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covid19_science

COVID-19 science

Introduction

  • Covid-19 is a viral pandemic caused by the pathogen SARS-CoV-2 which belongs to the coronaviridae / corona viruses (CoV)
  • It originated in Wuhan in China with 1st cases recognized in Dec 2019
  • it is thought to have evolved from a coronavirus in bats
  • it shares 96.2% identity at the nucleotide level with the coronavirus RaTG13, which was detected in horseshoe bats (Rhinolophus spp) in Yunnan province in 2013 1)

The SARS-CoV-2 virus

  • it is a spherical enveloped RNA virus of around 0.1 micron in diameter and being enveloped, this means it does not require host cell lysis to spread but it could replicate within the host cell and be secreted through usual cell processes and thus this could allow infectivity in the pre-syptomatic phase.2)
  • the virus surface has spike proteins which allow the virus to bind to ACE2 proteins on host cells and activate a cellular mechanism to enter the cell where it can replicate
  • as it is a virus it cannot replicate without being inside a host cell
  • CoVs employ a multi-subunit replication/transcription machinery.
    • A set of non-structural proteins (nsp) produced as cleavage products of the ORF1a and ORF1ab viral polyproteins assemble to facilitate viral replication and transcription.
    • A key component, the RNA-dependent RNA polymerase (RdRp, also known as nsp12), catalyzes the synthesis of viral RNA and thus plays a central role in the replication and transcription cycle of COVID-19 virus, possibly with the assistance of nsp7 and nsp8 as co-factors3)

Transmission

  • thought to be primarily via droplet spread hence close proximity or direct contact is important
  • lesser roles for aerosol spread (especially if aerosol generating procedures (AGPs) or poorly ventilated rooms) and fomite contact “indirect” spread
  • possible roles for faecal-oral spread and sexual transmission
  • a Japanese study estimated that the probability of direct transmission infection is almost 20 times higher indoors compared to outdoors
  • catching the virus whilst outdoors appears to be rare and requires close contact (although risk is probably higher if the infected person is exercising), in a Chinese study, only 1 in 314 outbreaks could be traced to outdoor contact
  • wearing masks dramatically reduce the numbers of virus particles in the air
  • see also:

Viral stability outside of host cells

Host cell mechanisms

  • the virus binds to the ACE2 protein on host cells but requires these cells to also express TMPRSS2 (or perhaps an alternate protein)
  • SARS-CoV-2 has a 10-20-fold higher affinity of ACE2 compared to SARS virus5)
  • binding of the coronavirus S (spike) protein to ACE2 triggers a conformational change in the S protein of the coronavirus, allowing for proteolytic digestion by host cell proteases (TMPRSS2)
  • the intracellular enzyme furin plays an important role in this viral life cycle of SARS-CoV-2 and this is distinctly different than SARS-CoV.6)
  • The furin cleavage site in the SARS-CoV-2S protein may provide a priming mechanism, and Alveolar type II cells were strongly positive for furin while transient secretory cells had an intermediate level of expression
  • After cellular detection of viral entry into a host cell, interferon (IFN) induction of interferon-stimulated genes (ISGs) is essential for host antiviral defense. IFNα also drives up-regulation of ACE2. SARS-CoV-2 could exploit species-specific interferon-driven up-regulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection 7)

Host cell ACE2 expression

which cells express both ACE2 and TMPRSS2

up-regulation on ACE2 expression

  • many believe that those who have higher expression of ACE2 or perhaps certain polymorphisms of ACE2 on their cells are at higher risk of severe illness and death although recent studies have failed to demonstrate a significant association with ACE inhibitors or angiotensin II receptor blockers (ARBs) with infection rates or severity of Covid-1911)12)
  • ACE2 receptor is not expressed on fetal or placental cells, and is minimally expression in children
  • factors which are known to increase ACE2 expression on cells include:
    • age
    • diabetes
      • both of which reduce the effect of Ang II on the AT1R which acts to reduce ACE2 expression via lysosomal internalization of ACE2
      • ARBs increase ACE2 receptor numbers by 3-5x
    • perhaps with genetic polymorphisms of ACE2
    • human influenza infection induces broader expression of ACE2 in upper airway epithelial cells
    • Covid-19 activated interferon alpha 13)

transmission to other species including pets

  • it has been shown that the virus can be transmitted to pets which may then become vectors and reservoirs for the virus, especially ferrets and young cats, while dogs have only low susceptibility, and pigs, chickens, and ducks are not susceptible to SARS-CoV-2 14)
  • ferrets and cats have only two amino acid differences in the SARS-CoV-2 spike-contacting regions of ACE2
  • ACE2 is mainly expressed in type II pneumocytes and serous epithelial cells of tracheo-bronchial submucosal glands in ferrets but seems to only be replicated in upper airways and not affect the lungs of ferrets

Prevention

Pathogenesis of illness

asymptomatic nasal carriage

  • the virus enters the nasal goblet and ciliated cells and is secreted along with nasal secretions which can then be spread to others primarily by droplet transmission
  • the high rates of transmission from asymptomatic infected persons makes control much more difficult and requires testing of all people especially in high risk environments such as aged care facilities 15)

mild URTI/LRTI illness +/- diarrhoea

  • infection of nasal cells may result in rhinorrhoea and spread down bronchi to the lung alveolar cells
  • this may result in cough, fever and SOB
  • even in this mild illness stage a ground glass radiologic appearance of the lungs is often evident suggesting the presence of alveolar fluid
  • some will develop silent hypoxia with mild symptoms and this is most likely due to the development of a V/Q shunt whereby pulmonary blood is still provided to alveolar regions with poor oxygen diffusion capacity
  • viral particles from the nose will also be ingested and presumably will be taken up by upper oesophageal cells as well as ileal and colonic enterocytes
    • this may cause diarrhoea (usually mild), nausea and abdominal pains in some patients
    • this may also be a mechanism for fecal-oral transmission

severe disease and CRS

  • up to 20% develop severe disease, and 5% become criticall ill most notably with severe pneumonitis / ARDS-like syndrome
  • this is thought to occur due to the development of cytokine release syndrome (CRS) and secondary hemophagocytic lymphohistiocytosis (sHLH)
  • The efficacy of IL-6–IL-6R antagonists for the treatment of CRS as well as sHLH underscores the central role of IL-6 signaling in the pathophysiology of cytokine-driven hyperinflammatory syndromes
  • ARDS results in severe hypoxia due to damage of the alveolar epithelial and endothelial capillary barriers, leading to fluid accumulation, alveolar collapse and reduced gas exchange
    • recovery partly relies upon fluid reabsorption and surfactant production which involve metabolic processes performed by the alveolar epithelial cells

cytokine release syndrome (CRS)

  • CRS was found to be the major cause of morbidity in patients infected with SARS virus and MERS
  • SARS-CoV efficiently infects primary human monocytes and dendritic cells, whereas MERS-CoV infects monocytes and T cells via dipeptidyl peptidase 4 (DPP4)
  • it is thought SARS-CoV-2 may function similarly to SARS-CoV in this regard
  • betacoronavirus infection of monocytes, macrophages, and dendritic cells results in16):
    • dendritic cell dysfunction is thought to lead to defective activation of T cells and resultant T cell apoptosis and exhaustion and lymphopenia.
    • their activation and secretion of IL-6 and other inflammatory cytokines
      • elevated serum IL-6 increases C reactive protein (CRP) and correlates with respiratory failure, ARDS, and adverse clinical outcomes
      • IL-6 can signal through three main pathways:
        • classic cis signaling:
          • IL-6 binds to membrane-bound IL-6 receptor (mIL-6R) in a complex with gp130;
          • downstream signal transduction is mediated by JAKs (Janus kinases) and STAT3 (signal transducer and activator of transcription 3).
          • Membrane-bound gp130 is ubiquitously expressed, whereas mIL-6R expression is restricted largely to immune cells.
          • Activation of cis signaling results in pleiotropic effects on the acquired immune system (B and T cells) as well as the innate immune system (neutrophils, macrophages, and natural killer (NK) cells), which can contribute to CRS
        • trans signaling:
          • high circulating concentrations of IL-6 bind to the soluble form of IL-6R (sIL-6R), forming a complex with a gp130 dimer on potentially all cell surfaces.
          • The resultant IL-6–sIL-6R–JAK-STAT3 signaling is then activated in cells that do not express mIL-6R, such as endothelial cells.
          • This results in a systemic “cytokine storm” involving secretion of vascular endothelial growth factor (VEGF), monocyte chemoattractant protein–1 (MCP-1), IL-8, and additional IL-6, as well as reduced E-cadherin expression on endothelial cells.
          • VEGF and reduced E-cadherin expression contribute to vascular permeability and leakage, which participate in the pathophysiology of hypotension and pulmonary dysfunction in ARDS.
        • trans presentation
          • IL-6 binding to mIL-6R expressed on an immune cell, which forms a complex with gp130 on T helper 17 (TH17) cells, leading to downstream T cell signaling that may be involved in ARDS
          • this can be blocked by IL‐6R inhibitors but not by IL‐6 inhibitors which can only suppress only cis and trans signaling

secondary hemophagocytic lymphohistiocytosis (sHLH)

  • sHLH is a hyperinflammatory syndrome (aka macrophage activation syndrome) characterized by:
    • CRS with elevated serum cytokines
    • cytopenias (low blood cell counts)
    • high concentrations of ferritin thought to be due to activation of CD163-expressing macrophages which have a role in reticuloendothelial iron signaling
    • multiorgan failure
covid19_science.txt · Last modified: 2020/05/21 18:24 by gary1