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Reasons to Consider SARS-Cov-2 Breaks Cell Adhesion to Enable Early Secondary Bacterial Infections
This is an attempt to show the distinct mechanism of how the virus triggers bacteria invasion.
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This is an attempt to show the distinct mechanism of how the virus triggers bacteria invasion.
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1. The hypothesis
After I learned about the data on secondary bacterial infections, I was wondering about what's the mechanism that enables it.
Metagenomics and endotoxin data did showed bacteria, but doctors and scientists around the world generally didn't detect bacteria.
After I learned about the data on secondary bacterial infections, I was wondering about what's the mechanism that enables it.
Metagenomics and endotoxin data did showed bacteria, but doctors and scientists around the world generally didn't detect bacteria.
Which means the patterns may be unique.
Perhaps the uniqueness of the virus is the way in which it triggers bacteria invasion?
Around the same time, doctors were reporting peculiar characteristics of the disease: blood rather than respiratory disease, non-ARDS, silent hypoxia.
Perhaps the uniqueness of the virus is the way in which it triggers bacteria invasion?
Around the same time, doctors were reporting peculiar characteristics of the disease: blood rather than respiratory disease, non-ARDS, silent hypoxia.
At May, I came up with a hypothesis that the virus breaks the adhesion (cell-cell and cell-ECM) but doesn't kill the cells:
https://twitter.com/joshux321/status/1264387117200756736
This could explain the bacterial invasion, also the non-ARDS (less inflammation), and blood properties (allow paracellular spread)
https://twitter.com/joshux321/status/1264387117200756736
This could explain the bacterial invasion, also the non-ARDS (less inflammation), and blood properties (allow paracellular spread)
The model was derived from Laurent Schwartz's cancer model, which prolonged disruption of boundaries induces cancer.
I extrapolated it to the short-term and includes the microbiome.
The virus breaks the epithelial (and endothelial) boundary, letting the bacteria in.
I extrapolated it to the short-term and includes the microbiome.
The virus breaks the epithelial (and endothelial) boundary, letting the bacteria in.
Schwartz happened to mention disrupting integrin can disrupt boundaries.
SARS-CoV-2 has RGD motif, which binds to integrin:
https://twitter.com/ViralZone/status/1234070453922205698?s=19
This cannot be directly translated to in vivo, hence at that time it was just speculation.
But do we see some new evidence now?
SARS-CoV-2 has RGD motif, which binds to integrin:
https://twitter.com/ViralZone/status/1234070453922205698?s=19
This cannot be directly translated to in vivo, hence at that time it was just speculation.
But do we see some new evidence now?
2. Evidence for breaking tight junction.
Transepithelial electrical resistance (TEER) recorded more loss of tight junction integrity on HAE cells infected by Cov2 compared to another coronavirus: https://twitter.com/joshux321/status/1303663785131913216?s=20
Transepithelial electrical resistance (TEER) recorded more loss of tight junction integrity on HAE cells infected by Cov2 compared to another coronavirus: https://twitter.com/joshux321/status/1303663785131913216?s=20
Subsequently the virus was detected in the basolateral space.
https://twitter.com/joshux321/status/1303664053118623746?s=20
This shows the possibility of paracellular spread of the virus.
Translating to in vivo, the bacteria may also get in paracellularly.
https://twitter.com/joshux321/status/1303664053118623746?s=20
This shows the possibility of paracellular spread of the virus.
Translating to in vivo, the bacteria may also get in paracellularly.
Some information on TEER: https://twitter.com/joshux321/status/1304274027956129794?s=20
3. Interlude: what else to look for?
Disorganization.
In Schwartz's model, cancer cells are disorganized. There's no coherent layer of cells, allowing malignant cells spread.
https://twitter.com/joshux321/status/1264391878650126336?s=20
Covid: if cells comprising the barrier are disorganized, bacteria can get in.
Disorganization.
In Schwartz's model, cancer cells are disorganized. There's no coherent layer of cells, allowing malignant cells spread.
https://twitter.com/joshux321/status/1264391878650126336?s=20
Covid: if cells comprising the barrier are disorganized, bacteria can get in.
Keywords for disorganization:
(Loss of)Cell polarity
Epithelial-to-Mesenchymal transition (EMT)
Endothelial-to-Mesenchymal transition (EndMT)
Atypia
Metaplasia
Syncytium/Syncytia
(Loss of)Cell polarity
Epithelial-to-Mesenchymal transition (EMT)
Endothelial-to-Mesenchymal transition (EndMT)
Atypia
Metaplasia
Syncytium/Syncytia
Also most straightforwardly:
Breaking of cell-cell adhesion (intercellular junction, tight junction)
And/or breaking of cell-ECM adhesion.
Breaking of cell-cell adhesion (intercellular junction, tight junction)
And/or breaking of cell-ECM adhesion.
4. Disorganization of the epithelial barrier
The distinct pattern of this disease that's gained attention is the blood or vascular pathology.
However, the histopathology has also shown unique features of epithelial change.
The distinct pattern of this disease that's gained attention is the blood or vascular pathology.
However, the histopathology has also shown unique features of epithelial change.
4.1 Reactive atypia (benign atypical cells)
"Detailed analysis of histological features" showed the patterns were atypical pneumocytes or "reactive atypia"
Paper:
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30434-5/fulltext
Comments: https://twitter.com/joshux321/status/1304038197249204224?s=20
"Detailed analysis of histological features" showed the patterns were atypical pneumocytes or "reactive atypia"
Paper:
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30434-5/fulltext
Comments: https://twitter.com/joshux321/status/1304038197249204224?s=20
The study showed distinct lesion patterns specific to SARS-CoV-2 induced tissue damage (compared to usual DAD regardless of infectious agent):
common: "type 2 pneumocyte hyperplasia with atypia"
some: "intra-alveolar scattered multinucleated giant cells"
common: "type 2 pneumocyte hyperplasia with atypia"
some: "intra-alveolar scattered multinucleated giant cells"
4.2 Abnormal Cellular Syncytia
Another study showed distinct features of epithelial changes:
"a large number of
dysmorphic pneumocytes, often forming large syncytial elements" with viral replications mostly in lungs epithelial and endothelial cells. https://www.medrxiv.org/content/10.1101/2020.06.22.20136358v1
Another study showed distinct features of epithelial changes:
"a large number of
dysmorphic pneumocytes, often forming large syncytial elements" with viral replications mostly in lungs epithelial and endothelial cells. https://www.medrxiv.org/content/10.1101/2020.06.22.20136358v1
Even though COVID-19 patients showed "relatively more modest inflammation", it uniquely presents "anomalous epithelial cells".
They "very often showed features of syncytia, characterized by several nuclei with an ample cytoplasm surrounded by a single plasma membrane"
They "very often showed features of syncytia, characterized by several nuclei with an ample cytoplasm surrounded by a single plasma membrane"
The discussion of syncytia in Covid is often about whether the virus can infect neighboring cells, bypassing the receptor binding (which may be a legitimate concern).
However, the side effect of syncytia forming would be breaking the barrier, letting microbes invade.
However, the side effect of syncytia forming would be breaking the barrier, letting microbes invade.
4.3 Collection of Studies on Syncytia
"multinucleation and grouping"
"Multinucleated syncytial cells with atypical enlarged pneumocytes"
"multinucleated giant cells" https://twitter.com/zzz_as_zzz/status/1277656761273548802
"multinucleation and grouping"
"Multinucleated syncytial cells with atypical enlarged pneumocytes"
"multinucleated giant cells" https://twitter.com/zzz_as_zzz/status/1277656761273548802
4.4 Apparent Syncytia may be Independent Cell Clusters
One study used 3D imaging technique and found the seemingly multinucleated giant cells are in fact clusters of independent cells. https://twitter.com/joshux321/status/1304040314202501120?s=20
One study used 3D imaging technique and found the seemingly multinucleated giant cells are in fact clusters of independent cells. https://twitter.com/joshux321/status/1304040314202501120?s=20
Whether it is syncytia or cluster of cells, it all points to the cell losing polarity (shape), breaking of original adhesion, and shows a sign of disorganization.
EMT (epithelial-to-mesenchymal transition) is a general term for the process of cell losing polarity and adhesion.
EMT (epithelial-to-mesenchymal transition) is a general term for the process of cell losing polarity and adhesion.
Speaking of EMT, a study showed direct EMT effect induced by the virus.
Even though the study is on vitro cancer cells, it is an additional interesting data point. https://twitter.com/joshux321/status/1281061499662811137?s=20
Even though the study is on vitro cancer cells, it is an additional interesting data point. https://twitter.com/joshux321/status/1281061499662811137?s=20
5. Disorganization of Endothelium
Study shows Covid endothelial cells lose cell-cell and cell-ECM adhesion, seemingly points to EndMT: https://twitter.com/joshux321/status/1284063825445048321?s=20
Study shows Covid endothelial cells lose cell-cell and cell-ECM adhesion, seemingly points to EndMT: https://twitter.com/joshux321/status/1284063825445048321?s=20
It also demonstrates enhanced angiogenesis:
"In lungs from Covid-19, the amount of new vessel growth — predominantly through a mechanism of intussusceptive angiogenesis — was 2.7 times as high as that in the lungs from patients with influenza"
EndMT relates to angiogenesis.
"In lungs from Covid-19, the amount of new vessel growth — predominantly through a mechanism of intussusceptive angiogenesis — was 2.7 times as high as that in the lungs from patients with influenza"
EndMT relates to angiogenesis.
This author echos the view of EndMT: https://twitter.com/Romy_Sohal/status/1299473109808902144?s=20
"massive liquefactive degeneration of endothelial cells, and their detachment from the vascular wall"
One IC patient: "Abnormal vessel structure. Multiple medium-size vessels appeared stenotic with abnormal wall structure..and endothelial cell detachment" https://twitter.com/joshux321/status/1310509462394777601?s=20
One IC patient: "Abnormal vessel structure. Multiple medium-size vessels appeared stenotic with abnormal wall structure..and endothelial cell detachment" https://twitter.com/joshux321/status/1310509462394777601?s=20
Interestingly, bronchial cartilage presents "atypical chondrocytes, apparently multi-nucleated"
Does SARS-CoV-2 also infect chondrocytes, or it's the consequences of the spike protein interacting with adhesion molecules?
Does SARS-CoV-2 also infect chondrocytes, or it's the consequences of the spike protein interacting with adhesion molecules?
Circulating endothelial cells correlates with severity of Covid-19: https://twitter.com/joshux321/status/1310932533685547011?s=20
6. Non-cytolytic SARS-CoV-2
As shown in the autopsy reports, the infected epithelial cells were dysmorphic but preserved. There was less inflammation than regular ARDS.
The virus seems largely non-cytolytic, i.e. doesn't kill cells.
As shown in the autopsy reports, the infected epithelial cells were dysmorphic but preserved. There was less inflammation than regular ARDS.
The virus seems largely non-cytolytic, i.e. doesn't kill cells.
"Krummel says. 'Flu is really cytopathic; if you add it to human cells in a petri dish, the cells burst within 18 hours.' But when UCSF researchers subjected human cells to SARS-CoV-2, many of the infected cells never perished. " https://www.ucsf.edu/magazine/covid-body
7. RGD motif, integrin, and examples of microbial translocation in other diseases
Revisiting Dr. Schwartz's model:
In healthy tissue, cells are "tied through a system of anchors" that maintain the coherent layers.
If the anchors are disrupted, the cells pile up and climb on each other. The tissue organization is compromised.
[ch1 p4] https://twitter.com/joshux321/status/1264388223783952384?s=20
In healthy tissue, cells are "tied through a system of anchors" that maintain the coherent layers.
If the anchors are disrupted, the cells pile up and climb on each other. The tissue organization is compromised.
[ch1 p4] https://twitter.com/joshux321/status/1264388223783952384?s=20
(Is this the reason of the independent cell clusters that resemble syncytia in Covid?)
Integrins are such anchors.
Integrin does not form the tight junction itself, but is a key mediator of cell polarity, thus influences the intercell junction formation. https://twitter.com/joshux321/status/1304615264533622785?s=20
Integrins are such anchors.
Integrin does not form the tight junction itself, but is a key mediator of cell polarity, thus influences the intercell junction formation. https://twitter.com/joshux321/status/1304615264533622785?s=20
As mentioned SARS-CoV-2 spike protein includes a RGD motif.
RGD is a tripeptide (Arg-Gly-Asp), that has binding affinity on many integrins.
It is an amino acid sequence included in some ECM proteins: fibronectin, laminin...
This allows cells to bind and interact with the ECM.
RGD is a tripeptide (Arg-Gly-Asp), that has binding affinity on many integrins.
It is an amino acid sequence included in some ECM proteins: fibronectin, laminin...
This allows cells to bind and interact with the ECM.
However, some pathogens use this RGD motif as an adhesin to attach to cells or as a ligand for cell entry.
Each disease caused by them would be unique, but one common effect would be disruption of the anchoring system: integrins, causing cells to lose polarity.
Each disease caused by them would be unique, but one common effect would be disruption of the anchoring system: integrins, causing cells to lose polarity.
7.1 HIV
Study showed exposure of epithelial cells to cell-free HIV virions, tat and gp120 proteins induce EMT and reduce tight junction expression.
Which would cause "paracellular spread of viral, bacterial, fungal, and other pathogens." https://twitter.com/joshux321/status/1279407635796639744?s=20
Study showed exposure of epithelial cells to cell-free HIV virions, tat and gp120 proteins induce EMT and reduce tight junction expression.
Which would cause "paracellular spread of viral, bacterial, fungal, and other pathogens." https://twitter.com/joshux321/status/1279407635796639744?s=20
In particuar, for control, "inactive mutant tat lacking its basic arginine-rich domain and RGD motif",
"did not reduce E-cadherin and did not activate vimentin and N-cadherin expression"
"did not reduce E-cadherin and did not activate vimentin and N-cadherin expression"
Note, the gp120 and tat proteins themselves are sufficient to causes these transformations in the in vitro experiments.
(Gp120 is a non-RGD integrin binding protein.
Tat utilize RGD to bind integrins.)
(Gp120 is a non-RGD integrin binding protein.
Tat utilize RGD to bind integrins.)
Microbial translocation in HIV: https://twitter.com/joshux321/status/1290828709356662784?s=19
SIV infection induce NETosis, which this author hypothized to caused by translocated microbes: https://twitter.com/joshux321/status/1290823993084133376?s=20
7.3 EBV
EBV BMRF-2 protein binds to integrin of epithelial cells.
https://pubmed.ncbi.nlm.nih.gov/12592401/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268893/
EBV BMRF-2 protein binds to integrin of epithelial cells.
https://pubmed.ncbi.nlm.nih.gov/12592401/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268893/
Is this the reason EBV triggers Lemierre syndrome? (through modifying the physical environment)
https://twitter.com/joshux321/status/1298981263395524609?s=20
Or there's other mechanism affects immune cell that only enables anaerobic bacteria?
https://twitter.com/joshux321/status/1298981263395524609?s=20
Or there's other mechanism affects immune cell that only enables anaerobic bacteria?
7.4 Some pathogens that bind to adhesion molecules and the side effect of losing intercellular junction
Integrin binding Yersinia: https://twitter.com/joshux321/status/1305498668951203841?s=20
Cause Diarrhea: https://twitter.com/joshux321/status/1306263748009578496?s=20
N meningitidis protein Opc use a sandwich mechanism to bind to integrins. (First bind to ECM molecules that contains RGD, such as fibronectin)
N meningitidis can cause meningitis by disrupting the blood brain barrier and subsequent paracellular entry: https://twitter.com/joshux321/status/1306515977824157696?s=20
N meningitidis can cause meningitis by disrupting the blood brain barrier and subsequent paracellular entry: https://twitter.com/joshux321/status/1306515977824157696?s=20
The 'sandwich' mechanism of Opc:
"Opc was shown to first bind to serum-derived integrin ligands, particularly vitronectin and to a lesser extent fibronectin, and subsequently form a trimolecular complex with the αvβ3 and α5β1 integrins " https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688670/
"Opc was shown to first bind to serum-derived integrin ligands, particularly vitronectin and to a lesser extent fibronectin, and subsequently form a trimolecular complex with the αvβ3 and α5β1 integrins " https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688670/
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