cGAS-STING tie signaloi DNA viruksista

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Doxorubicin 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116111/


DNA sensori tie, jos on DNA-virus.
Tähän jräejstelmäänkuuluu luonnollsien immuniteetin TRIm21-proteiini, muta näin suoraa  cGAS--STING tien  aktivoimista ei tapahdu ebholassa käsittääkseni.
Muistiin kuitenkin tämä asia:
https://www.nature.com/articles/cmi201312
Tässä ehkä on syt palata katsomaan TRIM21 kohtalo  EBOV viruksessa. Katsooko EBOV aiheelliseki  detonoida tämän  tekijän.
Muistaakseni EBOV infektiossa kehittyy kova monosyyttiperäinen sytokiinimyrsky.

• TRIM21 (RoSSA)  osallistuu kyllä monosyyttivaihteeseen jos on kapseloitunut , Ainakin HIV-1 viruksesta on aktsottu suhde TRIM21.een ja  TRIM21 pakkautuu virioniin mukaan.

 https://www.ncbi.nlm.nih.gov/pubmed/27773663/
Otan sitaatin muistiin:

 Abstract

Tripartite motif-containing protein 21 (TRIM21) play a dual role in the cytoplasm of the cells where it facilitates destruction of some antibody-coated viruses and some bacteria, and initiates synthesis of proinflammatory cytokines. Macrophages and CD16⁺ monocyte subset can particularly participate in a proinflammatory response caused by viral infection, however, the molecular mechanisms underlying these processes are not fully understood. The aim of this study was to determine the level of TRIM21-mRNA expression in monocyte subsets including: classical (CD14⁺⁺CD16^-), intermediate (CD14⁺⁺CD16⁺) and non-classical (CD14⁺CD16⁺⁺) monocytes, as well as during in vitro differentiation of the isolated monocytes towards dendritic cells or macrophages. Our results revealed that the level of TRIM21 mRNA expression was significantly lower in CD16- monocytes, when compared to CD16⁺ cells and the whole monocyte population, yet no significant differences were observed when CD16⁺ population was divided into intermediate and non-classical subsets. More pronounced differences were observed in the case of monocyte-derived macrophages (MDM) and dendritic cells (DCs). TRIM21-mRNA expression level was app. 6-fold higher in DCs, and app. 16-fold higher in MDM (p<0 by="" cd16="" compared="" cytokine="" freshly="" increased="" isolated="" may="" mechanism="" monocytes.="" new="" of="" our="" production="" proinflammatory="" results="" suggest="" sup="" the="" to="" when="">+

(intermediate and non-classical) monocytes and macrophages, at least in patients with acute or chronic infections, caused by enveloped viruses. We suggest that TRIM21 may be one of the factors associated with the "switching on" the proinflammatory programme in CD16⁺ monocytes or monocyte-derived macrophages.
Kuva
Normaalisti toimia  DNA virus---- STING - TRIM  signalointi

VLP rokotekehittelystä

Tällä saatiin aikaan varhainen IFN 1 tyypin interferonin tuotanto. IFNAR- (reseptorin) olemassaolo on edellytys, että tämä  strategia vaikuttaa.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342244/
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 Virally encoded anti-IFN proteins, VP24 and VP35 play major roles in EBOV virulence [7, 8]. VP35 blocks type I IFN induction in dendritic cells (DCs) and macrophages, and acts as a virulence factor necessary for a recombinant virus to attain infectivity in the host [9–12]. VP24, on the other hand, blocks IFN signaling by interfering with IFN activated JAK/STAT pathways [7].
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VLPs are subunit-based vaccines, extensively studied for a variety of infectious pathogens [25, 26]. VLPs prepared from EBOV and other filoviruses are composed of the matrix protein (VP40), glycoprotein (GP), and at times nucleoprotein (NP) and represent a potentially promising candidate for EBOV vaccine.
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 We next tested whether VLPs induce other ISGs, particularly those with negative regulatory activities. This question was of interest to us, since mice that did not receive VLPs expressed higher levels of proinflammatory cytokines and chemokines, which raised the possibility that IFN signaling exerts negative regulatory activity towards proinflammatory responses, perhaps by controlling NF-κB activation [36]. Shown in the lower panels in Fig. 2A and 2B is induction of IRGM1, USP18, TRIM21 and TRIM30. IRGM1 is an IFN inducible GTPase that inhibits LPS induced endotoxin shock in mice [37]. USP18 is an ISG15 deconjugating factor that negatively regulates TLR signaling and resultant cytokine induction [38]. Trim21 and Trim30 are members of the Tripartite motif family that downregulate TLR induced inflammatory responses [39–42]. Expression of these ISGs was also higher in the VLP injected group than that without VLPs both in liver and spleen. Similar to anti-viral ISGs, expression of these negative regulatory factors changed at the later stage (S1 Fig). These data indicate that VLPs accelerate induction of anti-viral and negative regulatory ISGs, which may help suppress EBOV’s anti-IFN antagonism (See Discussion).



Huom sekä TRIM30 että TRIm21  voivat puuttua interferonijärejstelmän kehkeyttämsien sekä cGAS-STING  signaalitiessä (joka havaitsee DNA.n)  että TLR- väliteisessä  patogeenin havaitsevassa signaalitiessä  ja tässä  VLP-rokotetapaukseesa kyse on vaikuttamisesta  TLR tietä  indusoidun  inflammatorisen vasteen  vaimentamisesta ( mikä on hyvin raju ja letaali EBOV-virusinfektiossa9.

 Sikäli on  hyvä että tämä  VPL rokote ei koostu DNA-materiaalista, joka ottaisi  mukaan mainitun cGAS- STING tien signaloinnin  tähän vaikeaan koktailiin.

Yleis KUVA jossa IFNAR reseptori näkyy.
Tämä kuvaa isäntäkehon varustuksia ja normaaleita  konvergoituvia signaaliteitä interferonijärjestelmässä, joka lopulta  antaa  diversiteetillä   interferonilla stimuloiduista geenistä(ISG)  antivirusvastetta solun asettuessa antivirusstatukseen.   On ymmärrettävää että evoluution aikana virukset ovat kehittäneet proteiineja jotka sofistisesti  lamaavat tämän järjestelmän.

https://www.researchgate.net/figure/IFN-stimulated-gene-expression-via-the-JAK-STAT-signaling-pathways-Upon-recognition-of_fig1_23626519