Rift Valley fever virus (RVFV) ja isäntäkehovaste

https://www.ncbi.nlm.nih.gov/pubmed/26038567/

Proc Natl Acad Sci U S A. 2015 Jun 2;112(22):E2920-9. doi: 10.1073/pnas.1418805112. Epub 2015 May 18.

Virus-induced translational arrest through 4EBP1/2-dependent decay of 5'-TOP mRNAs restricts viral infection.

Hopkins KC¹, Tartell MA¹, Herrmann C¹, Hackett BA¹, Taschuk F¹, Panda D¹, Menghani SV¹, Sabin LR², Cherry S³.

Abstract

The mosquito-transmitted bunyavirus, Rift Valley fever virus (RVFV), is a highly successful pathogen for which there are no vaccines or therapeutics.
Translational arrest is a common antiviral strategy used by hosts.

In response, RVFV inhibits two well-known antiviral pathways that attenuate translation during infection, PKR and type I IFN signaling.

 Despite this, translational arrest occurs during RVFV infection by unknown mechanisms.
 Here, we find that RVFV infection triggers the decay of core translation machinery mRNAs that possess a 5'-terminal oligopyrimidine (5'-TOP) motif in their 5'-UTR, including mRNAs encoding ribosomal proteins, which leads to a decrease in overall ribosomal protein levels.

We find that the RNA decapping enzyme NUDT16 selectively degrades 5'-TOP mRNAs during RVFV infection and this decay is triggered in response to mTOR attenuation via the translational repressor 4EBP1/2 axis.

Translational arrest of 5'-TOPs via 4EBP1/2 restricts RVFV replication, and this increased RNA decay results in the loss of visible RNA granules, including P bodies and stress granules. Because RVFV cap-snatches in RNA granules, the increased level of 5'-TOP mRNAs in this compartment leads to snatching of these targets, which are translationally suppressed during infection.

Therefore, translation of RVFV mRNAs is compromised by multiple mechanisms during infection.

Together, these data present a previously unknown mechanism for translational shutdown in response to viral infection and identify mTOR attenuation as a potential therapeutic avenue against bunyaviral infection.

KEYWORDS:

5′-TOP mRNA; RNA decay; RNA granule; Rift Valley fever virus; translational arrest

PMID:

26038567

PMCID:

PMC4460451

DOI:

10.1073/pnas.1418805112

[Indexed for MEDLINE]

Free PMC Article

hCMV ja APOBECK3A (2017)

 2018,   28.11.
 https://www.spandidos-publications.com/10.3892/mmr.2016.4778

Human cytomegalovirus RL13 protein interacts with host NUDT14 protein affecting viral DNA replication

NUDT14 proteiini on UDPG pyrofosfataasi, joka hydrolysoi UDPG:n tuottaen Glc-1-P ja UMP. 

RL13 on  ihmisen CMV:n myöhäisiä proteiineja ja tekemällä interaktion  NUDT14:n kanssa se  vähentää  NUDT14 proteiinia,  mikä edistää  virus DNA:n kopioita, NUDT14 ylössäätäminen ei kuitenkaan vaikuttanut  virus DNA:n määrään. 

 2017

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686750/

J Virol. 2017 Dec 1; 91(23): e01296-17.

Published online 2017 Nov 14. Prepublished online 2017 Sep 27. doi:  10.1128/JVI.01296-17

PMCID: PMC5686750

PMID: 28956761

APOBEC3A Is Upregulated by Human Cytomegalovirus (HCMV) in the Maternal-Fetal Interface, Acting as an Innate Anti-HCMV Effector

Yiska Weisblum,^a,b,c Esther Oiknine-Djian,^a,b,c Zichria Zakay-Rones,^b Olesya Vorontsov,^a,b,c Ronit Haimov-Kochman,^d Yuval Nevo,^e David Stockheim,^f Simcha Yagel,^d Amos Panet,^b and Dana G. Wolf^a,c

Jae U. Jung, Editor

Jae U. Jung, University of Southern California;

Author information ► Article notes ► Copyright and License information ► Disclaimer

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ABSTRACT

Human cytomegalovirus (HCMV) is the leading cause of congenital infection and is associated with a wide range of neurodevelopmental disabilities and intrauterine growth restriction. Yet our current understanding of the mechanisms modulating transplacental HCMV transmission is poor. The placenta, given its critical function in protecting the fetus, has evolved effective yet largely uncharacterized innate immune barriers against invading pathogens. Here we show that the intrinsic cellular restriction factor apolipoprotein B editing catalytic subunit-like 3A (APOBEC3A [A3A]) is profoundly upregulated following ex vivo HCMV infection in human decidual tissues—constituting the maternal aspect of the placenta. We directly demonstrated that A3A severely restricted HCMV replication upon controlled overexpression in epithelial cells, acting by a cytidine deamination mechanism to introduce hypermutations into the viral genome. Importantly, we further found that A3 editing of HCMV DNA occurs both ex vivo in HCMV-infected decidual organ cultures and in vivo in amniotic fluid samples obtained during natural congenital infection. Our results reveal a previously unexplored role for A3A as an innate anti-HCMV effector, activated by HCMV infection in the maternal-fetal interface. These findings pave the way to new insights into the potential impact of APOBEC proteins on HCMV pathogenesis.

Aedes egypti-moskiiton neurotranskriptomista

https://www.ncbi.nlm.nih.gov/pubmed/26738925/

BMC Genomics. 2016 Jan 6;17:32. doi: 10.1186/s12864-015-2239-0.

The neurotranscriptome of the Aedes aegypti mosquito.

Matthews BJ¹, McBride CS^2,3, DeGennaro M^4,5, Despo O^6,7, Vosshall LB^8,9.

Abstract
BACKGROUND:
A complete genome sequence and the advent of genome editing open up non-traditional model organisms to mechanistic genetic studies. The mosquito Aedes aegypti is an important vector of infectious diseases such as dengue, chikungunya, and yellow fever and has a large and complex genome, which has slowed annotation efforts. We used comprehensive transcriptomic analysis of adult gene expression to improve the genome annotation and to provide a detailed tissue-specific catalogue of neural gene expression at different adult behavioral states.
RESULTS:
We carried out deep RNA sequencing across all major peripheral male and female sensory tissues, the brain and (female) ovary. Furthermore, we examined gene expression across three important phases of the female reproductive cycle, a remarkable example of behavioral switching in which a female mosquito alternates between obtaining blood-meals from humans and laying eggs. Using genome-guided alignments and de novo transcriptome assembly, our re-annotation includes 572 new putative protein-coding genes and updates to 13.5 and 50.3 % of existing transcripts within coding sequences and untranslated regions, respectively. Using this updated annotation, we detail gene expression in each tissue, identifying large numbers of transcripts regulated by blood-feeding and sexually dimorphic transcripts that may provide clues to the biology of male- and female-specific behaviors, such as mating and blood-feeding, which are areas of intensive study for those interested in vector control. CONCLUSIONS:
This neurotranscriptome forms a strong foundation for the study of genes in the mosquito nervous system and investigation of sensory-driven behaviors and their regulation. Furthermore, understanding the molecular genetic basis of mosquito chemosensory behavior has important implications for vector control.


Yellow fever mosquito:  probable  chitinase: https://www.ncbi.nlm.nih.gov/gene/5576174

Uudenlainen rokote influenssaa vstaan . Väitöskirja 2018 V. Bernasconi

Väitös on edessäpäin Göteborgin Yliopistossa.
Respondentti: Valentina  Bernasconi. Broadly protective nanoparticle-based mucosal vaccine against Influenza virus infection.
Opponentti:  professori Bjarne Bogen, Oslo.

Mistä on kysymys?

Suomennan abstraktia.  Minulla on abstrakti, joka oli tarjolla biomedisiinisessa kirjastossa , kun kävin siellä 12.11. 2018.
Viitettä  nettilinkiin ei näytä  olevan abstraktissa, mutta ilmeisesti otsikolla se on haettavissa. ISBN 978-91-7833-151-2 (Print)
ISBN 978-91-7833-152-9 (PDF).

Suomennan abstraktilehtisestä sisältöä.

" Influenssa on  yksi päätauti  ihmisten virussairauksissa  ja se  kaataa  3- 5 miljoonaa ihmistä vuosittain  vaikean asteiseen  influenssaan  ja noin 250 000- 500 000  menehtyy   sen takia. Pandemisen influenssan  vastainen rokote  on hyvin kysytty ja tehokkain keino   globaalisti leviävien  uusien  esiin puhjenneiden  influenssaviruskantojen  aiheuttamien  tautien riskin  vähentämisessä. Injektiona annettu viruksenvastainen rokote vaatii koulutettua henkilökuntaa ja tiettyä riskiäkin on  kontaminoitujen infektioiden leviämisestä. Sen sijaan  limakalvorokotteet  voitaisiin  tehdä tehokkaammiksi käyttämällä parempia formulointeja ja adjuvantteja.
Tämä tutkijaryhmä on nyt hahmotellut kaksi intranasaalista rokotekandidaattia pandemista flunssaa vastaan perustaen rokoteten kanta-konservoituun M2e peptidiin, joka on  ympätty  CTA1-DD limakalvoadjuvanttiin. Aiemmin on havaittu, että fuusioproteiini CTA1-3M2e-DD stimuloi protektiivista immuniteettia.  Tässä työssä koetettiin edelleen kohentaa sen rokoteominaisuuksia asettamalle se  polysakkaridiin tai liposomipartikkeleihin, joita  annostetaan nenän limakalvolle. Tutkijoiden löydöt viittaavat selvästi siihen, että  tällaiset  kombinoidut  limakalvorokotteet antavat vahvaa pohjaa  tulevien limakalvorokotteiden kehittelyyn. Tässä on kombinoitu vahva CTA1-DD immunomodulaattori ja nanopartikkelit.  Lopuksi väitöskirjatyö antaa  optimistista näkymää mahdollisuudesta kehittää laajasti protektiivinen limakalvorokote influenssaa vastaan  myös nuorille lapsille eikä ainoastaan aikuisille".

Tämä väitöstyö perustuu seuraaville osatöille:

"Porous nanoparticles with self-adjuvanted M2e-fusion protein and recombinant hemagglutinin provide strong and broadly protective immunity against influenza virus infection."
Valentina Bernasconi, Beatrice Bernocchi, Liang Ye, Minh Quan Le, Ajibola Omokanye, Rodolphe Carpentier, Karin Schön, Xavier Saelens, Peter Staeheli, Didier Betbeder, Nils Lycke.
Frontiers in Immunology, 12 September 2018.*
http://doi.org/10.3389/fimmu.2018.02060

Tässä artikkelissa on tätä uutta  tehokasta  rokotetyyppiä kokeiltu hiirille ja freteille . (Ei ihmisille vielä tässä vaiheessa. Työryhmä on hyvin kansainvälinen.

Käsikirjoitusvaiheessa ovat  seuraavat kaksi artikkelia:

A novel combined vaccine consisting of an enzymatically active fusion protein adjuvant and lipid nanoparticles provides broadly protective immunity against influenza infection. Valentina Bernasconi, Karin Norling, Sabina Burazerovic, Karin Schön, Anneli Strömberg, Marta Bally, Fredrik Höök, Nils Lykke.
Manuscript.

targeting follicular dendritic cells with CTA1-DD adjuvant effetively promotes immune responses in neonatala mice and recovery from influenza infection. Sophie Schussek, Valentina Bernasconi, Anneli Strömberg, Karin Schön, Nils Lycke.
Manuscript

Väitöstilaisuus on kuun lopussa.
Yllämainittu * julkaistu  artikkeli antaa laajan taustatieon niille jotka ovat  asiaan ja terminologiaan  perehtyneitä. Saattaa muuten olla hyvä idea. saattaa olla myös paremmin kattava, koska  on helpompi  adminstraatiotapa ja ehkä  laajempi kohdeväestö. Tulee vain mieleen, minkälaisia (hallitsemattomia) ylireaktioita  tehokas  rokote voi herättää immuunvasteesta.  Aika asian selvittää.

Muistiin  19.11. 2018

KAtson myös PubMed hakulaiteella kuinka monta vastausta saa kun hakee sanoilla
intranasal influenzavaccine
Vastauksia
Showing results for intranasal influenza vaccine. Your search for intranasal influenza vaccine retrieved no results.

Kuitenkin freteillä  possuilla tehty intranasaali rokotus löytyi viime kuulta.

• https://www.sciencedirect.com/science/article/pii/S0264410X18313549?via%3Dihub

Vaccine. 2018 Oct 12. pii: S0264-410X(18)31354-9. doi: 10.1016/j.vaccine.2018.10.002. [Epub ahead of print]Immunogenicity and efficacy of the monovalent, trivalent and quadrivalent intranasal live attenuated influenza vaccines containing different pdmH1N1 strains.

Yeolekar LR¹, Ganguly M¹, Tyagi P¹, Ingle NB¹, Stittelaar KJ², Waal L², Scorza FB³, Mahmood K³, Dhere RM⁴

• Int J Nanomedicine. 2018 Oct 24;13:6699-6715. doi: 10.2147/IJN.S178809. eCollection 2018.

Liposomal nanoparticle-based conserved peptide influenza vaccine and monosodium urate crystal adjuvant elicit protective immune response in pigs.
Dhakal S^1,2, Cheng X³, Salcido J³, Renu S^1,2, Bondra K^1,2, Lakshmanappa YS^1,2, Misch C^1,2, Ghimire S^1,2, Feliciano-Ruiz N^1,2, Hogshead B^1,2, Krakowka S⁴, Carson K³, McDonough J³, Lee CW^1,2, Renukaradhya GJ^1,2

• Sivumennen: Löytyi intranasaali rokote verenpaineeseen!
• https://www.ncbi.nlm.nih.gov/pubmed/30328017

TACE/ADAM17 sheddase ja EBOV shed Gp

Periaatteesa ADAM17 inhibiittori joko estää ADAM17 sheddaasi finktiota, voisi vähentää esim EBOV indfektiossa  EBOV- gp aprtikkeleiden shed muotoa joka kylväytyy. Intestianalsita ADAM17  inhiboi  tai ainakin vähentää MUC1- sheddaasi-funktiosta alkoholi, jolla on lääkemerkitystä.

Kuva  TACE- funktiosta , millä EBOV gp kylväytyy:  Tästä aiheuttaa tavaton sytokiinimyrsky.  TACE sinänsä muistuttaa käärmeen myrkyn disintegriiniä, jonka  tehtävä on liudentaa uhri  nielemiskuntoon. 

.

• Format: Abstract

Curr Drug Targets. 2016;17(16):1908-1927.

Targeting ADAM17 Sheddase Activity in Cancer.

Rossello A, Nuti E, Ferrini S¹, Fabbi M.

Abstract

A disintegrin and metalloprotease (ADAM)17 is a sheddase, capable of releasing the ectodomains of membrane proteins such as growth factors (e.g. Epidermal Growth Factor Receptor ligands), cytokines and their receptors, adhesion and signaling molecules. These activities regulate several physiological and pathological processes including inflammation, tumor growth and metastatic progression. In this review, we will summarize ADAM17 biology and focus on its role in cancer and the possible usage of ADAM17 inhibitors in cancer therapy. Recent achievements in this area include the development of small molecule metalloprotease inhibitors with enhanced specificity for ADAM17, monoclonal antibodies, and synthetic short RNA molecules for gene silencing. These approaches successfully inhibited cancer cell growth and invasiveness or sensitized them to cytotoxic drugs, ionizing radiations or targeted therapies, in preclinical studies. These findings suggest the repositioning of ADAM17 inhibitors, which have yet proven unsuccessful as anti-inflammatory agents, for the development of new anti-cancer therapies, particularly in EGFR ligand-dependent cancers. Future studies should address ADAM17 inhibitors as short-term treatments in combination with different anti-cancer therapies.

PMID:

27469341

[Indexed for MEDLINE]

Gammasäteily ja Lassa, Marburg sek EBOV virukset

https://www.ncbi.nlm.nih.gov/pubmed/7153317

Genome
https://www.eurosurveillance.org/images/dynamic/EE/V20N20/art21131.pdf

Voiko EBOV läpäistä ehjän ihon?

http://www.virology.ws/2014/10/19/can-ebola-virus-infect-via-the-skin/

http://www.who.int/water_sanitation_health/WASH_and_Ebola.pdf

Ruoan kuumennus 100 asteeseen C tappaa EBOV viruksen ruoasta

https://efsa.onlinelibrary.wiley.com/doi/pdf/10.2903/j.efsa.2014.3884

(2016) Geneettisiä syitä H1N1- influenssan fataaliin kulkuun:

https://www.ncbi.nlm.nih.gov/pubmed/26597256

J Infect Dis. 2016 Apr 1;213(7):1180-8. doi: 10.1093/infdis/jiv550. Epub 2015 Nov 23.

Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza.Schulert GS¹, Zhang M²,  Abstract BACKGROUND: Severe H1N1 influenza can be lethal in otherwise healthy individuals and can have features of reactive hemophagocytic lymphohistiocytosis (HLH). HLH is associated with mutations in lymphocyte cytolytic pathway genes, which have not been previously explored in H1N1 influenza. METHODS: Sixteen cases of fatal influenza A(H1N1) infection, 81% with histopathologic hemophagocytosis, were identified and analyzed for clinical and laboratory features of HLH, using modified HLH-2004 and macrophage activation syndrome (MAS) criteria. Fourteen specimens were subject to whole-exome sequencing. Sequence alignment and variant filtering detected HLH gene mutations and potential disease-causing variants. Cytolytic function of the PRF1 p.A91V mutation was tested in lentiviral-transduced NK-92 natural killer (NK) cells. RESULTS: Despite several lacking variables, cases of influenza A(H1N1) infection met 44% and 81% of modified HLH-2004 and MAS criteria, respectively. Five subjects (36%) carried one of 3 heterozygous LYST mutations, 2 of whom also possessed the p.A91V PRF1 mutation, which was shown to decrease NK cell cytolytic function. Several patients also carried rare variants in other genes previously observed in MAS. CONCLUSIONS: This cohort of fatal influenza A(H1N1) infections confirms the presence of hemophagocytosis and HLH pathology. Moreover, the high percentage of HLH gene mutations suggests they are risk factors for mortality among individuals with influenza A(H1N1) infection. KEYWORDS: H1N1 influenza; LYST; cytolytic pathway; hemophagocytosis; macrophage activation syndrome; perforin

Free PMC Article

(2017) B-influenza virus triggeröinyt vauvalle MAS , makrofagien aktivaatiosyndroman

https://www.ncbi.nlm.nih.gov/pubmed/29279647

Indian J Crit Care Med. 2017 Nov;21(11):802-803. doi: 10.4103/0972-5229.218137.

Influenza B Virus Triggering Macrophage Activation Syndrome in an Infant.

Jayashree K¹, Rao S¹, Kamath N¹.

Abstract

Macrophage activation syndrome (MAS) is a potentially fatal complication caused by excessive activation and expansion of macrophages and T lymphocytes. It can be triggered by various infections and is characterized by the development of cytopenias, hyperferritinemia, liver dysfunction, and coagulopathy. We report a 10-month-old female infant with fever, convulsions, and hepatosplenomegaly. Laboratory data of bicytopenia, low erythrocyte sedimentation rate, and elevated liver enzymes suggested MAS. This was supported by the presence of hyperferritinemia with hypertriglyceridemia. MAS was triggered by influenza B virus. She responded to treatment with immunoglobulin and steroid.

KEYWORDS:

Bicytopenia; hyperferritinemia; hypertriglyceridemia; secondary hemophagocytic lymphohistiocytosis; thrombocytopenia

PMID:

29279647

PMCID:

PMC5699014

DOI:

10.4103/0972-5229.218137

Free PMC Article