SARS2 tartuntateistä

https://www.thelancet.com/journals/langas/article/PIIS2468-1253(20)30048-0/fulltext

Luuydin ja koronavirus

(1)  Sarsin osalta  mainittu reaktiivinen hemofagosytoosi.

Bone Marrow  (Luuydin)  ja   koronavirukset fokuksessa.

https://ajp.amjpathol.org/article/S0002-9440(10)61329-6/fulltext#cesec80

In some cases, evidence of reactive hemophagocytosis or bone marrow hypoplasia was present.^{13, 25, 38} In other cases, however, active bone marrow without reactive hemophagocytosis has been demonstrated.¹¹ In situ hybridization and IHC have detected neither viral genomic sequences nor antigens.^{30, 31} Both viral isolation and RT-PCR performed on bone marrow were negative.^{11, 25, 31}

 2)  Voisiko  SARS2 infektiossa kehittyöä jollekulle hemofagosytoottinen oireyhtymä luuytimeen?
Tästä näkyy muutama maininta netissä   " Harvemmin esiintyy reaktiivista hemofagosytoosia" LÄHDE:
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1829448/

3)  Mitä tarkoittaa HEMOFAGOSYTOOSI? 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062561/

Hemophagocytosis is the engulfment of hematopoietic cells by activated macrophages acting outside of usual immune system regulations. Hemophagocytic lymphohistiocytosis (HLH) covers a wide array of related diseases including HLH, autosomal recessive familial HLH (FHL), familial erythrophagocytic lymphohistiocytosis, viral-associated hemophagocytic syndrome, and autoimmune-associated macrophage activation syndrome (MAS). These disorders feature severe cytopenias due to this uncontrolled hemophagocytosis. Other laboratory signs and clinical symptoms result from disordered immune regulation and cytokine storm. The term primary HLH refers to an underlying genetic abnormality causing the disorder, whereas secondary HLH indicates that the disorder is secondary to underlying conditions such as infection, autoimmune/rheumatologic, malignant, or metabolic conditions. For the purposes of this review, FHL will indicate cases with a primary genetic cause, secondary HLH will refer to cases secondary to infection, malignancy, or metabolic disorders, and MAS will refer to cases associated with autoimmune diseases.

Much has been learned about HLH in the 75 years since it was first discovered. One of the earliest descriptions of the disease was in 1939 when Scott and Robb-Smith1 described a disorder featuring erythrophagocytosis by proliferating histiocytes in the lymphoreticular system and called it “histiocytic medullary reticulosis” or HMR. It was later classified among malignant histiocytosis. Later in 1952, the familial form of HLH, FHL, was more fully described by Farquhar and Claireaux2 with the cases of two siblings who succumbed to HLH, and later in 1958, another sibling from this same family presented in the same manner.3 Risdall was among the first to describe a viral association with HLH and proposed that the condition be called virus-associated HLH, distinct from malignant histiocytosis.4 In the years since, researchers have recognized the wide scope of this disease and the fact that infection often triggers both primary and secondary HLH. Regardless of cause, physiologically, HLH is characterized by defective cytotoxic cell function coupled with unbridled macrophage activity, leading to excessive cytokine production, subsequent immune dysregulation, and tissue damage. Left untreated, the dysregulated inflammatory response causes severe neutropenia, and patients often die from bacterial or fungal infections. The condition carries high morbidity and mortality.5 Long-term survival in 1983 was estimated to be as low as 4%.6 The median survival without treatment is estimated at <2 a="" aria-expanded="false" aria-haspopup="true" class=" bibr popnode tag_hotlink tag_tooltip" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062561/#b6-jbm-5-069" id="__tag_383968853" months.="" role="button">6

Miten ihmisen immunologinen interferonijärjestelmä ja sen reseptorit voat kehittyneet evoluution aikana (2017

https://www.frontiersin.org/articles/10.3389/fimmu.2017.00209/full
Immunologisen puolustuskyvyn kehittyminen on kaiken elollisen olemassaolon perustavia piirteiä.

Chris J. Secombes* and Jun Zou

• Scottish Fish Immunology Research Centre, University of Aberdeen, Aberdeen, UK

The earliest jawed vertebrates (Gnathostomes) would likely have had interferon (IFN) genes, since they are present in extant cartilaginous fish (sharks and rays) and bony fish (lobe-finned and ray-finned fish, the latter consisting of the chondrostei, holostei, and teleostei), as well as in tetrapods. They are thought to have evolved from a class II helical cytokine ancestor, along with the interleukin (IL)-10 cytokine family. The two rounds of whole genome duplication (WGD) that occurred between invertebrates and vertebrates (1) may have given rise to additional loci, initially containing an IL-10 ancestor and IFN ancestor, which have duplicated further to give rise to the two loci containing the IL-10 family genes, and potentially the IFN type I and IFN type III loci (2). The timing of the divergence of the IFN type II gene from the IL-10 family genes is not clear but was also an early event in vertebrate evolution. Further WGD events at the base of the teleost fish, and in particular teleost lineages (cyprinids, salmonids), have duplicated the loci further, giving rise to additional IFN genes, with tandem gene duplication within a locus a common occurrence. Finally, retrotransposition events have occurred in different vertebrate lineages giving rise to further IFN loci, with large expansions of genes at these loci in some cases. This review will initially explore the likely IFN system present in the earliest Gnathostomes by comparison of the known cartilaginous fish genes with those present in mammals and will then explore the changes that have occurred in gene number/diversification, gene organization, and the encoded proteins during vertebrate evolution.

Artikkeli interferoneista 2001

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC89003/

Influensa A viruksen (IAV) tehokas evaasiotie. tuhoamalla sekä IFNAR1 että IFNGR1. .

J Virol. 2018 Mar 14;92(7). pii: e00006-18. doi: 10.1128/JVI.00006-18. Print 2018 Apr 1.

Casein Kinase 1α Mediates the Degradation of Receptors for Type I and Type II Interferons Caused by Hemagglutinin of Influenza A Virus.

Xia C^1,2, Wolf JJ^1,2, Vijayan M^1,2, Studstill CJ^1,2, Ma W³, Hahm B^4,2.

Author information

Abstract

Although influenza A virus (IAV) evades cellular defense systems to effectively propagate in the host, the viral immune-evasive mechanisms are incompletely understood. Our recent data showed that hemagglutinin (HA) of IAV induces degradation of type I IFN receptor 1 (IFNAR1). Here, we demonstrate that IAV HA induces degradation of type II IFN (IFN-γ) receptor 1 (IFNGR1), as well as IFNAR1, via casein kinase 1α (CK1α), resulting in the impairment of cellular responsiveness to both type I and II IFNs. IAV infection or transient HA expression induced degradation of both IFNGR1 and IFNAR1, whereas HA gene-deficient IAV failed to downregulate the receptors. IAV HA caused the phosphorylation and ubiquitination of IFNGR1, leading to the lysosome-dependent degradation of IFNGR1. Influenza viral HA strongly decreased cellular sensitivity to type II IFNs, as it suppressed the activation of STAT1 and the induction of IFN-γ-stimulated genes in response to exogenously supplied recombinant IFN-γ. Importantly, CK1α, but not p38 MAP kinase or protein kinase D2, was proven to be critical for HA-induced degradation of both IFNGR1 and IFNAR1. Pharmacologic inhibition of CK1α or small interfering RNA (siRNA)-based knockdown of CK1α repressed the degradation processes of both IFNGR1 and IFNAR1 triggered by IAV infection. Further, CK1α was shown to be pivotal for proficient replication of IAV. Collectively, the results suggest that IAV HA induces degradation of IFN receptors via CK1α, creating conditions favorable for viral propagation. Therefore, the study uncovers a new immune-evasive pathway of influenza virus.IMPORTANCE Influenza A virus (IAV) remains a grave threat to humans, causing seasonal and pandemic influenza. Upon infection, innate and adaptive immunity, such as the interferon (IFN) response, is induced to protect hosts against IAV infection. However, IAV seems to be equipped with tactics to evade the IFN-mediated antiviral responses, although the detailed mechanisms need to be elucidated. In the present study, we show that IAV HA induces the degradation of the type II IFN receptor IFNGR1 and thereby substantially attenuates cellular responses to IFN-γ. Of note, a cellular kinase, casein kinase 1α (CK1α), is crucial for IAV HA-induced degradation of both IFNGR1 and IFNAR1. Accordingly, CK1α is proven to positively regulate IAV propagation. Thus, this study unveils a novel strategy employed by IAV to evade IFN-mediated antiviral activities. These findings may provide new insights into the interplay between IAV and host immunity to impact influenza virus pathogenicity.

Copyright © 2018 American Society for Microbiology.

INFgamma interferoni ja sen reseptoridimeeri IFNGR1/ IFNGR2

• https://www.ncbi.nlm.nih.gov/gene/3458

IFNG (12q15) IFN gamma interferoni.

• Gammainterferonin reseptorit  muodostavat heterodimeerin IFNGR1 ja IFNG2.

Lisätietoa  IFNGR1  reseptoriosasta:

IFNGR1 (6q23.2), CD119, IMD27A, IMD27B.
https://www.ncbi.nlm.nih.gov/gene/3459 

Official Symbol

IFNGR1provided by HGNC

Official Full Name

interferon gamma receptor 1provided by HGNC

Also known as

CD119; IFNGR; IMD27A; IMD27B

Summary

This gene (IFNGR1) encodes the ligand-binding chain (alpha) of the gamma interferon receptor. Human interferon-gamma receptor is a heterodimer of IFNGR1 and IFNGR2. A genetic variation in IFNGR1 is associated with susceptibility to Helicobacter pylori infection. In addition, defects in IFNGR1 are a cause of mendelian susceptibility to mycobacterial disease, also known as familial disseminated atypical mycobacterial infection. [provided by RefSeq, Jul 2008]

Expression

Ubiquitous expression in spleen (RPKM 51.4), fat (RPKM 48.1) and 25 other tissues See more

Preferred Names

interferon gamma receptor 1

Names

AVP, type 2

CD119 antigen

CDw119

IFN-gamma receptor 1

IFN-gamma-R-alpha

IFN-gamma-R1

antiviral protein, type 2

immune interferon receptor 1

interferon-gamma receptor alpha chain

(.... IFNGR1 rakenteesta ) (1..489 aminohappoa)
https://www.ncbi.nlm.nih.gov/protein/NP_000407.1

( 25.. 113)  "FN3"
(161..317 ) (Reseptorikohta)

Interferon gamma receptor (IFNGR1)

This family consists of several eukaryotic and viral interferon gamma receptor proteins. Molecular interactions among cytokines and cytokine receptors in eukaryotes form the basis of many cell-signaling pathways relevant to immune function. Human interferon-gamma (IFN-gamma) signals through a multimeric receptor complex consisting of two different but structurally related transmembrane chains: the high-affinity receptor-binding subunit (IFN-gammaRalpha) and a species specific accessory factor (AF-1 or IFN-gammaRbeta). The vaccinia viral interferon gamma receptor has been shown to be secreted from infected cells during early infection. The structure has been halved such that the N-terminus of this family is now represented by Tissue_fac pfam01108.

 N-Glycosylation sites 34N, 79N, 86N, 179N, 240N
 246-266  TM domain ( transmembraaninen kohta) 
Phosphorylation sites   372T, 378S, 403S
Huom tässä on tumareseptorisignaali lvdll, koska tämä osa voi mennä tumaan aktivoidun  STAT1dimeerin kanssa. Katso reseptorin kuvaa ja selitystä. 

ORIGIN      
        1 mallfllplv mqgvsraemg tadlgpssvp tptnvtiesy nmnpivywey qimpqvpvft
       61 vevknygvkn sewidacini shhycnisdh vgdpsnslwv rvkarvgqke sayakseefa
      121 vcrdgkigpp kldirkeekq imidifhpsv fvngdeqevd ydpettcyir vynvyvrmng
      181 seiqykiltq keddcdeiqc qlaipvssln sqycvsaegv lhvwgvttek skevcitifn
      241 ssikgslwip vvaalllflv lslvficfyi kkinplkeks iilpkslisv vrsatletkp
      301 eskyvslits yqpfslekev vceeplspat vpgmhtednp gkvehteels sitevvttee
      361 nipdvvpgsh ltpieresss plssnqsepg sialnsyhsr ncsesdhsrn gfdtdsscle
      421 shsslsdsef ppnnkgeikt egqelitvik aptsfgydkp hvlvdllvdd sgkesligyr
      481 ptedskefs
//

Lisätietoa  IFNGR2  reseptorigeenistä
https://www.ncbi.nlm.nih.gov/gene/3460

Also known as

AF-1; IFGR2; IMD28; IFNGT1

Summary

This gene (IFNGR2) encodes the non-ligand-binding beta chain of the gamma interferon receptor. Human interferon-gamma receptor is a heterodimer of IFNGR1 and IFNGR2. Defects in IFNGR2 are a cause of mendelian susceptibility to mycobacterial disease (MSMD), also known as familial disseminated atypical mycobacterial infection. MSMD is a genetically heterogeneous disease with autosomal recessive, autosomal dominant or X-linked inheritance. [provided by RefSeq, Jul 2008]

Expression

Ubiquitous expression in placenta (RPKM 30.0), appendix (RPKM 25.4) and 25 other tissues See more

Preferred Names

interferon gamma receptor 2

Names

IFN-gamma receptor 2

IFN-gamma-R-beta

IFN-gamma-R2

interferon gamma receptor accessory factor-1 (AF-1)

interferon gamma receptor beta chain

interferon gamma transducer 1, (IFNGT1)

 

Ref.  " Data suggest IFNG plays various roles in dynamics of inflammation in subjects with underlying autoimmunity modeled as "canonical" and "non-canonical" pathways; in canonical pathway, IFNG dimerizes and binds to IFNGR1 in IFNGR1/IFNGR2 hetero-multimer; STAT transcription factors are involved in non-canonical pathway. (IFNG = interferon gamma; IFNGR = IFNG receptor; STAT = signal transducers and activators of transcription)"

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572907/

(FIGURE!) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572907/figure/F2/

 https://www.ncbi.nlm.nih.gov/protein/?term=Homo+sapiens+IFNGR2
ja rakenteesta yksityiskohtia 
 https://www.ncbi.nlm.nih.gov/protein/NP_001316057.1
IFNGR2, AF-1, INFGR2, IFNGT1 IMP28
(21q22.11) 
Rakenne: (1..356)
47..145 "FN3"
158..256 ""FN3"

ORIGIN      
        1 mrptllwsll lllgvfaaaa aappaqltle tyqewcndsa athdplsqlp apqhpkirly
       61 naeqvlswep valsnstrpv vyqvqfkytd skwftadims igvnctqita tecdftaasp
      121 sagfpmdfnv tlrlraelga lhsawvtmpw fqhyrnvtvg ppenievtpg egsliirfss
      181 pfdiadtsta ffcyyvhywe kggiqqvkgp frsnsisldn lkpsrvyclq vqaqllwnks
      241 nifrvghlsn iscyetmada stelqqvili svgtfsllsv lagacfflvl kyrglikywf
      301 htppsiplqi eeylkdptqp ilealdkdss pkddvwdsvs iisfpekeqe dvlqtl
//

 

Onko uudella SARS2- koronaviruksella neurotrooppisia piirteitä?

Kerään tähän tietoja .
On mainittu muutamisas artikkeleissa lehdistössä, että virus aiheutta  tuskatiloja, paniikkia ja myös konfuusiota, jotka kyllä ovat ohimeneviäkin toipuneilla. Neurologisista jälkitgaudeista on liian varhaista sanoa mitään. Kova väsymys kuuluu tulehdukseen.
Pari vanhaa tietoa koronavirusten neurotropismista netistä googlaamalla:
 

Neuroinvasive and neurotropic human respiratory ... - NCBI

www.ncbi.nlm.nih.gov › pubmed

Översätt den här sidan

av M Desforges - ‎2014 - ‎Citerat av 11 - ‎Relaterade artiklar

Neuroinvasive and neurotropic human respiratory coronaviruses: potential ... respiratory distress syndrome, or even severe acute respiratory syndrome (SARS).   Abstract

In humans, viral infections of the respiratory tract are a leading cause of morbidity and mortality worldwide. Several recognized respiratory viral agents have a neuroinvasive capacity since they can spread from the respiratory tract to the central nervous system (CNS). Once there, infection of CNS cells (neurotropism) could lead to human health problems, such as encephalitis and long-term neurological diseases. Among the various respiratory viruses, coronaviruses are important pathogens of humans and animals. Human Coronaviruses (HCoV) usually infect the upper respiratory tract, where they are mainly associated with common colds. However, in more vulnerable populations, such as newborns, infants, the elderly, and immune-compromised individuals, they can also affect the lower respiratory tract, leading to pneumonia, exacerbations of asthma, respiratory distress syndrome, or even severe acute respiratory syndrome (SARS). The respiratory involvement of HCoV has been clearly established since the 1960s. In addition, for almost three decades now, the scientific literature has also demonstrated that HCoV are neuroinvasive and neurotropic and could induce an overactivation of the immune system, in part by participating in the activation of autoreactive immune cells that could be associated with autoimmunity in susceptible individuals. Furthermore, it was shown that in the murine CNS, neurons are the main target of infection, which causes these essential cells to undergo degeneration and eventually die by some form of programmed cell death after virus infection. Moreover, it appears that the viral surface glycoprotein (S) represents an important factor in the neurodegenerative process. Given all these properties, it has been suggested that these recognized human respiratory pathogens could be associated with the triggering or the exacerbation of neurological diseases for which the etiology remains unknown or poorly understood.

Neurotropic coronavirus infections - ResearchGate

www.researchgate.net › publication › 28634587...

Neurotropism and neuroinvasiveness have also has been described for two other members of the Coronaviridae family, HCoV-OC43 and SARS-coronavirus ...

(Jokin vanha koronavirus oli varsin neurotrooppinen Viruksen hepatiitti-koronavirus on osoitautunutoelvan hyvä koe-eläinmalli  myös mahdollisista enkefaliiteista ja  demyelinisoivista seuraamuksista. Ihmisellä havaittiin tämän alunperin vain talvallisia vilustumisa aiheuttavan viruksen
 mahdollisuus  päästä aivoihin  tekemään enkefaliitteja. ne taas voivat oolla eri asteisia, lievissä virus puhdistuu vähitellen itsestään  eikä jätä jälkitauteja. Joissain tapauksissa  myelinisaatiohäiriö progredioituu ja enkefaliitti  voi olla hengenvaarallinen.   ne ihmisvirukset mitkä ensimmäistä kertaa liitettiin  neurotrooppisuuteen olivat  varhain jo 1960 luvulla  löydetyt   embecovirus betakoronavirus  HCoV-OC43 ja  HCoV-229E, Duvinavirus, alfakoronavirus .  Myös  aiemmasta SARS CoV virukssta maintian neurotrooppisuutta.

Abstract

Introduction/classification

 Mouse hepatitis virus (MHV) is a member of the Coronaviridae family in the order Nidovirales. Coronaviruses are classified into one of three antigenic groups, with MHV classified as a member of group 2 [1]. 

 Members of the Coronaviridae family infect a wide range of species including humans, cows, pigs, chickens, dogs, cats, bats, and mice. In addition to causing clinically relevant disease in humans ranging from mild upper respiratory infection (e.g., HCoV [human coronavirus]-OC43 and HCoV-229E responsible for a large fraction of common colds) to severe acute respiratory syndrome (SARS) [2, 3], coronavirus infections in cows, chickens, and pigs exact a significant annual economic toll on the livestock industry. MHV is a natural pathogen of mice that generally is restricted to replication within the gastrointestinal tract [4, 5]. 

However, there exist several laboratory strains of MHV that have adapted to replicate efficiently in the central nervous system (CNS) of mice and other rodents. Depending on the strain of MHV, virulence and pathology ranges from mild encephalitis with subsequent clearance of the virus and the development of demyelination to rapidly fatal encephalitis. 

Thus, the neurotropic strains of MHV have proved to be useful systems in which to study processes of virus- and immune-mediated demyelination, virus clearance and/or persistence in the CNS, and mechanisms of virus evasion from the immune system. 

Neurotropism and neuroinvasiveness have also has been described for two other members of the Coronaviridae family, HCoV-OC43 and SARS-coronavirus (CoV) (Table 4.1). © Cambridge University Press 2008 and Cambridge University Press, 2009.

CoV enkefaltiitilta suojauksessa on Interferoni tyyppi I signaloinnin säilyminen tärkeä

(Osa koronaviruksista  tiedetään neurotrooppisiksi ja sen takia  kliinisissä oireissa pitäisi huomat  aivoperäiset oireet. Lapsilla jotkut koronavirukset aiheuttavat enkefaliittia)  


https://www.ncbi.nlm.nih.gov/pubmed/17928334

J Virol. 2008 Jan;82(1):300-10. Epub 2007 Oct 10.

Type I interferons are essential in controlling neurotropic coronavirus infection irrespective of functional CD8 T cells.

Ireland DD¹, Stohlman SA, Hinton DR, Atkinson R, Bergmann CC.  Abstract

Neurotropic coronavirus infection induces expression of both beta interferon (IFN-beta) RNA and protein in the infected rodent central nervous system (CNS).
However, the relative contributions of type I IFN (IFN-I) to direct, cell-type-specific virus control or CD8 T-cell-mediated effectors in the CNS are unclear.

IFN-I receptor-deficient (IFNAR(-/-)) mice infected with a sublethal and demyelinating neurotropic virus variant and those infected with a nonpathogenic neurotropic virus variant both succumbed to infection within 9 days. Compared to wild-type (wt) mice, replication was prominently increased in all glial cell types and spread to neurons, demonstrating expanded cell tropism.

 Furthermore, increased pathogenesis was associated with significantly enhanced accumulation of neutrophils, tumor necrosis factor alpha, interleukin-6, chemokine (C-C motif) ligand 2, and IFN-gamma within the CNS.

The absence of IFN-I signaling did not impair induction or recruitment of virus-specific CD8 T cells, the primary adaptive mediators of virus clearance in wt mice. Despite similar IFN-gamma-mediated major histocompatibility complex class II upregulation on microglia in infected IFNAR(-/-) mice, class I expression was reduced compared to that on microglia in wt mice, suggesting a synergistic role of IFN-I and IFN-gamma in optimizing class I antigen presentation.

 These data demonstrate a critical direct antiviral role of IFN-I in controlling virus dissemination within the CNS, even in the presence of potent cellular immune responses.

By limiting early viral replication and tropism, IFN-I controls the balance of viral replication and immune control in favor of CD8 T-cell-mediated protective functions.

PMID:

17928334

PMCID:

PMC2224360

DOI:

10.1128/JVI.01794-07

[Indexed for MEDLINE]

Free PMC Article

( Tässä on muuten syy, miksi pitäisi kehittää koronavirusrokotteita. ne tulevat aina toistumaan maapallolla ja niissäon enkefaliittivaaransa  nuorisolle. tällä hetkellä parhaimmillaankin rokotteenkehitelyyn menee yli 90 päivää Israelin  arvion mukaan).

Miten  ihmipatogeeniset  koronavirukset   kiertävät  interferonijärjrstelmää?

Interferonijärjestelmän molekyylit : IFNAR1 ja IFNAR2 IFNAR resedptorin muodostuksessa.

 COVID-19 virus  aiheuttaa  IRF3 alalssäätymisen, IFN-beta välitteisen  suoran interferonisignaloinnin  tyrehtymisen ja IFNAR1-reseptorin hajoittumisen. mikä myöhästyttää nopean suoran immuunivasteen ja painottaa päinvastoin  myöhemmin alkavaa  vastetta, joka on  sytokiinimyrskyn tapaista ja tällöin nähdään  mm IFNgamma, TNFa ja runsaasti interleukiineja kohonneina. 

https://www.ncbi.nlm.nih.gov/gene/3454

IFNAR1   (21q22.11) 

Preferred Names

interferon alpha/beta receptor 1

Names

CRF2-1

IFN-R-1

IFN-alpha/beta receptor 1

alpha-type antiviral protein

beta-type antiviral protein

cytokine receptor class-II member 1

cytokine receptor family 2 member 1

interferon (alpha, beta and omega) receptor 1

interferon receptor 1

interferon-alpha/beta receptor alpha chain

interferon-beta receptor 1

type I interferon receptor 1

Also known as

AVP; IFRC; IFNAR; IFNBR; IFN-alpha-REC

Summary

The protein encoded by this gene is a type I membrane protein that forms one of the two chains of a receptor for interferons alpha and beta. Binding and activation of the receptor stimulates Janus protein kinases, which in turn phosphorylate several proteins, including STAT1 and STAT2. The encoded protein also functions as an antiviral factor. [provided by RefSeq, Jul 2008]

Expression

Ubiquitous expression in thyroid (RPKM 14.1), urinary bladder (RPKM 11.9) and 25 other tissues See more

Orthologs

mouse all

(peptidin rakenteesta: 1-557 aminohappoa , propeptidi.  peptidi on opteimpi ja siinä o nuseita  erityisrakenteita , runsaasti glykosylaatiota  solun ulkopuolella olevassa osassa ja fosforylaatiokohtia solunsisäpuolella olevassa osassa )

(25..114) " FN3" Fibronectin type 3 domain; One of three types of internal repeats found in the plasma protein fibronectin. Its tenth fibronectin type III repeat contains an RGD cell recognition sequence in a flexible loop between 2 strands. Approximately 2% of all animal proteins contain the FN3 repeat; including extracellular and intracellular proteins, membrane spanning cytokine receptors, growth hormone receptors, tyrosine phosphatase receptors, and adhesion molecules. FN3-like domains are also found in bacterial glycosyl hydrolases.

(126..224) "interfer-bind"

Interferon-alpha/beta receptor, fibronectin type III

Members of this family adopt a secondary structure consisting of seven beta-strands arranged in an immunoglobulin-like beta-sandwich, in a Greek-key topology. They are required for binding to interferon-alpha.

(334..430) "interfer-bind"  FN3 type

(437..457)  transmebrane domain ( kalvon läpäisevä jakso)

(491-500 ) important for interaction with   TYK2
 466Y,481Y, 495S, 535S  phosphorylation  site

https://www.ncbi.nlm.nih.gov/protein/NP_000620.2

ORIGIN      
        1 mmvvllgatt lvlvavapwv lsaaaggknl kspqkvevdi iddnfilrwn rsdesvgnvt
       61 fsfdyqktgm dnwiklsgcq nitstkcnfs slklnvyeei klriraeken tsswyevdsf
      121 tpfrkaqigp pevhleaedk aivihispgt kdsvmwaldg lsftyslviw knssgveeri
      181 eniysrhkiy klspettycl kvkaalltsw kigvyspvhc ikttvenelp ppenievsvq
      241 nqnyvlkwdy tyanmtfqvq wlhaflkrnp gnhlykwkqi pdcenvkttq cvfpqnvfqk
      301 giyllrvqas dgnntsfwse eikfdteiqa fllppvfnir slsdsfhiyi gapkqsgntp
      361 viqdypliye iifwentsna erkiiekktd vtvpnlkplt vycvkaraht mdeklnkssv
      421 fsdavcektk pgntskiwli vgicialfal pfviyaakvf lrcinyvffp slkpssside
      481 yfseqplknl llstseeqie kcfiienist iatveetnqt dedhkkyssq tsqdsgnysn
      541 edesesktse elqqdfv
//

(Alla oleva kuva on netistä kun ligandi ilmenee, reseptori dimerisoituu. )
https://www-ssrl.slac.stanford.edu/content/science/highlight/2012-04-30/how-single-receptor-discriminates-between-variety-different-ligands


...

Reseptorikompelksin toinen osapuoli:
IFNAR2  (21q22.11)
https://www.ncbi.nlm.nih.gov/gene/3455
isoform b structure:
 https://www.ncbi.nlm.nih.gov/protein/NP_000865.2

ORIGIN      
        1 mllsqnafif rslnlvlmvy islvfgisyd spdytdesct fkislrnfrs ilswelknhs
       61 ivpthytlly timskpedlk vvkncanttr sfcdltdewr stheayvtvl egfsgnttlf
      121 scshnfwlai dmsfeppefe ivgftnhinv mvkfpsivee elqfdlslvi eeqsegivkk
      181 hkpeikgnms gnftyiidkl ipntnycvsv ylehsdeqav iksplkctll ppgqesesae
      241 sakiggiitv flialvltst ivtlkwigyi clrnslpkvl rqGlakgwna Vaihrcshna
      301 lqsetpelkQ ssclsfpssW dykraslcps d

Putative domain of unknown function
 

Region (24--120)  Tissue factor
This family is found in 
metazoa, and is very similar to the fibronectin type III domain. The 
family is found in cytokine receptors, interleukin and interferon 
receptors and coagulation factor III proteins. It occurs multiple times,
 as does fn3, family pfam00041.

The region (134..231) 

Interferon-alpha/beta receptor, fibronectin type III
Members  of this family adopt a secondary structure consisting of seven 
beta-strands arranged in an immunoglobulin-like beta-sandwich, in a 
Greek-key topology. They are required for binding to interferon-alpha.

This GVQW (293..239) 
 short domain is often found nested inside other longer domains. The 
function is not known, but the domain carries a highly conserved GVQW 
motif. It is possile that this is an AluS that has expanded in Human and
 Macaque genomes. 

Miten  sinkkikloridi antioksidanttina vaikuttaa tähän järjestelmään:  https://www.ncbi.nlm.nih.gov/pubmed/19362011/

SARS virus ja APOBEC

https://www.sciencedirect.com/science/article/pii/S0042682209001834
Sars viruksen  N-proteiini ja APOBECG tekevät interaktion, muta tässä vaiheessa virus suorittaa  virioninsa pakkaamista ja  vie tätä  antiviraalista kompleksia virioniin mukaan.

TOLL reseptorit ja SARS ? Miten evaasio?

https://mbio.asm.org/content/6/3/e00638-15

Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection

Allison L. Totura, Alan Whitmore, Sudhakar Agnihothram, Alexandra Schäfer, Michael G. Katze, Mark T. Heise, Ralph S. Baric

W. Ian Lipkin, Editor

DOI: 10.1128/mBio.00638-15

SARS ja TRIM25 . Sars N-proteiini -TRIM25 SPRY-domain interaktio ja evasio

1. 1. Bowie AG,
   2. Unterholzner L

   . 2008. Viral evasion and subversion of pattern-recognition receptor signalling. Nat Rev Immunol 8:911–922. doi:10.1038/nri2436.

   CrossRefPubMedWeb of ScienceGoogle Scholar

2.  https://jvi.asm.org/content/91/8/e02143-16

Virus-Cell Interactions

The Severe Acute Respiratory Syndrome Coronavirus Nucleocapsid Inhibits Type I Interferon Production by Interfering with TRIM25-Mediated RIG-I Ubiquitination

Yong Hu, Wei Li, Ting Gao, Yan Cui, Yanwen Jin, Ping Li, Qingjun Ma, Xuan Liu, Cheng Cao

Stanley Perlman, Editor
 

SARS ja komplementti

mBio. 2018 Oct 9;9(5). pii: e01753-18. doi: 10.1128/mBio.01753-18.
https://bmcinfectdis.biomedcentral.com/articles/10.1186/1471-2334-9-51

Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis. Gralinski LE¹, Sheahan TP¹, Morrison TE², Menachery VD^1,3, Jensen K¹, Leist SR¹, Whitmore A⁴, Heise MT⁴, Baric RS⁵.Abstract

Acute respiratory distress syndrome (ARDS) is immune-driven pathologies that are observed in severe cases of severe acute respiratory syndrome coronavirus (SARS-CoV) infection. SARS-CoV emerged in 2002 to 2003 and led to a global outbreak of SARS. As with the outcome of human infection, intranasal infection of C57BL/6J mice with mouse-adapted SARS-CoV results in high-titer virus replication within the lung, induction of inflammatory cytokines and chemokines, and immune cell infiltration within the lung.

 Using this model, we investigated the role of the complement system during SARS-CoV infection.

We observed activation of the complement cascade in the lung as early as day 1 following SARS-CoV infection.

To test whether this activation contributed to protective or pathologic outcomes, we utilized mice deficient in C3 (C3^-/-), the central component of the complement system. Relative to C57BL/6J control mice, SARS-CoV-infected C3 ^-/- mice exhibited significantly less weight loss and less respiratory dysfunction despite equivalent viral loads in the lung. Significantly fewer neutrophils and inflammatory monocytes were present in the lungs of C3 ^-/- mice than in C56BL/6J controls, and subsequent studies revealed reduced lung pathology and lower cytokine and chemokine levels in both the lungs and the sera of C3 ^-/- mice than in controls.

 These studies identify the complement system as an important host mediator of SARS-CoV-induced disease and suggest that complement activation regulates a systemic proinflammatory response to SARS-CoV infection.

Furthermore, these data suggest that SARS-CoV-mediated disease is largely immune driven and that inhibiting complement signaling after SARS-CoV infection might function as an effective immune therapeutic.

IMPORTANCE The complement system is a critical part of host defense to many bacterial, viral, and fungal infections. It works alongside pattern recognition receptors to stimulate host defense systems in advance of activation of the adaptive immune response. In this study, we directly test the role of complement in SARS-CoV pathogenesis using a mouse model and show that respiratory disease is significantly reduced in the absence of complement even though viral load is unchanged. Complement-deficient mice have reduced neutrophilia in their lungs and reduced systemic inflammation, consistent with the observation that SARS-CoV pathogenesis is an immune-driven disease. These data suggest that inhibition of complement signaling might be an effective treatment option following coronavirus infection.
Copyright © 2018 Gralinski et al.

Göteborg yksi CoV+ case. Ulkomailta tullut.

Italiassa on  tautia olemassa. Viikko sitten  30 v nuorimies poika tullut RuotsiinItalian turistimatkalta ja kolmen päivän päästä tulosta alkanut oireilla ja tänään iltapäivällä on saatu  tulos  nCoV+. Häntä hoidetaan Sahlgrenskassa ja kontakteja  kartoitetaan.

Miten CoV vaikuttaa lapsiin? Hengitystietulehduksia ja enkefaliitejakin

Uudesta  SARS2 viruksesta en ole löytänyt erityistä artikkelia lapsien  tautimuodosta yleensä. Korostetaan että  lähinnä  vanhempi väki ja immuunikyvyltään heikommat ja  muita tauteja potevat olisivat  eniten  sairaita, miehet varsinkin.
 Sattumoisin  huomasin vuodelta 2016 kiinalaisen artikkelin, jossa tehtiin  katsahdusta lasten    CoV enkefaliitteja ja CoV keuhkotulehduksia  sairastumisista.  Viruksen nimeä ei tässä  mainittu tarkemmin.   Siis kyse oli  tavallisesta  kylmettymis-koronaviruksista, joilla niilläkin voi olla vakavia oireitaan.
Sairaalaan oli otettu enkefaliittiepäilynä  183 lasta ja heistä 22 :lla oli CoV-laji aiheutajana.  Akuuttia respiratorista  oireyhtymää  (ARDS)  potevia  lapsia otettiin  sairaalaan 236 ja heistä  26 lapsella oli CoV viruslajin aiheuttama tauti.  Kummassakin CoV virustauteja potevassa ryhmässä oli enemmän poikia ( 18  resp. 20).
Tehtiin  vertailu   CoV virustauteja poteneiden ryhmien kesken oireista ja löydöksistä ja verenkuvamuutoksista  ja vertailtiin myös terveeseen kontrolliryhmään (26 lasta). Iät olivat alle 16 vuotta, keskimääräinen ikä 36 kk.
Enkefaliittiryhmä toipui oireettomaksi.  Respiratorisesta ryhmästä  4:n kunto huononi ja muut  toipuivat oireettomiksi.
Artikkeli mainitsee  CoV viruksen osoittavan lapsilla neurotrooppisuutta ja se mahdollisuus  tulee ottaa  huomioon.
Periferisestä verenkuvasta katsottiin  lymfosyytit,  eosinofiilit,  neutrofiilit ja monosyytit ja niiden muuttumiset  taudin vaikutukseta.  Katsottiin myös G-CSF ja GM-CSF, interleukiinit IL-6, IL-8 ja MCP-1   koronavirusenkefaliittilapsilta.lapsilta. nimittäin vakavat koronavirukset SARS ja MERS  aiehuttavat  korkeita  intgerleukiinien seerumipitoisuuksia (IL-6, IL-8 ja MCP-1) Näistä voi jäädä  jälkitauteja.  Artikkelissa taulukoidaan  taustatiedot ja tyypilliset oireet, hoito ja  tutkimukset ( enkefaliitissa mm MRI, CT, EEG, CSF; Respiratorista tautia potevilta otettiin mm keuhkoröntgentutkimuksia.
 Artikkeli painottaa  sitä, että tulee ottaa huomioon lapsilla  koronaviruksen neurotrooppinen piirre. Vielähän ei ole rokotusta  koronavirusta vastaan.

 https://www.karger.com/Article/FullText/453066

Intervirology 2016;59:163-169

https://doi.org/10.1159/000453066

Coronavirus Infections in the Central Nervous System and Respiratory Tract Show Distinct Features in Hospitalized Children Li Y.d · Li H.b · Fan R.a · Wen B.a · Zhang J.a · Cao X.c · Wang C.a · Song Z.a · Li S.a · Li X.a · Lv X.e · Qu X.a · Huang R.b · Liu W.a Author affiliations Corresponding Author Keywords: CoronavirusRespiratory tractCentral nervous systemCytokine  Coronavirus (CoV) is an enveloped virus with a large positive-sense, single-stranded RNA genome [1,2,3] belonging to the Coronaviridae family [4].  Human pathogenic CoVs include HCoV-229E, HCoV-OC43, HCoV-HKU1, HCoV-NL63, severe acute respiratory syndrome CoV (SARS-CoV), and Middle East respiratory syndrome CoV (MERS-CoV) [5,6,7].  Human pathogenic CoVs are associated with a wide range of respiratory illnesses, including common colds, pneumonia, and bronchiolitis [7]. Additionally, several studies have described that CoVs are associated with CNS diseases such as acute disseminated encephalomyelitis and multiple sclerosis [8,9,10].  Respiratory tract infection contributes to high morbidity and mortality with a worldwide disease burden estimated at 112,900,000 disability-adjusted life years and 3.5 million deaths [11]. Furthermore, the mortality of viral encephalitis ranges from 4.6 to 29% and nearly 50% of survivors are at a high risk of developing neurological disorders [12]. ... In this study, we conducted a comprehensive analysis to investigate clinical features and cytokine profiles in hospitalized children diagnosed with either central nervous system (CNS) or respiratory tract infection of CoV. The inclusion criteria in this study for the diagnosis of clinically suspected acute encephalitic patients were modified according to the previous study as follows [25]: (1) age <16 2="" a="" altered="" and="" at="" axillary="" consciousness="" convulsion="" days:="" duration="" encephalitis-like="" fever="" following="" headache="" hospitalized="" illness="" least="" levels="" neck="" of="" or="" signs="" stiffness="" symptoms="" the="" with="" years="">24 h, and focal neurological signs. A total of 183 hospitalized children with clinically suspected acute encephalitis and 236 children with acute respiratory tract infection were enrolled from May 2014 to April 2015 at the Children's Hospital of Chenzhou (Hunan Province, China).

SARS CoV ja sen kymotrypsiinin kaltaisen proteaasin (3CLPro) estäjien kehittely

Search results

Items: 4

Select item 302174951.

Structurally- and dynamically-driven allostery of the chymotrypsin-like proteases of SARS, Dengue and Zika viruses.

Lim L, Gupta G, Roy A, Kang J, Srivastava S, Shi J, Song J.

Prog Biophys Mol Biol. 2019 May;143:52-66. doi: 10.1016/j.pbiomolbio.2018.08.009. Epub 2018 Sep 11. Review.

Coronavirus 3C-like and Flavivirus NS2B-NS3 proteases utilize the chymotrypsin fold to harbor their catalytic machineries but also contain additional domains/co-factors. Over the past decade, we aimed to decipher how the extra domains/co-factors mediate the catalytic machineries of SARS 3C-like, Dengue and Zika NS2B-NS3 proteases by characterizing their folding, structures, dynamics and inhibition with NMR, X-ray crystallography and MD simulations, and the results revealed: 1) the chymotrypsin fold of the SARS 3C-like protease can independently fold, while, by contrast, those of Dengue and Zika proteases lack the intrinsic capacity to fold without co-factors. 2) Mutations on the extra domain of SARS 3C-like protease can transform the active catalytic machinery into the inactive collapsed state by structurally-driven allostery. 3) Amazingly, even without detectable structural changes, mutations on the extra domain are sufficient to either inactivate or enhance the catalytic machinery of SARS 3C-like protease by dynamically-driven allostery. 4) Global networks of correlated motions have been identified: for SARS 3C-like protease, N214A inactivates the catalytic machinery by decoupling the network, while STI/A and STIF/A enhance by altering the patterns of the network. The global networks of Dengue and Zika proteases are coordinated by their NS2B-cofactors. 5) Natural products were identified to allosterically inhibit Zika and Dengue proteases through binding a pocket on the back of the active site. Therefore, by introducing extra domains/cofactors, nature develops diverse strategies to regulate the catalytic machinery embedded on the chymotrypsin fold through folding, structurally- and dynamically-driven allostery, all of which might be exploited to develop antiviral drugs.

Similar articles
 

Select item 256141102.

Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors.

Shimamoto Y, Hattori Y, Kobayashi K, Teruya K, Sanjoh A, Nakagawa A, Yamashita E, Akaji K.

Bioorg Med Chem. 2015 Feb 15;23(4):876-90. doi: 10.1016/j.bmc.2014.12.028. Epub 2014 Dec 20.

The design and evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL(pro)) are described. Focusing on hydrophobic interactions at the S2 site, the decahydroisoquinolin scaffold was designed by connecting the P2 site cyclohexyl group of the substrate-based inhibitor to the main-chain at the α-nitrogen atom of the P2 position via a methylene linker. Starting from a cyclohexene enantiomer obtained by salt resolution, trans-decahydroisoquinolin derivatives were synthesized. All decahydroisoquinolin inhibitors synthesized showed moderate but clear inhibitory activities for SARS 3CL(pro), which confirmed the fused ring structure of the decahydroisoquinolin functions as a novel scaffold for SARS 3CL(pro) inhibitor. X-ray crystallographic analyses of the SARS 3CL(pro) in a complex with the decahydroisoquinolin inhibitor revealed the expected interactions at the S1 and S2 sites, as well as additional interactions at the N-substituent of the inhibitor.

Similar articles
 

Select item 193624793.

New developments for the design, synthesis and biological evaluation of potent SARS-CoV 3CL(pro) inhibitors.

Regnier T, Sarma D, Hidaka K, Bacha U, Freire E, Hayashi Y, Kiso Y.

Bioorg Med Chem Lett. 2009 May 15;19(10):2722-7. doi: 10.1016/j.bmcl.2009.03.118. Epub 2009 Mar 28.

A series of trifluoromethyl, benzothiazolyl or thiazolyl ketone-containing peptidic compounds as SARS-CoV 3CL protease inhibitors were developed and their potency was evaluated by in vitro protease inhibitory assays. Three candidates had encouraging results for the development of new anti-SARS compounds

 https://www.ncbi.nlm.nih.gov/pmc/?term=19362479%5BPMID%5D&report=imagesdocsum

Free PMC Article

Similar articles

Select item 162506324.

Design and synthesis of peptidomimetic severe acute respiratory syndrome chymotrypsin-like protease inhibitors.

Ghosh AK, Xi K, Ratia K, Santarsiero BD, Fu W, Harcourt BH, Rota PA, Baker SC, Johnson ME, Mesecar AD.

J Med Chem. 2005 Nov 3;48(22):6767-71.

Design, synthesis, and biological evaluation of peptidomimetic severe acute respiratory syndrome chymotrypsin-like protease (SARS-3CLpro) inhibitors for severe acute respiratory syndrome coronavirus (SARS-CoV) are described. These inhibitors exhibited antiviral activity against SARS-CoV in infected cells in the micromolar range. An X-ray crystal structure of our lead inhibitor (4) bound to SARS-3CLpro provided important drug-design templates for the design of small-molecule inhibitors.

Similar articles

(jatkuu) SARS2 ja AGE2 tutkimuksen tuoreita referenssejä

References

1. 1.↵
   Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W, China Novel Coronavirus I, Research T. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020. doi: 10.1056/NEJMoa2001017. PubMed PMID: 31978945.

   CrossRefPubMedGoogle Scholar
2. 2.↵
   Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020. Epub 2020/02/06. doi: 10.1038/s41586-020-2012-7. PubMed PMID: 32015507.

   CrossRefPubMedGoogle Scholar
3. 3.↵
   Gallagher TM, Buchmeier MJ. Coronavirus spike proteins in viral entry and pathogenesis. Virology. 2001;279(2):371–4. doi: 10.1006/viro.2000.0757. PubMed PMID: 11162792.

   CrossRefPubMedWeb of ScienceGoogle Scholar
4. 4.↵
   Simmons G, Zmora P, Gierer S, Heurich A, Pohlmann S. Proteolytic activation of the SARS-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research. Antiviral Res. 2013;100(3):605–14. doi: 10.1016/j.antiviral.2013.09.028. PubMed PMID: 24121034; PMCID: PMC3889862.

   CrossRefPubMedWeb of ScienceGoogle Scholar
5. 5.↵
   Belouzard S, Chu VC, Whittaker GR. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc Natl Acad Sci U S A. 2009;106(14):5871–6. doi: 10.1073/pnas.0809524106. PubMed PMID: 19321428; PMCID: PMC2660061.

   Abstract/FREE Full TextGoogle Scholar
6. 6.↵
   Li F, Li W, Farzan M, Harrison SC. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science. 2005;309(5742):1864–8. doi: 10.1126/science.1116480. PubMed PMID: 16166518.

   Abstract/FREE Full TextGoogle Scholar
7. 7.↵
   Millet JK, Whittaker GR. Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis. Virus Res. 2015;202:120–34. doi: 10.1016/j.virusres.2014.11.021. PubMed PMID: 25445340; PMCID: PMC4465284.

   CrossRefPubMedGoogle Scholar
8. 8.↵
   Simmons G, Gosalia DN, Rennekamp AJ, Reeves JD, Diamond SL, Bates P. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci U S A. 2005;102(33):11876–81. doi: 10.1073/pnas.0505577102. PubMed PMID: 16081529; PMCID: PMC1188015.

   Abstract/FREE Full TextGoogle Scholar
9. 9.↵
   Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450–4. doi: 10.1038/nature02145. PubMed PMID: 14647384.

   CrossRefPubMedGoogle Scholar
10. 10.
    Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875–9. doi: 10.1038/nm1267. PubMed PMID: 16007097.

    CrossRefPubMedWeb of ScienceGoogle Scholar
11. 11.↵
    Hoffmann M, Kleine-Weber H, Krüger N, Müller M, Drosten C, Pöhlmann S. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. bioRxiv. 2020.

    Google Scholar   https://www.biorxiv.org/content/10.1101/2020.01.31.929042v1.abstract
12. 12.↵
    Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh C-L, Abiona O, Graham BS, McLellan JS. Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation. bioRxiv. 2020.

    Google Scholar
13. 13.↵
    Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000;87(5):E1–9. doi: 10.1161/01.res.87.5.e1. PubMed PMID: 10969042.

    CrossRefPubMedWeb of ScienceGoogle Scholar
14. 14.
    Zhang H, Kang Z, Gong H, Xu D, Wang J, Li Z, Cui X, Xiao J, Meng T, Zhou W, Liu J, Xu H. The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes. bioRxiv. 2020.

    Google Scholar
15. 15.↵
    Zhao Y, Zhao Z, Wang Y, Zhou Y, Ma Y, Zuo W. Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov. bioRxiv. 2020.

    Google Scholar
16. 16.↵
    Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, Oliveira-dos-Santos AJ, da Costa J, Zhang L, Pei Y, Scholey J, Ferrario CM, Manoukian AS, Chappell MC, Backx PH, Yagil Y, Penninger JM. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002;417(6891):822–8. doi: 10.1038/nature00786. PubMed PMID: 12075344.

    CrossRefPubMedWeb of ScienceGoogle Scholar
17. 17.
    Raizada MK, Ferreira AJ. ACE2: a new target for cardiovascular disease therapeutics. J Cardiovasc Pharmacol. 2007;50(2):112–9. doi: 10.1097/FJC.0b013e3180986219. PubMed PMID: 17703127.

    CrossRefPubMedWeb of ScienceGoogle Scholar
18. 18.↵
    Zisman LS, Keller RS, Weaver B, Lin Q, Speth R, Bristow MR, Canver CC. Increased angiotensin-(1-7)-forming activity in failing human heart ventricles: evidence for upregulation of the angiotensin-converting enzyme Homologue ACE2. Circulation. 2003;108(14):1707–12. doi: 10.1161/01.CIR.0000094734.67990.99. PubMed PMID: 14504186.

    Abstract/FREE Full TextGoogle Scholar
19. 19.↵
    Zhang H, Wada J, Hida K, Tsuchiyama Y, Hiragushi K, Shikata K, Wang H, Lin S, Kanwar YS, Makino H. Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys. J Biol Chem. 2001;276(20):17132–9. doi: 10.1074/jbc.M006723200. PubMed PMID: 11278314.

    Abstract/FREE Full TextGoogle Scholar
20. 20.↵
    Hamming I, Cooper ME, Haagmans BL, Hooper NM, Korstanje R, Osterhaus AD, Timens W, Turner AJ, Navis G, van Goor H. The emerging role of ACE2 in physiology and disease. J Pathol. 2007;212(1):1–11. doi: 10.1002/path.2162. PubMed PMID: 17464936.

    CrossRefPubMedWeb of ScienceGoogle Scholar
21. 21.↵
    Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T, Ryan D, Fisher M, Williams D, Dales NA, Patane MA, Pantoliano MW. ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J Biol Chem. 2004;279(17):17996–8007. doi: 10.1074/jbc.M311191200. PubMed PMID: 14754895.

    Abstract/FREE Full TextGoogle Scholar
22. 22.↵
    Song W, Gui M, Wang X, Xiang Y. Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2. PLoS Pathog. 2018;14(8):e1007236. doi: 10.1371/journal.ppat.1007236. PubMed PMID: 30102747; PMCID: PMC6107290.

    CrossRefPubMedGoogle Scholar
23. 23.↵
    Kirchdoerfer RN, Wang N, Pallesen J, Wrapp D, Turner HL, Cottrell CA, Corbett KS, Graham BS, McLellan JS, Ward AB. Receptor binding and proteolysis do not induce large conformational changes in the SARS-CoV spike. bioRxiv. 2018.

    Google Scholar
24. 24.↵
    Kowalczuk S, Broer A, Tietze N, Vanslambrouck JM, Rasko JE, Broer S. A protein complex in the brush-border membrane explains a Hartnup disorder allele. FASEB J. 2008;22(8):2880–7. doi: 10.1096/fj.08-107300. PubMed PMID: 18424768.

    CrossRefPubMedWeb of ScienceGoogle Scholar
25. 25.↵
    Seow HF, Broer S, Broer A, Bailey CG, Potter SJ, Cavanaugh JA, Rasko JE. Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. Nat Genet. 2004;36(9):1003–7. doi: 10.1038/ng1406. PubMed PMID: 15286788.

    CrossRefPubMedWeb of ScienceGoogle Scholar
26. 26.↵
    Kleta R, Romeo E, Ristic Z, Ohura T, Stuart C, Arcos-Burgos M, Dave MH, Wagner CA, Camargo SR, Inoue S, Matsuura N, Helip-Wooley A, Bockenhauer D, Warth R, Bernardini I, Visser G, Eggermann T, Lee P, Chairoungdua A, Jutabha P, Babu E, Nilwarangkoon S, Anzai N, Kanai Y, Verrey F, Gahl WA, Koizumi A. Mutations in SLC6A19, encoding B⁰AT1, cause Hartnup disorder. Nat Genet. 2004;36(9):999–1002. doi: 10.1038/ng1405. PubMed PMID: 15286787.

    CrossRefPubMedWeb of ScienceGoogle Scholar
27. 27.↵
    Broer A, Klingel K, Kowalczuk S, Rasko JE, Cavanaugh J, Broer S. Molecular cloning of mouse amino acid transport system B0, a neutral amino acid transporter related to Hartnup disorder. J Biol Chem. 2004;279(23):24467–76. doi: 10.1074/jbc.M400904200. PubMed PMID: 15044460.

    Abstract/FREE Full TextGoogle Scholar
28. 28.↵
    Penmatsa A, Wang KH, Gouaux E. X-ray structure of dopamine transporter elucidates antidepressant mechanism. Nature. 2013;503(7474):85–90. doi: 10.1038/nature12533. PubMed PMID: 24037379; PMCID: PMC3904663.

    CrossRefPubMedGoogle Scholar
29. 29.↵
    Coleman JA, Green EM, Gouaux E. X-ray structures and mechanism of the human serotonin transporter. Nature. 2016;532(7599):334–9. doi: 10.1038/nature17629. PubMed PMID: 27049939; PMCID: PMC4898786.

    CrossRefPubMedGoogle Scholar
30. 30.↵
    Yan R, Zhao X, Lei J, Zhou Q. Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex. Nature. 2019. doi: 10.1038/s41586-019-1011-z. PubMed PMID: 30867591.

    CrossRefPubMedGoogle Scholar
31. 31.↵
    Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, Seidah NG, Nichol ST. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69. doi: 10.1186/1743-422X-2-69. PubMed PMID: 16115318; PMCID: PMC1232869.

    CrossRefPubMedGoogle Scholar
32. 32.↵
    Lee Y, Wiriyasermkul P, Jin C, Quan L, Ohgaki R, Okuda S, Kusakizako T, Nishizawa T, Oda K, Ishitani R, Yokoyama T, Nakane T, Shirouzu M, Endou H, Nagamori S, Kanai Y, Nureki O. Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc. Nat Struct Mol Biol. 2019;26(6):510–7. doi: 10.1038/s41594-019-0237-7. PubMed PMID: 31160781.

    CrossRefPubMedGoogle Scholar
33. 33.↵
    Shulla A, Heald-Sargent T, Subramanya G, Zhao J, Perlman S, Gallagher T. A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry. J Virol. 2011;85(2):873–82. doi: 10.1128/JVI.02062-10. PubMed PMID: 21068237; PMCID: PMC3020023.

    Abstract/FREE Full TextGoogle Scholar
34. 34.↵
    Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pohlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol. 2014;88(2):1293–307. doi: 10.1128/JVI.02202-13. PubMed PMID: 24227843; PMCID: PMC3911672.

    Abstract/FREE Full TextGoogle Scholar
     https://jvi.asm.org/content/88/2/1293?ijkey=c54b09b4431c63e8e642702704460d7d6deedcda&keytype2=tf_ipsecsha