding site [55].
Chikungunya virus drug discovery: still a long way to go?
Published in Expert Opinion on Drug Discovery, 2019
María-Jesús Pérez-Pérez, Leen Delang, Lisa F. P. Ng, Eva-María Priego
A schematic representation of the replication cycle of CHIKV is shown in Figure 1(a) [9]. CHIKV is a spherical enveloped virus with a positive-sense ribonucleic acid (RNA) genome of approximately 11.8 kilobases that consists of two open reading frames encoding for four non-structural proteins (nsPs) and five structural proteins (Figure 1(b)) [10]. Together, the nsPs make up the replication complex of the virus. Upon virus entry, translation of the nsPs into polyprotein (nsP1-2–3-4) is carried out by the host ribosomes [10,11]. After translation, the polyprotein undergoes autocatalysis to yield nsP4 and P123 [10]. nsP4 is the RNA polymerase involved in synthesizing the full complementary negative strand of the virus genome [10]. Further cleavage of P123 into nsP1, nsP2, and nsP3 yields the full replication complex required to synthesize the new positive-sense strands [10].