Neurotropic influenza A virus infection causes prion protein misfolding into infectious prions in neuroblastoma cells

Misfolding of the cellular prion protein, PrPC, into the amyloidogenic isoform, PrPSc, which forms infectious protein aggregates, the so-called prions, is a key pathogenic event in prion diseases. No pathogens other than prions have been identified to induce misfolding of PrPC into PrPSc and propagate infectious prions in infected cells. Here, we found that infection with a neurotropic influenza A virus strain (IAV/WSN) caused misfolding of PrPC into PrPSc and generated infectious prions in mouse neuroblastoma cells through a hit-and-run mechanism. The structural and biochemical characteristics of IAV/WSN-induced PrPSc were different from those of RML and 22L laboratory prions-evoked PrPSc, and the pathogenicity of IAV/WSN-induced prions were also different from that of RML and 22L prions, suggesting IAV/WSN-specific formation of PrPSc and infectious prions. Our current results may open a new avenue for the role of viral infection in misfolding of PrPC into PrPSc and formation of infectious prions

VERA monitoring of the radio jet 3C 84 during 2007--2013: detection of non-linear motion

We present a kinematic study of the subparsec-scale radio jet of the radio galaxy 3C 84/NGC 1275 with the VLBI Exploration of Radio Astrometry (VERA) array at 22 GHz for 80 epochs from 2007 October to 2013 December. The averaged radial velocity of the bright component "C3" with reference to the radio core is found to be $0.27 pm 0.02c$ between 2007 October and 2013 December. This constant velocity of C3 is naturally explained by the advancing motion of the head of the mini-radio lobe. We also find a non-linear component in the motion of C3 with respect to the radio core. We briefly discuss possible origins of this non-linear motion.Comment: 11 pages, 7 figures, 8 tables (table 1 - 5 are supplementaries), accepted for publication on PAS

Characterization of compound missense mutation and deletion of carnitine palmitoyltransferase II in a patient with adenovirus-associated encephalopathy

Background : In mammals, carnitine palmitoyltransferase (CPT) system is a pivotal component of energy metabolism through mitochondrial fatty acid oxidation. The majority of patients with fatal or handicapped influenza-associated encephalopathy exhibit thermolabile compound homo/heterozygous mutations of CPT II. Objective : Compound CPT II mutations, [c.647A G (p.Q216R)], [c.1102G A (p.V368I)], [c.1939A G (p.M647V)] and [c.745delG (p.G249EfsX16)], were found in a patient with adenovirus-associated encephalopathy and his family. The properties of these CPT II mutations were analyzed in COS-7 cells. Methods : CPT II mutations in the patient and his family were expressed in COS-7 cells and their molecular masses, enzyme activities, thermal instabilities and halflives were analyzed. Results : We identified two novel CPT II mutations in the patient, [c.647A G (p.Q216R)] and [c.745delG (p.G249EfsX16)]. The CPT II Q216R mutation showed mild reduction of activity, thermal instability and short half-life but compound mutations with Q216R+V368I+M647V showed further enhancement of these disabilities, although mutations V368I and M647V had no such effects. CPT II mutation [c.745delG (p.G249 EfsX16)] abolished enzyme activity and showed short half-life. Conclusion : The thermal instability and short half-life of the novel CPT II mutations, [c.647A G (p.Q216R)] and [c.745delG (p.G249EfsX16)], could play important roles in energy crisis in the pathogenesis of virus-associated encephalopathy

Mechanisms of matrix metalloproteinase-9 upregulation and tissue destruction in various organs in influenza A virus infection

Severe influenza is characterized clinicopathologically by multiple organ failure, although the relationship amongst virus and host factors that influence this morbid outcome and the underlying mechanisms of action remain unclear. The present study identified marked upregulation of matrix metalloproteinase (MMP)-9 and pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) in various organs after intranasal infection of influenza A WSN virus. MMP-9 and TNF-α were upregulated in the lung, the site of initial infection, as well as in the brain and heart. The infection-induced MMP-9 upregulation was inhibited by anti-TNF-α antibodies and by anti-oxidative reagents pyrrolidine dithiocarbamate and N-acetyl-L-cysteine, which inhibit activation of nuclear factor kappa B (NF-χB), as well as by nordihydroguaiaretic acid, which inhibits activation of activator protein 1 (AP-1). In addition, MMP-9 upregulation via TNF-α was also suppressed by inhibitors of mitogen-activated protein kinases (MAPKs), such as extracellular signalregulated kinase 1/2 and p38, and partly by a c-Jun N-terminal kinase inhibitor. These results indicated that the influenza-induced MMP-9 upregulation in various organs is mediated through MAPK-NF-χB- and/or AP-1-dependent mechanisms. Strategies that neutralize TNF-α as well as inhibitors of MAPK-NF-χB- and/or AP-1-dependent pathways may be useful for suppressing the MMP-9 effect and thus preventing multiple organ failure in severe influenza

PrP in M2 macrophages and influenza

The cellular prion protein, PrPC, is a glycosylphosphatidylinositol anchored-membrane glycoprotein expressed most abundantly in neuronal and to a lesser extent in non-neuronal cells. Its conformational conversion into the amyloidogenic isoform in neurons is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. However, the normal functions of PrPC remain largely unknown, particularly in non-neuronal cells. Here we show that stimulation of PrPC with anti-PrP monoclonal antibodies (mAbs) protected mice from lethal infection with influenza A viruses (IAVs), with abundant accumulation of anti-inflammatory M2 macrophages with activated Src family kinases (SFKs) in infected lungs. A SFK inhibitor dasatinib inhibited M2 macrophage accumulation in IAV-infected lungs after treatment with anti-PrP mAbs and abolished the anti-PrP mAb-induced protective activity against lethal influenza infection in mice. We also show that stimulation of PrPC with anti-PrP mAbs induced M2 polarization in peritoneal macrophages through SFK activation in vitro and in vivo. These results indicate that PrPC could activate SFK in macrophages and induce macrophage polarization to an anti-inflammatory M2 phenotype after stimulation with anti-PrP mAbs, thereby eliciting protective activity against lethal infection with IAVs in mice after treatment with anti-PrP mAbs. These results also highlight PrPC as a novel therapeutic target for IAV infection

重症心身障害児に対する喉頭気管分離・気管食道吻合術と喉頭気管分離術の臨床的効果

Objective: Outcomes of tracheoesophageal diversion and laryngotracheal separation were evaluated in 15 neurologically impaired children treated for intractable aspiration. Methods: A retrospective analysis of the hospital records was carried out in 15 consecutive pediatric patients who underwent either tracheoesophageal diversion or laryngotracheal separation with trumpet-shaped tracheotomy from 1999 to 2006 in Kagawa Children’s Hospital. Results: The number of hospital admissions for aspiration pneumonia after surgery was significantly decreased in 6 patients who were cared for at home. The parent-reported number of secretion suctioning was decreased after surgery especially in patients with pre-operative tracheotomy or intubation. Four patients fed through naso-gastric tube progressed with oral diet post-operatively, whereas 3 patients who had pre-operative tracheotomy developed temporary post-operative tracheocutaneous fistula that was managed by local wound care. Conclusion: It is suggested that tracheoesophageal diversion and laryngotracheal separation decrease the morbidity of pediatric patients and improve their quality of life and that of their parents. It is suggested that the risk of developing post-operative fistula is higher in pediatric patients with than without pre-operative tracheotomy