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Anti-proliferative role of recombinant lethal toxin of Bacillus anthracis on primary mammary ductal carcinoma cells revealing its therapeutic potential.

Oncotarget. 2017 May 30;8(22):35835-35847

Authors: Khandia R, Pattnaik B, Rajukumar K, Pateriya A, Bhatia S, Murugkar H, Prakash A, Pradhan HK, Dhama K, Munjal A, Joshi SK

Bacillus anthracis secretes three secretary proteins; lethal factor (LF), protective antigen (PA) and edema factor (EF). The LF has ability to check proliferation of mammary tumors, chiefly depending on mitogen activated protein kinase (MAPK) signaling pathway. Evaluation of therapeutic potential of recombinant LF (rLF), recombinant PA (rPA) and lethal toxin (rLF + rPA = LeTx) on the primary mammary ductal carcinoma cells revealed significant (p < 0.01) reduction in proliferation of tumor cells with mean inhibition indices of 28.0 ± 1.37% and 19.6 ± 1.47% respectively. However, treatment with rPA alone had no significant anti-proliferative effect as evident by low mean inhibition index of 3.4 ± 3.87%. The higher inhibition index observed for rLF alone as compared to LeTx is contrary to the existing knowledge on LF, which explains the requirement of PA dependent endocytosis for its enzymatic activity. Therefore, the plausible existence of PA independent mode of action of LF including direct receptor mediated endocytosis or modulation of signal transduction cascade via unknown means is hypothesized. In silico protein docking analysis of other cellular receptors for any plausibility to play the role of receptor for LF revealed c-Met receptor showing strongest affinity for LF (H bond = 19; Free energy = -773.96), followed by nerve growth factor receptor (NGFR) and human epidermal growth factor receptor (HER)-1. The study summarizes the use of rLF or LeTx as therapeutic molecule against primary mammary ductal carcinoma cells and also the c-Met as potential alternative receptor for LF to mediate and modulate PA independent signal transduction.

PMID: 28415766 [PubMed - in process]

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Taxonomy of the order Mononegavirales: update 2017.

Arch Virol. 2017 Apr 07;:

Authors: Amarasinghe GK, Bào Y, Basler CF, Bavari S, Beer M, Bejerman N, Blasdell KR, Bochnowski A, Briese T, Bukreyev A, Calisher CH, Chandran K, Collins PL, Dietzgen RG, Dolnik O, Dürrwald R, Dye JM, Easton AJ, Ebihara H, Fang Q, Formenty P, Fouchier RA, Ghedin E, Harding RM, Hewson R, Higgins CM, Hong J, Horie M, James AP, Jiāng D, Kobinger GP, Kondo H, Kurath G, Lamb RA, Lee B, Leroy EM, Li M, Maisner A, Mühlberger E, Netesov SV, Nowotny N, Patterson JL, Payne SL, Paweska JT, Pearson MN, Randall RE, Revill PA, Rima BK, Rota P, Rubbenstroth D, Schwemmle M, Smither SJ, Song Q, Stone DM, Takada A, Terregino C, Tesh RB, Tomonaga K, Tordo N, Towner JS, Vasilakis N, Volchkov VE, Wahl-Jensen V, Walker PJ, Wang B, Wang D, Wang F, Wang LF, Werren JH, Whitfield AE, Yan Z, Ye G, Kuhn JH

In 2017, the order Mononegavirales was expanded by the inclusion of a total of 69 novel species. Five new rhabdovirus genera and one new nyamivirus genus were established to harbor 41 of these species, whereas the remaining new species were assigned to already established genera. Furthermore, non-Latinized binomial species names replaced all paramyxovirus and pneumovirus species names, thereby accomplishing application of binomial species names throughout the entire order. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).

PMID: 28389807 [PubMed - as supplied by publisher]

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Emergence of a deviating genotype VI pigeon paramyxovirus type-1 isolated from India.

Arch Virol. 2017 Jul;162(7):2169-2174

Authors: Ganar K, Das M, Raut AA, Mishra A, Kumar S

Pigeon paramyxovirus type 1 (PPMV-1) is an antigenic variant of avian paramyxovirus type 1 (APMV-1), which infects pigeons. The virus causes high morbidity and mortality, creating an alarming state for the poultry industry. The present work describes the molecular and pathogenic characterization of a PPMV-1 strain isolated from pigeon in Bhopal, India. Complete genome sequence analysis revealed a genome of 15,192 nucleotides encoding six genes organized in the order 3'-N-P-M-F-HN-L-5'. The fusion gene sequence analysis showed the presence of multiple basic amino acids (112)R-R-Q-K-R-F(117) at the cleavage site corresponding to pathogenic strains. The mean death time and intracerebral pathogenicity index values indicated a mesogenic nature for the PPMV-1 isolate. On phylogenetic analysis, the strain clustered with genotype VI viruses, including isolates from pigeon and dove. The Bhopal strain showed significant intra and inter-genotype evolutionary distance, suggesting the emergence of a new sub-genotype, VIj.

PMID: 28349356 [PubMed - in process]

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Armillifer armillatus infestation in Human; public health scenario of a snake parasite: a report of three cases.

Pan Afr Med J. 2016;25:45

Authors: Aiyekomogbon JO, Meseko CA, Abiodun OO

We report cases of Armillifer Armillatus infestation in three Nigerian adults within two and half years in our health facility. The first patient was a 70 year old farmer and a regular consumer of snake meat for over 50 years. He presented in February, 2014 for follow-up visit as he was a known systemic hypertensive patient. He was incidentally discovered to have multiple comma-shaped calcific lesions in the lungs and liver on a chest radiograph. These were better demonstrated on abdominal ultrasound and computed tomographic scans. He was asymptomatic. The second patient was a 42 year old male civil servant who presented in December 2015 with dry cough and right loin pain for five and three days respectively. His past medical history revealed that he had been treated previously for pneumonia. He has never eaten snake meat but consumed Alligator (Amphibious reptile) for many years but stopped about 12 years ago. Similar calcific lesions were also noted in his liver and lung parenchyma on chest radiograph and abdominal ultrasound scan. The third patient was an 80 year old man who presented in April, 2014 with dizziness and diminished urine output of one day duration. He was a farmer who has been consuming snake meat for many years, and has been on management for systemic arterial hypertension and prostatic hypertrophy. Chest radiograph and abdomino-pelvic ultrasound incidentally revealed multiple comma-shaped calcific lesions in the lungs and liver. The liver function test parameters were all within normal limits but the electrolytes were deranged and he was anaemic with a Packed Cell Volume of 27%. A diagnosis of Armillifer Armillatus infestation was made in these patients, and they were conservatively managed with Mebendazole. The third case was catherized and the deranged electrolytes were corrected. The first patient was lost to follow-up, whiles the second and third had no remarkable symptoms on subsequent follow-up visits.

PMID: 28250869 [PubMed - indexed for MEDLINE]

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Role of H7 hemagglutinin in murine infectivity of influenza viruses following ocular inoculation.

Virology. 2017 Feb;502:13-19

Authors: Belser JA, Sun X, Creager HM, Johnson A, Ridenour C, Chen LM, Tumpey TM, Maines TR

H7 subtype influenza viruses have demonstrated an ocular tropism in humans, causing conjunctivitis and not respiratory symptoms in many infected individuals. However, the molecular determinants which confer ocular tropism are still poorly understood. Here, we used a murine model of ocular inoculation to demonstrate that H7 influenza viruses are more likely to cause infection following ocular exposure than are non-H7 subtype viruses. We included investigation regarding the potential role of several properties of influenza viruses with murine infectivity following ocular inoculation, including virus lineage, pathogenicity, and HA cleavage site composition. Furthermore, we examined the potential contribution of internal proteins to murine ocular infectivity. These studies establish a link between H7 subtype viruses and the risk of heightened infectivity in a mammalian species following ocular exposure, and support the development of non-traditional inoculation methods and models to best understand the human risk posed by influenza viruses of all subtypes.

PMID: 27960109 [PubMed - indexed for MEDLINE]

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Taxonomy of the order Mononegavirales: update 2016.

Arch Virol. 2016 Aug;161(8):2351-60

Authors: Afonso CL, Amarasinghe GK, Bányai K, Bào Y, Basler CF, Bavari S, Bejerman N, Blasdell KR, Briand FX, Briese T, Bukreyev A, Calisher CH, Chandran K, Chéng J, Clawson AN, Collins PL, Dietzgen RG, Dolnik O, Domier LL, Dürrwald R, Dye JM, Easton AJ, Ebihara H, Farkas SL, Freitas-Astúa J, Formenty P, Fouchier RA, Fù Y, Ghedin E, Goodin MM, Hewson R, Horie M, Hyndman TH, Jiāng D, Kitajima EW, Kobinger GP, Kondo H, Kurath G, Lamb RA, Lenardon S, Leroy EM, Li CX, Lin XD, Liú L, Longdon B, Marton S, Maisner A, Mühlberger E, Netesov SV, Nowotny N, Patterson JL, Payne SL, Paweska JT, Randall RE, Rima BK, Rota P, Rubbenstroth D, Schwemmle M, Shi M, Smither SJ, Stenglein MD, Stone DM, Takada A, Terregino C, Tesh RB, Tian JH, Tomonaga K, Tordo N, Towner JS, Vasilakis N, Verbeek M, Volchkov VE, Wahl-Jensen V, Walsh JA, Walker PJ, Wang D, Wang LF, Wetzel T, Whitfield AE, Xiè JT, Yuen KY, Zhang YZ, Kuhn JH

In 2016, the order Mononegavirales was emended through the addition of two new families (Mymonaviridae and Sunviridae), the elevation of the paramyxoviral subfamily Pneumovirinae to family status (Pneumoviridae), the addition of five free-floating genera (Anphevirus, Arlivirus, Chengtivirus, Crustavirus, and Wastrivirus), and several other changes at the genus and species levels. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).

PMID: 27216929 [PubMed - indexed for MEDLINE]

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RIG-I ligand enhances the immunogenicity of recombinant H7HA protein.

Cell Immunol. 2016 Jun-Jul;304-305:55-8

Authors: Cao W, Liepkalns JS, Kamal RP, Reber AJ, Kim JH, Hofstetter AR, Amoah S, Stevens J, Ranjan P, Gangappa S, York IA, Sambhara S

Avian H7N9 influenza virus infection with fatal outcomes continues to pose a pandemic threat and highly immunogenic vaccines are urgently needed. In this report we show that baculovirus-derived recombinant H7 hemagglutinin protein, when delivered with RIG-I ligand, induced enhanced antibody and T cell responses and conferred protection against lethal challenge with a homologous H7N9 virus. These findings indicate the potential utility of RIG-I ligands as vaccine adjuvants to increase the immunogenicity of recombinant H7 hemagglutinin.

PMID: 27106062 [PubMed - indexed for MEDLINE]

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Characterization of Influenza Vaccine Hemagglutinin Complexes by Cryo-Electron Microscopy and Image Analyses Reveals Structural Polymorphisms.

Clin Vaccine Immunol. 2016 06;23(6):483-95

Authors: McCraw DM, Gallagher JR, Harris AK

Influenza virus afflicts millions of people worldwide on an annual basis. There is an ever-present risk that animal viruses will cross the species barrier to cause epidemics and pandemics resulting in great morbidity and mortality. Zoonosis outbreaks, such as the H7N9 outbreak, underscore the need to better understand the molecular organization of viral immunogens, such as recombinant influenza virus hemagglutinin (HA) proteins, used in influenza virus subunit vaccines in order to optimize vaccine efficacy. Here, using cryo-electron microscopy and image analysis, we show that recombinant H7 HA in vaccines formed macromolecular complexes consisting of variable numbers of HA subunits (range, 6 to 8). In addition, HA complexes were distributed across at least four distinct structural classes (polymorphisms). Three-dimensional (3D) reconstruction and molecular modeling indicated that HA was in the prefusion state and suggested that the oligomerization and the structural polymorphisms observed were due to hydrophobic interactions involving the transmembrane regions. These experiments suggest that characterization of the molecular structures of influenza virus HA complexes used in subunit vaccines will lead to better understanding of the differences in vaccine efficacy and to the optimization of subunit vaccines to prevent influenza virus infection.

PMID: 27074939 [PubMed - indexed for MEDLINE]

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Two Outbreak Sources of Influenza A (H7N9) Viruses Have Been Established in China.

J Virol. 2016 Jun 15;90(12):5561-73

Authors: Wang D, Yang L, Zhu W, Zhang Y, Zou S, Bo H, Gao R, Dong J, Huang W, Guo J, Li Z, Zhao X, Li X, Xin L, Zhou J, Chen T, Dong L, Wei H, Li X, Liu L, Tang J, Lan Y, Yang J, Shu Y

UNLABELLED: Due to enzootic infections in poultry and persistent human infections in China, influenza A (H7N9) virus has remained a public health threat. The Yangtze River Delta region, which is located in eastern China, is well recognized as the original source for H7N9 outbreaks. Based on the evolutionary analysis of H7N9 viruses from all three outbreak waves since 2013, we identified the Pearl River Delta region as an additional H7N9 outbreak source. H7N9 viruses are repeatedly introduced from these two sources to the other areas, and the persistent circulation of H7N9 viruses occurs in poultry, causing continuous outbreak waves. Poultry movements may contribute to the geographic expansion of the virus. In addition, the AnH1 genotype, which was predominant during wave 1, was replaced by JS537, JS18828, and AnH1887 genotypes during waves 2 and 3. The establishment of a new source and the continuous evolution of the virus hamper the elimination of H7N9 viruses, thus posing a long-term threat of H7N9 infection in humans. Therefore, both surveillance of H7N9 viruses in humans and poultry and supervision of poultry movements should be strengthened.
IMPORTANCE: Since its occurrence in humans in eastern China in spring 2013, the avian H7N9 viruses have been demonstrating the continuing pandemic threat posed by the current influenza ecosystem in China. As the viruses are silently circulated in poultry, with potentially severe outcomes in humans, H7N9 virus activity in humans in China is very important to understand. In this study, we identified a newly emerged H7N9 outbreak source in the Pearl River Delta region. Both sources in the Yangtze River Delta region and the Pearl River Delta region have been established and found to be responsible for the H7N9 outbreaks in mainland China.

PMID: 27030268 [PubMed - indexed for MEDLINE]

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Cryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate.

MBio. 2016 Mar 22;7(2):e00257

Authors: Tran EE, Podolsky KA, Bartesaghi A, Kuybeda O, Grandinetti G, Wohlbold TJ, Tan GS, Nachbagauer R, Palese P, Krammer F, Subramaniam S

UNLABELLED: Influenza viruses expressing chimeric hemagglutinins (HAs) are important tools in the quest for a universal vaccine. Using cryo-electron tomography, we have determined the structures of a chimeric HA variant that comprises an H1 stalk and an H5 globular head domain (cH5/1 HA) in native and antibody-bound states. We show that cH5/1 HA is structurally different from native HA, displaying a 60° rotation between the stalk and head groups, leading to a novel and unexpected "open" arrangement of HA trimers. cH5/1N1 viruses also display higher glycoprotein density than pH1N1 or H5N1 viruses, but despite these differences, antibodies that target either the stalk or head domains of hemagglutinins still bind to cH5/1 HA with the same consequences as those observed with native H1 or H5 HA. Our results show that a large range of structural plasticity can be tolerated in the chimeric spike scaffold without disrupting structural and geometric aspects of antibody binding.
IMPORTANCE: Chimeric hemagglutinin proteins are set to undergo human clinical trials as a universal influenza vaccine candidate, yet no structural information for these proteins is available. Using cryo-electron tomography, we report the first three-dimensional (3D) visualization of chimeric hemagglutinin proteins displayed on the surface of the influenza virus. We show that, unexpectedly, the chimeric hemagglutinin structure differs from those of naturally occurring hemagglutinins by displaying a more open head domain and a dramatically twisted head/stalk arrangement. Despite this unusual spatial relationship between head and stalk regions, virus preparations expressing the chimeric hemagglutinin are fully infectious and display a high glycoprotein density, which likely helps induction of a broadly protective immune response.

PMID: 27006464 [PubMed - indexed for MEDLINE]