2019 on koottu yhteen NLRP12 inflammasomin tekemä RIG1 sensorin -helikaasin alassäätö.

Epub 2019 Mar 19.

NLRP12 Regulates Anti-viral RIG-I Activation via Interaction with TRIM25

Szu-Ting Chen  ¹ , Liang Chen  ² , Diego Shih-Chieh Lin  ³ , Sei-Yi Chen  ⁴ , Yen-Po Tsao  ⁵ , Haitao Guo  ⁶ , Fei-Ju Li  ⁷ , Wei-Ting Tseng  ⁷ , Jason W Tam  ⁶ , Chih-Wei Chao  ⁷ , W June Brickey  ² , Ivan Dzhagalov  ⁸ , Moon-Jung Song  ⁹ , Hye-Ri Kang  ⁹ , Jae U Jung  ¹⁰ , Jenny P-Y Ting  ¹¹

Affiliations

• PMID: 30902577
• PMCID: PMC6459718
• DOI: 10.1016/j.chom.2019.02.013

Free PMC article

Abstract

Establishing the balance between positive and negative innate immune mechanisms is crucial for maintaining homeostasis. Here we uncover the regulatory crosstalk between two previously unlinked innate immune receptor families: RIG-I, an anti-viral cytosolic receptor activated type I interferon production, and NLR (nucleotide-binding domain, leucine repeat domain-containing protein). We show that NLRP12 dampens RIG-I-mediated immune signaling against RNA viruses by controlling RIG-I's association with its adaptor MAVS. The nucleotide-binding domain of NLRP12 interacts with the ubiquitin ligase TRIM25 to prevent TRIM25-mediated, Lys63-linked ubiquitination and activation of RIG-I. NLRP12 also enhances RNF125-mediated, Lys48-linked degradative ubiquitination of RIG-I. Vesicular stomatitis virus (VSV) infection downregulates NLRP12 expression to allow RIG-I activation. Myeloid-cell-specific Nlrp12-deficient mice display a heightened interferon and TNF response and are more resistant to VSV infection. These results indicate that NLRP12 functions as a checkpoint for anti-viral RIG-I activation.

Copyright © 2019 Elsevier Inc. All rights reserved.

https://pubmed.ncbi.nlm.nih.gov/30902577/

RIG-1 on sama kuin DDX58 , RNA helikaasi, joka tunnistaa erilaisia virusRNA rakenteita solussa

Hienosäätöä tulee RIG1:iin  monista sinkkiproteiineista ja niitä säätelemällä  taas inflammasomit vaikuttavat  tähän RNA- helikaasiin, joka voisi  tunnistaa  soluun tulleen  viruksen RNA:ta. Esim NLRP12 johtaa  RIG-1 molekyyliä silppuriin   ja  NNLRC5  estää RIG-1- MAVS  ineraktion.

Aliases for DDX58 Gene

• GeneCards Symbol: DDX58 ²
• DExD/H-Box Helicase 58 ^{2 3 5}
• RIG-I ^{2 3 4 5}
• RIG-1 ^{2 4 5}
• RIG1 ^{2 3 5}
• Antiviral Innate Immune Response Receptor RIG-I ^{3 4}
• DEAD (Asp-Glu-Ala-Asp) Box Polypeptide 58 ^{2 3}
• Retinoic Acid-Inducible Gene 1 Protein ^{3 4}
• Retinoic Acid-Inducible Gene I Protein ^{3 4}
• ATP-Dependent RNA Helicase DDX58 ^{3 4}
• DEAD Box Protein 58 ^{3 4}

• RNA Helicase RIG-I ^{2 3}
• DKFZp434J1111 ^{2 5}
• FLJ13599 ^{2 5}
• RLR-1 ^{3 4}
• DEAD/H (Asp-Glu-Ala-Asp/His) Box Polypeptide ³
• Probable ATP-Dependent RNA Helicase DDX58 ³
• Retinoic Acid Inducible Gene I ²
• RIG-I-Like Receptor 1 ⁴
• EC 3.6.4.13 ⁴
• SGMRT2 ³
• RIGI ³

External Ids for DDX58 Gene

 

Entrez Gene Summary for DDX58 Gene

• DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases which are implicated in a number of cellular processes involving RNA binding and alteration of RNA secondary structure. This gene encodes a protein containing RNA helicase-DEAD box protein motifs and a caspase recruitment domain (CARD). It is involved in viral double-stranded (ds) RNA recognition and the regulation of the antiviral innate immune response. Mutations in this gene are associated with Singleton-Merten syndrome 2. [provided by RefSeq, Aug 2020]

GeneCards Summary for DDX58 Gene

DDX58 (DExD/H-Box Helicase 58) is a Protein Coding gene. Diseases associated with DDX58 include Singleton-Merten Syndrome 2 and Singleton-Merten Syndrome. Among its related pathways are Metabolism of proteins and SARS-CoV-2 Infection. Gene Ontology (GO) annotations related to this gene include nucleic acid binding and hydrolase activity. An important paralog of this gene is ENSG00000288684.

UniProtKB/Swiss-Prot Summary for DDX58 Gene

• Innate immune receptor that senses cytoplasmic viral nucleic acids and activates a downstream signaling cascade leading to the production of type I interferons and pro-inflammatory cytokines (PubMed:15208624, PubMed:16125763, PubMed:15708988, PubMed:16127453, PubMed:16153868, PubMed:17190814, PubMed:18636086, PubMed:19122199, PubMed:19211564, PubMed:29117565, PubMed:28469175, PubMed:31006531). Forms a ribonucleoprotein complex with viral RNAs on which it homooligomerizes to form filaments (PubMed:15208624, PubMed:15708988). The homooligomerization allows the recruitment of RNF135 an E3 ubiquitin-protein ligase that activates and amplifies the RIG-I-mediated antiviral signaling in an RNA length-dependent manner through ubiquitination-dependent and -independent mechanisms (PubMed:28469175, PubMed:31006531).
  (Kommentti RNF135  RING zinc finger-proteiini omaa muita nimiä:L13, MMFD, REUL, Riplet)
  
   
  Upon activation, associates with mitochondria antiviral signaling protein (MAVS/IPS1) that activates the IKK-related kinases TBK1 and IKBKE which in turn phosphorylate the interferon regulatory factors IRF3 and IRF7, activating transcription of antiviral immunological genes including the IFN-alpha and IFN-beta interferons (PubMed:28469175, PubMed:31006531). 
   
  Ligands include 5'-triphosphorylated ssRNAs and dsRNAs but also short dsRNAs (<1 kb in length) (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). In addition to the 5'-triphosphate moiety, blunt-end base pairing at the 5'-end of the RNA is very essential (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). Overhangs at the non-triphosphorylated end of the dsRNA RNA have no major impact on its activity (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). A 3'overhang at the 5'triphosphate end decreases and any 5'overhang at the 5' triphosphate end abolishes its activity (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). 
   Detects both positive and negative strand RNA viruses including members of the families Paramyxoviridae: Human respiratory syncytial virus (RSV)  and measles virus (MeV), Rhabdoviridae: vesicular stomatitis virus (VSV), Orthomyxoviridae: influenza A and B virus, Flaviviridae: Japanese encephalitis virus (JEV), hepatitis C virus (HCV), dengue virus (DENV) and west Nile virus (WNV) (PubMed:21616437, PubMed:21884169). It also detects rotaviruses and reoviruses (PubMed:21616437, PubMed:21884169).
   Detects and binds to SARS-CoV-2 RNAs which is inhibited by m6A RNA modifications (Ref.65).
   Also involved in antiviral signaling in response to viruses containing a dsDNA genome such as Epstein-Barr virus (EBV) (PubMed:19631370). Detects dsRNA produced from non-self dsDNA by RNA polymerase III, such as Epstein-Barr virus-encoded RNAs (EBERs). May play important roles in granulocyte production and differentiation, bacterial phagocytosis and in the regulation of cell migration.

  • DDX58_HUMAN,O95786

 

Inflammasomi NLRP12 säätelee RIG-1 proteiinia TRIM25 ja RNF125 sinkkisormiproteiinien avulla.

 https://www.genecards.org/cgi-bin/carddisp.pl?gene=NLRP12

Genecards tietoa tästä inflammasomista, joka järjestää  RIG-1 RNA-virussensoria  silppuroitumaan unikitiiniproteosomijärjestelmässä..

Aliases for NLRP12 Gene

• GeneCards Symbol: NLRP12 ²
• NLR Family Pyrin Domain Containing 12 ^{2 3 5}
• PYPAF7 ^{2 3 4 5}
• CLR19.3 ^{2 3 5}
• NALP12 ^{3 4 5}
• RNO2 ^{2 3 5}
• PAN6 ^{2 3 5}
• Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat And Pyrin Domain Containing 12 ^{2 3}
• NACHT, LRR And PYD Domains-Containing Protein 12 ^{3 4}

• PYRIN-Containing APAF1-Like Protein 7 ^{3 4}
• Regulated By Nitric Oxide ^{3 4}
• Monarch1 ^{2 5}
• RNO ^{3 4}
• NACHT, Leucine Rich Repeat And PYD Containing 12 ²
• Monarch 1 ³
• Monarch-1 ⁴
• FCAS2 ³

Protein details for NLRP12 Gene (UniProtKB/Swiss-Prot)

Protein Symbol:

P59046-NAL12_HUMAN

Recommended name:

NACHT, LRR and PYD domains-containing protein 12

Protein attributes for NLRP12 Gene

Size:1061 amino acidsMolecular mass: 120173 Da

Quaternary structure:Interacts (via pyrin domain) with ASC. Interacts (via pyrin domain) with FAF1 (via UBA domain) (PubMed:21978668). Interacts with MAP3K14; this interaction promotes proteasomal degradation of MAP3K14 (PubMed:17237370). Interacts with NOD2; this interaction promotes degradation of NOD2 through the ubiquitin-proteasome pathway (PubMed:30559449). Interacts with HSPA1A and HSPA8 (PubMed:17947705). Interacts with HSP90AA1 (PubMed:17947705, PubMed:30559449).

 

 Interacts with TRIM25 (alias RNF147, ZNF147, EFP) ; this interaction inhibits DDX58-mediated signaling pathway (  alias RIG-1 sensoritie)  (PubMed:30902577).

 

 Kommentti:  

TRIM 25 on sinkkisormiproteiini, jolla on RING- tyyppinen sinkkisormi (ZNF147, RNF147)  ja tämä suorittaa DDX5 (-proteiinin aktivaation ubikitinoimalla lysiinin K63, mutta tätä aktivaatiota estää  NLRP12. 

 

Lisäksi NLPR12 vaikuttaa, että toinen RING-tyyppinen sinkkisormiproteiini RNF125 (TRAC1)  ubikitinoi  DDX58-proteiinin toiseen lysiiniin K48, jolloin se suuntautuu proteosomaaliseen silppuriin.

Gene Families for NLRP12 Gene

HGNC:Pyrin domain containing

• NLR family

IUPHAR :

• NOD-like receptor family

Protein Domains for NLRP12 Gene

InterPro:

• P-loop_NTPase
• LRR_dom_sf
• Leu-rich_rpt
• DAPIN
• DEATH-like_dom_sf
• See all 9 »

Blocks:

• Leucine-rich repeat signature
• Pyrin domain
• Leucine-rich repeat, ribonuclease inhibitor subtype

 RNF125 proteiinista lisää tietoa. Se säätelee positiivisesti T-solureseptorin signalointiteitä.

• This gene encodes a novel E3 ubiquitin ligase that contains a RING finger domain in the N-terminus and three zinc-binding and one ubiquitin-interacting motif in the C-terminus. As a result of myristoylation, this protein associates with membranes and is primarily localized to intracellular membrane systems. The encoded protein may function as a positive regulator in the T-cell receptor signaling pathway. [provided by RefSeq, Mar 2012]

GeneCards Summary for RNF125 Gene

RNF125 (Ring Finger Protein 125) is a Protein Coding gene. Diseases associated with RNF125 include Tenorio Syndrome and Overgrowth Syndrome. Among its related pathways are DDX58/IFIH1-mediated induction of interferon-alpha/beta and Innate Immune System. Gene Ontology (GO) annotations related to this gene include ligase activity and ubiquitin-protein transferase activity. An important paralog of this gene is RNF166.

UniProtKB/Swiss-Prot Summary for RNF125 Gene

• E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins, such as DDX58/RIG-I, MAVS/IPS1, IFIH1/MDA5, JAK1 and p53/TP53 (PubMed:15843525, PubMed:17460044, PubMed:17643463, PubMed:26027934, PubMed:26471729, PubMed:25591766, PubMed:27411375). Acts as a negative regulator of type I interferon production by mediating ubiquitination of DDX58/RIG-I at 'Lys-181', leading to DDX58/RIG-I degradation (PubMed:17460044, PubMed:26471729). Mediates ubiquitination and subsequent degradation of p53/TP53 (PubMed:25591766). Mediates ubiquitination and subsequent degradation of JAK1 (PubMed:26027934). Acts as a positive regulator of T-cell activation (PubMed:15843525).

  • RN125_HUMAN,Q96EQ8

Lisätietoa RNF125  ja sen  kaltaisista RING-sinkkisormiproteiineista (RNFs)  proteiineista:

. 2008 Feb 15;410(1):101-11.

doi: 10.1042/BJ20070995.

T-cell regulator RNF125/TRAC-1 belongs to a novel family of ubiquitin ligases with zinc fingers and a ubiquitin-binding domain

Ana Lucia Giannini  ¹ , Yifang Gao, Marie-José Bijlmakers

 

Eri rokotteenjälkeistä myokardiittia ja perikardiittia arvioitu 2021

 https://www.mdpi.com/2076-393X/9/10/1186

Open AccessFeature PaperArticle

Shedding the Light on Post-Vaccine Myocarditis and Pericarditis in COVID-19 and Non-COVID-19 Vaccine Recipients

by

Rima Hajjo

^1,2,3,*,

Dima A. Sabbah

¹,

Sanaa K. Bardaweel

⁴ and

Alexander Tropsha

²

Academic Editors: Soo-Hong Lee, Jagathesh Chandra Rajendran, Hansoo Park and K.S JaganathanVaccines 2021, 9(10), 1186; https://doi.org/10.3390/vaccines9101186

Received: 22 September 2021 / Revised: 12 October 2021 / Accepted: 13 October 2021 / Published: 15 October 2021 (This article belongs to the Special Issue The COVID Vaccine)Abstract

Myocarditis and pericarditis have been linked recently to COVID-19 vaccines without exploring the underlying mechanisms, or compared to cardiac adverse events post-non-COVID-19 vaccines. We introduce an informatics approach to study post-vaccine adverse events on the systems biology level to aid the prioritization of effective preventive measures and mechanism-based pharmacotherapy by integrating the analysis of adverse event reports from the Vaccine Adverse Event Reporting System (VAERS) with systems biology methods. Our results indicated that post-vaccine myocarditis and pericarditis were associated most frequently with mRNA COVID-19 vaccines followed by live or live-attenuated non-COVID-19 vaccines such as smallpox and anthrax vaccines. The frequencies of cardiac adverse events were affected by vaccine, vaccine type, vaccine dose, sex, and age of the vaccinated individuals. Systems biology results suggested a central role of interferon-gamma (INF-gamma) in the biological processes leading to cardiac adverse events, by impacting MAPK and JAK-STAT signaling pathways. We suggest that increasing the time interval between vaccine doses minimizes the risks of developing inflammatory adverse reactions. We also propose glucocorticoids as preferred treatments based on system biology evidence. Our informatics workflow provides an invaluable tool to study post-vaccine adverse events on the systems biology level to suggest effective mechanism-based pharmacotherapy and/or suitable preventive measures. View Full-Text

Keywords: COVID-19; myocarditis; pericarditis; SARS-CoV-2; systems biology; vaccine; VAERS

▼ Show Figures

Fosfaatit, kinaasit, fosfataasit, inositolipyrofosfaatit, inositolifosfolipididefosforylaasit...

 Olen  tässä jälleen  kirjoittanut vihkooni muistiinpanoja fosfataaseista, tällä kertaa seriini/threoniini-proteiinifosfataasien  pienehköstä ryhmästä. 

 Välillä katson vanhoista muistiinpanoista  Sars-2  viruksen interaktioproteiineja erilaisiin ihmisen kinaaseihin.  Fosfataasiinterkatiosita ei löydy niin paljon  esimerkkejä.

Kinaaseja ja fosfataaseja on  aika paljon . Onhan " fosfori" sellainen molekyyli, joka ei koskaan esiinny yksin  biologisessa materiaalissa- paitsi tietysti jos  ihminen joutuu  kemiallisen myrkytyksen kohteeksi.

Fosfaattienmetabolinen  alue on hyvin laaja ja vasta tällä vuosituhannella  alettu n-hdä sitä tarkemmin,koska sillä alueella tapahtuvat ilmiöt ovat niin nopieta ja vaikeita havaita. kuten inositoliaineenvaihdunnan  fosfaattien siirtelyt lipidien ja ja liukoisten muotojen välillä.  Inositolifosfaatit edustavat  orgaanisen  fosfaatin  puolta ja  sitten on epäorgaanisen fosfaatin  saantia myös  ravinnossa, varsinkin teollisissa  valmisruoissa. Kehossa on  hyvinvointiyhteiskunnassa miltei luonnostaan epätasapainoa  orgaanisen ja  epäorgaanisen  fosfaatin alueen  heijastumissa-  mikä tulee signaalivälittäjien tasossa  kuten IP3 ja ja IP6-muotojon  välisessä suhteessa esiin.  IP6-muoto on se joka voi poistua solusta ja käydä  munuaisissa osallistumassa fosfaattitasapainon säätelyyn.  Fosfaatti on  yksi  joni, joka osallistuu kehon puskurijärjestelmiin, joten  fosfaatin aineenvaihdunnan tulisi olla integroitua kuin   hyvin jodhetun valtion  tieverkkojen liikennöinti.  Mutta käytännössä  fosfaatin liikenteessä on mitä moninaisimpia  "sähkökatkoksia", häiriöitä ja  vääräänjohtavia  signaaleita tienhaaroissa ellei suoranaisia ketjukolareita.  Sars-2 virus on tavattoman perehtynyt  aiheuttamaan fosfaattiaineenvaihduntaan  liikennehäiriöitä ja anarkiaa.

https://pubmed.ncbi.nlm.nih.gov/32397291/

 

 

 

 

Miksi Sars-2 koronavirus voi olla hyvin tuhoisa?

Tämä artikkeli on lokakuulta 2020 ja hahmottelee  sars-2 viruksen otetta ihmisen puolustusjärjestelmään. Tämäntapainen tietämys  auttoi lopulta  terapiastrategioiden luomisessa ja mortaliteetin vähentämisessä:

. 2020 Oct 9;5(1):235.

doi: 10.1038/s41392-020-00334-0.

SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation

Shufen Li ^{#  1} , Yulan Zhang   

• DOI: 10.1038/s41392-020-00334-0

Free PMC article  Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure (MOF)  in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently  (2020) unknown. Here we report that SARS-CoV-2 infection activates caspase-8  ( extrinsic pathway of apoptosis) to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.

 RIPK, receptor interacting protein 1 ja 3.

https://www.genecards.org/cgi-bin/carddisp.pl?gene=RIPK1&keywords=MLKL

 https://www.genecards.org/cgi-bin/carddisp.pl?gene=RIPK3&keywords=MLKL

 MLKL Mixed lineage kinase domain-like protein

 https://www.genecards.org/cgi-bin/carddisp.pl?gene=MLKL&keywords=MLKL

PGAM5 S/T-protein phosphatase mitochondrial

https://www.genecards.org/cgi-bin/carddisp.pl?gene=PGAM5&keywords=PGAM5

Huom uusi tieto: PGAM5 on myös KEAP1 (Kelch proteiini) substraatti. Aiemmin on puhuttu vain NRF2 proteiinista KEAP1 substraattina!  Tätä  systeemiä täytyy ajatella!

 https://www.sciencedirect.com/science/article/pii/S2213231721003463

 DNM1L  Dynamin1like  (GTPase)

https://www.genecards.org/cgi-bin/carddisp.pl?gene=DNM1L&keywords=DNM1L

EBV viruksen ja Sars-2 koronaviruksen samanaikaisinfektio

1.  2021 Jan-Dec;9:23247096211040626.

doi: 10.1177/23247096211040626.

Epstein-Barr Virus Coinfection in COVID-19

Asim Nadeem  ¹ , Krithika Suresh  ¹ , Hassan Awais  ¹ , Saba Waseem  ¹

• PMCID: PMC8392798
• DOI: 10.1177/23247096211040626

Free PMC article

Abstract

Epstein-Barr virus (EBV), a member of the herpes virus family, is a causative agent for infectious mononucleosis in young adults. It has an asymptomatic and subclinical distribution in about 90% to 95% of the world population based on seropositivity. EBV is associated with various lymphomas, nasopharyngeal carcinoma, and in immunocompromised states can give rise to aggressive lymphoproliferative disorders. Symptomatic patients mostly present with mild hepatitis, rash, oral symptoms, lymphadenopathy, and generalized malaise.

 Recently with the COVID-19 (coronavirus disease-2019) pandemic, hepatitis has been found to be related to acute EBV and cytomegalovirus  (CMV) reactivation versus acute infection in the absence of other major causes. We describe a case of EBV coinfection in a patient with resolving mild COVID-19 infection.

Keywords: COVID-19; EBV; hepatitis. 

 

2.

  https://pubmed.ncbi.nlm.nih.gov/34791940/

 

. 2021 Nov 18;8850666211053990.

Reactivation of EBV and CMV in Severe COVID-19- Epiphenomena or Trigger of Hyperinflammation in Need of Treatment? A Large Case Series of Critically ill Patients

Jan-Hendrik Naendrup et al. 

DOI: 10.1177/08850666211053990 

Conclusion: Critically ill patients with COVID-19 are at a high risk for EBV and CMV reactivations. Whether these reactivations are a cause of hyperinflammation and require targeted treatment remains uncertain. However, in patients with clinical deterioration or signs of hyperinflammation targeted treatment might be beneficial and warrants further studying.

Akuutti EBV infektio voi olla haitaksi otettaessa Coronarokotusta.

 Tosin saattaa olla, että rokotetyyppi vaikuttaa myös. Tässä artikkelissa on  kertomus 43-vuotiaasta terveestä kiinalaisesta maanviljelijästä, joka sai Cov-rokotteena  inaktivoitua sars-2 virusta. Hänelle tuli HLH-reaktio ja  tilanne hoidettiin sen diagnoosin mukaisesti . Henkilö toipui. Johtopäätöksenä toivotaan akuutin EBV tulehduksen ja muun  akuutin virustulehduksen poissulkemista ennen  vastaavan koronarokotuksen ottamista.  Suomessa annetut rokotteet eivät ole  valmistettu   artikkelin kuvaamalla tavalla.

EBV and Covid-19 haku: 169 vastausta  Pubmed

https://pubmed.ncbi.nlm.nih.gov/34088334/

Abstract

Cases of thrombotic thrombocytopenia induced by coronavirus disease 2019 (COVID-19) vaccines have been reported recently. Herein, we describe the first case of another critical disorder, hemophagocytic lymphohistiocytosis (HLH), in a healthy individual after COVID-19 vaccination. A 43-year-old Chinese farmer developed malaise, vomiting, and persistent high fever (up to 39.7 °C) shortly after receiving the first dose of the inactivated SARS-CoV-2 vaccine. The initial evaluation showed pancytopenia (neutrophil count, 0.70 × 10⁹/L; hemoglobin, 113 g/L; platelet, 27 × 10⁹/L), elevated triglyceride (2.43 mmol/L), and decreased fibrinogen (1.41 g/L). Further tests showed high serum ferritin levels (8140.4 μg/L), low NK cell cytotoxicity (50.13%-60.83%), and positive tests for Epstein-Barr virus (EBV) DNA. Hemophagocytosis was observed in the bone marrow. Therefore, HLH was confirmed, and dexamethasone acetate (10 mg/day) was immediately prescribed without etoposide. Signs and abnormal laboratory results resolved gradually, and the patient was discharged. HLH is a life-threatening hyperinflammatory syndrome caused by aberrantly activated macrophages and cytotoxic T cells, which may rapidly progress to terminal multiple organ failure. In this case, HLH was induced by the COVID-19 vaccination immuno-stimulation on a chronic EBV infection background. This report indicates that it is crucial to exclude the presence of active EBV infection or other common viruses before COVID-19 vaccination.

Keywords: COVID-19; Coagulopathy; Epstein–Barr virus; Hemophagocytic lymphohistiocytosis; SARS-CoV-2 vaccine.

See this image and copyright information in PMC

Fig. 1

Synopsis of the clinical course. a Hemophagocytosis in the bone marrow: the arrows indicate phagocytosis of platelets and erythrocytes by a number of hemophagocytes, b Dynamic changes of the body temperature and ferritin level, c Dynamic changes of the coagulation parameters, d Dynamic changes of the blood cell counts. T: body temperature; Fib: fibrinogen; APTT: activated partial thromboplastin time; WBC: white blood cell; Hb: hemoglobin; PLT: platelet

GITHUB mainintoja Japanissa esiintyvistä Sars-2 varianttien alalinjoista viime aikoina

 Otan sitaatteja GITHUB tekstissä,  ja muutaman eritysimaininnan siitä  vyyhdimäisestä tilanteesta, jota  tiedemiehet ovat tottuneet tässä selvittelemään  etsiessään  johtolankoja joihinkin  erityisiin mutaatioihin Minusta jotkut mutaatiot eivät varsinaisesti ole evoluutiota, vaan vain energiatilan loppumista  viruksen rakenteen  koostamisyrityksissä ja  sitten stoikkastisesta  muutoksesta, joka ihan  sattumoisin on tapahtunut  ja kuitenkin on saattanut koostumusta vielä  muutaman kerran  toistua, mutta linjaa ei  sen koommin  ole  esiintynyt eikä merkattu.  Jokin kohta  rakeknteessa saattaa olla erityisen altis muuttumaan eri varianteissa olosuhteista ja energiatilasta ( tai lähinnä energian puutteesta)  riippuen, eikä siksi että  ne olisivat jotain samaa linjaa.  Japanissa on kuitenkin päivittäiset tartuntatapaukset vielä suuri luku! Tämä virus on tosi loinen, sillä se kehrää ihmisen proteiinit ja mineraalit niin että moni laihtuu tämän infektion aikana haitallisesti- lisäksi hajun ja makuaistin poissaolo vähentää  ravinnonottoa ja ihmisen yleiskunnon heiketessä virus menestyy  edelleen. Vaikka pandemia muuttuisi endemiaksi se ei tarkoita että  ei pitäisi asiaan kiinnittää huomiota. Endemiaksi muuttuminen voi olla yleiskuntojen alenemistilaa.  

Closed GITHUBs

#687, BA.2.3.18 Japan 138 sekvenssiä. Milestone 14.7.2022

https://github.com/cov-lineages/pango-designation/issues/687

Spike:I692F, Membrane:I76V.

#745, BA.2.56.1 Milestone 13.6. 2022

https://github.com/cov-lineages/pango-designation/issues/745,

Description Potential sublineage of: BA.2.56 (the European sublineage with spike L452M from the BA.2 root) Earliest sequence: 2022/03/27 (Japan-Hyogo prefecture) Most recent sequence: 2022/05/21 (Japan-Kochi prefecture)Mutations on top of BA.2:

Gene	Amino changes
ORF1a	R226K  (67/75)
Spike	H69Y, L452M, W886L
ORF3a	A31S (48/75)

#605, BA.2.3.11 Milestone 13.6. 2022.

https://github.com/cov-lineages/pango-designation/issues/605

Proposal for new sub-lineage of BA.2.3 with C13326T (ORF1ab: T4354I) and A20214G (synonymous) in Japan (858 sequences as of 2022-06-07, 13.4% of BA.2.3 in Japan) #605

".. this proposed sublineage is only 4.5% (=130/2864) of the BA.2.3 isolated in Japan, which is a small number.However, our proposed sublineage is characterized by its high locality within Japan.
Therefore, I believe that it would be useful for genome surveillance in Japan if this proposed sublineage can be easily confirmed together with the conventional BA.2.3 and BA.2.3.1, the main lineage of the BA.2 lineage in Japan. Thank you in advance for your consideration.

7.6. 2022: For the updated data, the proposed lineage has increased to 13.4 % (= 858 / 6399) of BA.2.3 in Japan.

13.6.2022 Chrisruis: Thanks @takaabe8050 The geographical focus of this clade in Japan means that it has an associated epidemiological event so warrants a designation. We spotted this independently and added it as BA.2.3.11. Thanks again

#600 , BA.2.24, Milestone 2.5. 2022.

https://github.com/cov-lineages/pango-designation/issues/600

A BA.2 lineage with Spike:339N seems to be growing in Tokyo.

#590, XAC Milestone 10.6. 2022

Potential BA.2*/BA.1*/BA.2* Recombinant with Double Breakpoints (244 Seqs in Israel, Germany, Canada, Ireland, Netherland, Sweden, Japan, India, UK and US as of 2022-06-10) #590

https://github.com/cov-lineages/pango-designation/issues/590

c19850727 commented on 2 Jun

171 sequences as of 2022-06-01, and now newly found in India-KA and Japan ex-US.

• (Tärkeä välihuomautus! TÄSTÄ SAA YLEISKÄSITYSTÄ NÄITTEN VARIANtTIEN ANALYSOIMISESTA!)

AngieHinrichs commented on 2 Jun

"Tangential, but I still want to make the distinction: BA.2 and its descendants (BA.3, BA.4, BA.5) BA.3, BA.4 and BA.5 are not believed to be descendants of BA.2 (or they would be BA.2.X), but rather separate emergences from the Omicron reservoir along with BA.1 and BA.2. (There is some discussion for BA.3 in #367; the Pango lineage designation committee had some internal discussions about BA.4/BA.5 that unfortunately didn't make it into #517.) BA.4 and BA.5 are similar to BA.2, but lacking enough BA.2 mutations that it seems more likely that they arose separately within the Omicron reservoir. BA.4 and BA.5 split off from the BA.2 branch of the UCSC/UShER tree, but that is only because that's where they fit in with the fewest substitutions (including reversions to reference for BA.2 mutations that are not found in BA.4 & BA.5). The tree's basal Omicron branches are a mess because there are many different combinations of false reversions found in sequences, and (as far as I know) no actual pre-BA.* ancestral Omicron sequences. ktmeaton commented on 2 Jun: "Thank you for catching and correcting that @AngieHinrichs! Just to clarify, the topology of 22A (BA.4) and 22B (BA.5) falling within the diversity of 21L (BA.2) is not true to their evolutionary origin because there is underlying mutation conflicts? Or am I misinterpreting the tree or your explanation? Thanks!" https://user-images.githubusercontent.com/14981272/171708141-6364bdf6-4e70-4b62-9b4f-9dafe617bdb6.png

AngieHinrichs commented on 2 Jun :

"21L on that tree is much broader than BA.2. It includes recombinants (the sequences that appear below the 22A label; England/PHEC-YYFJF3T/2022 says BA.2 in the pop-up but it's XW), BA.4, BA.5, and BA.2 (the yellow-orange and red sequences above 22B). 21L is more like "Omicron minus BA.1 and BA.3". "I think it actually does show the separation of BA.2, BA.4 and BA.5, if you define BA.2 as the sequences above 22B. Some reversions are still required to get that structure -- the branch leading to 22A and 22B has a reversion on 23040 (shared by BA.1, BA.2 and BA.3), and the branch to 22B has 5 more reversions (again, tree structures can't be perfect when recombination might have been involved). 22A and 22B are also missing C9866T which is in nearly all BA.2 sequences, although as @corneliusroemer has pointed out, lack of C9866T might actually be ancestral for BA.2.

Hi @InfrPopGen, I think we've resolved the major outstanding issue in this proposal with the consensus that this is a BA.1/BA.2 recombinant with double breakpoints. Are there any other problems to resolve before an official designation?  Title: Potential BA.2*/BA.1*/BA.2* Recombinant with Double Breakpoints (244 Seqs in Israel, Germany, Canada, Ireland, Netherland, Sweden, Japan, India, UK and US as of 2022-06-10) on 10 Jun

InfrPopGen commented on 10 Jun

"Thanks for submitting (and apologies for the delay). We've added recombinant lineage XAC with 126 newly designated sequences, and 3 updated designations".

#591 , XW, Milestone 10.6. 2022.

Potential BA.1*/BA.2* Recombinant with Likely Breakpoint at NSP3 (53 Seqs as of 2022-05-11 in Japan, Germany, Slovenia, Canada, UK and US) designated recombinant

c19850727 commented on 28 Apr

Although this potential recombinant sublineage doesn't meet the minimum criteria of 50 sequences, I thought it's still worth proposing considering it has been found in multiple regions in a relatively short period of time. Recombinant between: BA.1* & BA.2* Earliest sequence: 2022/3/13 (Japan ex-Finland) Most recent sequence: 2022/4/17 (UK-England) Countries circulating: UK (England), US (MD, CO, NY), Canada (ON), Germany (BW, NW, BB, BE, NI, SN), Japan (ex-Finland) Likely breakpoint: between 2834 and 4183 (NSP3). Private mutations: C10507T, C12756T (ORF1a:T4164I), G16020T Conserved Nuc mutations (those in red frames are likely from the donor from the BA.1 side):

 

#587   Possible BA.2.3 sublineage with ORF1a:K798N starting in Northern Mariana Islands and Guam (779 sequences in Cov-Spectrum) #587

 https://github.com/cov-lineages/pango-designation/issues/587

InfrPopGen commented on 11 May

Thank you for proposing this lineage for designation. Unfortunately, it does not quite meet the criteria for designation at present. There is no clear estimated growth advantage for BA.2.3* + ORF1a:K798N, ORF1b:A88V above BA.2* or BA.2.3*, according to CoV-spectrum (indeed it is estimated as negative in comparison with BA.2.3*). Although, this lineage appears to have played a major role in the N Marianas, it is not associated with any other epidemiological trait (e.g. increased hospitalisation, transmissibility). Should the situation change, please feel free to re-propose, as a new issue, for designation with the additional evidence.

#569   BA.2.10.2   Milestone 10.5. 2022.

https://github.com/cov-lineages/pango-designation/issues/569

fedeGueli: " While checking for japanese airport surveillance sequences from India @c19850727 (Sakaguchi Hitoshi) highlighted me that a significant share of the last samples was carrying the E:R61L mutation.
Looking at Japanese sequences we found that a BA.2.10 sublineage with E:R61L circulates there .
Here we want to propose it, but it is worth mentioning and monitoring that multiple BA.2 sublineages carry this sublineage and one of them is actually growing quite fast in Switzerland.

InfrPopGen commented on 10 May

Thanks for submitting. We've added lineage BA.2.10.2 with 50 newly designated sequences, and 1 updated designations from BA.2.10. Defining mutation(s) G26426T (E:61L).   #522, XU , BA.1/BA.2 https://github.com/cov-lineages/pango-designation/issues/522   Description Recombinant between: BA.1* & BA.2 Earliest sequence: 2022/1/20 (Japan ex-India) Most recent sequence: 2022/3/4 (India-Maharashtra) Countries circulating: India (3 seqs in Gurajat and 2 seqs in Maharashtra), Japan (1 seq from imported case with travel history to India) Likely breakpoint: between 6518 and 9343 (NSP3 or NSP4). Conserved Nuc mutations (those in red frames are likely from the donor from the BA.1 side): chrisruis commented on 19 Apr Thanks @c19850727 We've added this as XU.