Tavo

Changes in the environment generate changes in gene expression patterns. Those changes will also modify the nucleotide and the amino acid pools inside the cell.

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Tavo

This over time creates a series of waves of resources inside the cell. If we frame a viral infection as a resource optimization problem then a virus will have seasons with low and high resource availability.

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Tavo

If the virus adapts to the cellular resources, then the seasonality of the virus could be traced by measuring an environmental variable or by selecting genes with high similarity to the virus.

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Tavo

Detecting highly similar genes could provide some insight into the kind of dysregulation resulting from the acute phase infection.

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Tavo

The following will be a long evolving thread of previously selected genes with high similarity to SARS-Cov2. And its possible involvement in long covid. But some disclaimers.

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Tavo

This is not medical advice, it's just an effort to broaden the discussion regarding post-acute sequelae and long covid. I have a substack on which I describe other methods to analyze genomic data.
tavoglc.substack.com/

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Tavo

Posts data and code are free and open source, feel free to subscribe if you think the following can be useful. Supporting this project will allow me to continue to work on these analyses.

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Tavo

Due to its seasonality(solar radiation changes), I think that one of the main dysregulations is the circadian one. Scheduling of circadian events could be disrupted and some daily variations in symptom severity might also be possible.

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Tavo

One of the main regulators of the circadian function inside cells is the CLOCK protein, a gen with high compositional similarity to SARS-Cov. CLOCK is involved in chromatin organization and the circadian cycle.
genecards.org/cgi-bin/carddisp

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Tavo

Delayed sleep phase disorder(DSPD) and Major depressive disorder are diseases associated with CLOCK. DSPD disrupts the timing of biological rhythms such as sleep, periods of alertness, body temperature, and hormonal cycles.
en.wikipedia.org/wiki/Delayed_

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Tavo

Involvement between SARS Cov2 and the circadian rhythm has been proposed before.
onlinelibrary.wiley.com/doi/fu

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Tavo
Follow

Specific molecular machinery involved in circadian regulation and highjacked by SARSCov2 infection has already been found. BMAL1, a protein that interacts with CLOCK to synchronize the circadian rhythm, regulates the entry of the virus into the cell.
sciencedirect.com/science/arti

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Tavo

And either pharmacological or genetic targeting of BMAL1 reduces SARSCov2 replication.

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Tavo

Pharmacological interventions targeting CLOCK have also been successful in COVID-19 treatment. Lithium an inducer of clock gene expression has shown inhibitory effects of SARS Cov2 replication at the preclinical level.
sciencedirect.com/science/arti

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Tavo

As well as a faster recovery rate, lowering the days with lymphopenia in a randomized clinical trial setting.
frontiersin.org/articles/10.33

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Tavo

Also, electronic health records showed a lower incidence of COVID-19 cases in subjects with therapeutic levels of lithium in their blood.
cambridge.org/core/journals/th

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Tavo

Treating long covid is harder to assess, but there is at least one clinical trial assessing the efficacy with what appears to be promising results.
buffalohealthyliving.com/long-

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Tavo

For some reason, I forgot to add the list of selected genes. This one contains the RefSeq Id

github.com/TavoGLC/SARSCov2Sol

And this one contains the gene description from the refseq file.

github.com/TavoGLC/SARSCov2Sol

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Tavo

Another common symptom of long covid is exercise intolerance. Although it is an uncommon symptom many other diseases generate exercise intolerance. One of those is Catecholaminergic polymorphic ventricular tachycardia (CPVT).
en.wikipedia.org/wiki/Catechol

CPVT causes an abnormal heart rate (arrhythmia) that can be fatal and is triggered by conditions of high excitement such as physical exercise. Mutations in Calmodulin 2, a calcium-handling protein, lead to CPVT.
pubmed.ncbi.nlm.nih.gov/255574

Calmodulin 2 is also associated with a series of cardiac diseases and Sudden Infant Death Syndrome. The main mechanism behind this is due to lower calcium affinity impairing calcium signaling.
journals.plos.org/plosone/arti

Calmodulin 2 is also another protein with high compositional similarity to SARSCov2 and also has a role inside the SARSCov2 infection pathway. Calmodulin interaction with ACE2 is important for the infection process.
link.springer.com/article/10.1

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Tavo

Glycogen storage disease is also another exercise-intolerant disease. Particularly GSD III involves the liver, skeletal, and heart muscle, one cause of such disease is a mutation in the AGL gene.
ncbi.nlm.nih.gov/books/NBK2637

The AGL gene is a gene with high similarity to the SARS Cov2 genome and codifies for the AGL protein, a protein that debranches glycogen. Exercise intolerance in the scheme of GSD III has been suggested to be an energy deficiency.
pubmed.ncbi.nlm.nih.gov/235071

Direct involvement of AGL with SARSCov2 infection has not been found, however pharmacological treatments aiming at AGL have been found to inhibit viral replication.
academic.oup.com/glycob/articl

While Duvoglustat, another molecule that targets AGL only has been proposed as a treatment for viral infections.
pubs.acs.org/doi/full/10.1021/

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Tavo

Another glycogen disease is Fanconi-Bickel Syndrome, among the main symptoms of this disease are myalgia, muscle cramp, and muscle rigidity. A gene associated with this disease is the SLC2A2 also known as GLUT2, a gene with high similarity to the SARSCov2 genome.
malacards.org/card/fanconi_bic

GLUT2 is also associated with type 2 diabetes, a condition with a rising number of cases and COVID-19 infection increases the chances of developing the disease.
thelancet.com/journals/landia/

Specific dysregulation of GLUT2 due to SARSCov2 infection results in altered expression patterns of GLUT2 in the pancreas, altering its function.
ncbi.nlm.nih.gov/pmc/articles/

It has also been suggested as a possible target for dysregulation by SARSCov2 infection in the intestine leading to diarrhea.
journals.physiology.org/doi/fu

Treatment targeting GLUT2 has not been used to treat SARSCov2 infection or long covid. However, the diabetes treatment metformin has been used to treat infection with successful results for patients with type 2 diabetes.
nature.com/articles/s41598-022

Regarding Long Covid metformin has been tested in a clinical trial with positive outcomes. However, the authors acknowledge the limitation of a lack of established criteria to define long covid.
ncbi.nlm.nih.gov/pmc/articles/

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Tavo

Metabolic alterations have been present in a series of genes, particularly involving diabetes. This suggests the highjacking of the insulin pathway from the virus, a component of this pathway is the PIK3C3 protein and its gene that is highly similar to the SARS Cov2 genome.
genecards.org/cgi-bin/carddisp

One of the diseases in which PIK3C3 has been involved is Neurodegeneration with Brain Iron Accumulation (NBIA) "disorder characterized by an abnormal accumulation of iron in the brain and progressive degeneration of the nervous system"
malacards.org/card/neurodegene

Iron accumulation has been suggested as a consequence of covid-19 by multiple studies.
alz-journals.onlinelibrary.wil

However, a direct measurement of iron accumulation in the brain remains to be assessed.
degruyter.com/document/doi/10.

PIK3C3 has been involved in the early steps of viral infection, particularly due to its involvement in endosome recycling.
sciencedirect.com/science/arti

Multiple studies have shown that PIK3 inhibitors inhibit SARS Cov2 viral replication in cell culture.
nature.com/articles/s41588-021

Exvivo analysis showed that inhibitors of PIK3 inhibited SARS Cov2 infection in ex vivo lung tissue cultures.
onlinelibrary.wiley.com/doi/ab

Clinically PIK3 inhibitors have shown decreased rates of COVID-19 in cancer patients.
jamanetwork.com/journals/jamao

Quercetin, another PIK3 inhibitor has also shown faster recovery rates when used with antiviral drugs in a clinical trial setting.
sciencedirect.com/science/arti

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Tavo

Mutations in BCAT1 can produce Hypervalinemia and hyperleucine-isoleucinemia (HVLI) a condition with high levels of leucine and isoleucine in plasma. Generating headaches and memory impairment as well as metabolic acidosis.
malacards.org/card/hypervaline

Abnormal levels of branch chains amino acids in plasma have been found in COVID-19 patients.
ncbi.nlm.nih.gov/pmc/articles/

Treatments targeting BCAT1 have shown success in treating some of the post-acute sequelae symptoms. Gabapentin improves parosmia (altered perception of smells) after COVID-19 infection.
ncbi.nlm.nih.gov/pmc/articles/

Also, a case report has shown that gabapentin can be used to manage the tinnitus that resulted from the COVID-19 infection
sciencedirect.com/science/arti

Mutations in HDAC2 can produce Chronic obstructive pulmonary disease, a disease characterized by shortness of breath, wheezing, productive cough, and chest tightness.
malacards.org/card/pulmonary_d

Specific manipulation of HDAC2 by SARS Cov 2 is regulated by NSP5, this manipulation results in the downregulation of MHCII.
biorxiv.org/content/10.1101/20

SARS Cov 2 main protease can also cleave HDAC2 and reduce the interferon response.
jbc.org/article/S0021-9258(23)

ACE2 expression is regulated by different HDACs making them a target for COVID-19 treatment.
link.springer.com/content/pdf/

Panobinostat an HDAC2 inhibitor showed a decrease of viral entry on cell culture.
pubs.acs.org/doi/full/10.1021/

While Theophylline, another HDAC2 inhibitor has been used to treat several post-acute sequelae symptoms such as sinus bradycardia.
mdpi.com/2039-7283/11/2/47

Atrioventricular block.
heartrhythmcasereports.com/art

And the improvement of smell function over a randomized controlled trial.
jamanetwork.com/journals/jamao

PANK3 is a gene related to Neurodegeneration with Brain Iron Accumulation 1 and Woodhouse-Sakati Syndrome.
genecards.org/cgi-bin/carddisp

A target of PANK3 is Pantothenic acid or B5, and B5 offers a protective effect against COVID-19.
web.archive.org/web/2022111701

CHN1 is a gene related to Duane Retraction Syndrome 2 a condition with restricted horizontal eye movement.
malacards.org/card/duane_retra

Alterations in eye movement have been found as a post-acute of COVID-19.
ncbi.nlm.nih.gov/pmc/articles/

CHN1 plasma levels are correlated with inflammation and disease severity.
frontiersin.org/articles/10.33

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Tavo

INPP4B is differentially expressed in COVID-19 patients. Particularly had a negative correlation with disease severity.
sciencedirect.com/science/arti

DSC2 is a gene related to Arrhythmogenic right ventricular cardiomyopathy. A disease characterized by the breakdown of the myocardium and an increased risk of sudden death.
medlineplus.gov/genetics/condi

SARS Cov 2 infected cardiomyocytes with mutations in the DSC2 gene showed an increased viral load in cell culture.
jacc.org/doi/full/10.1016/S073

LAMP2 is a gene related to Left Ventricular Noncompaction, this disease is characterized by impaired cardiac development. Some of the symptoms of this disease are blood clots, shortness of breath, exercise intolerance, and sudden death.
malacards.org/card/left_ventri

LAMP2 also has a role during SARS Cov 2 infection, as a specific spike mutation accumulates in LAMP2-positive membranes.
ncbi.nlm.nih.gov/pmc/articles/

Furthermore, LAMP2 interacts with the 5' end of the SARS Cov 2 genome regulating the amount of viral RNA inside the infected cell.
journals.asm.org/doi/full/10.1

High expression of AGPAT5 in the livers of COVID-19 patients has been found.
nature.com/articles/s41392-020

TLR3 mutations are related to immunodeficiency that increases the susceptibility to herpes simplex virus (HSV), varicella-zoster virus (VZV), influenza A virus (IAV), hantavirus, and possibly respiratory syncytial virus (RSV).
malacards.org/card/immunodefic

Also, mutations in TLR3 are markers of COVID-19 disease severity in males.
tandfonline.com/doi/full/10.10

TLR3 induces the innate immune response against the SARS-Cov2 infection.
mdpi.com/1999-4915/14/2/189

A case report of interferon therapy in patients with TLR3 mutations shows that interferon therapy could be beneficial to patients that present such mutations.
link.springer.com/article/10.1

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Tavo

ADAM10 is a gene related to the neurodegenerative Alzheimer's disease.
malacards.org/card/alzheimer_d

Regarding SARS Cov2 infection ADAM10 mediates the priming of the spike protein and lung cell fusion.
embopress.org/doi/full/10.1525

ADAM10 inhibition reduces the entry of viral particles in cell culture.
journals.asm.org/doi/full/10.1

ADAM10 inhibition by Disulfiram has shown positive effects, as it inhibits the interaction between ACE2 and the spike protein in cell culture.
ncbi.nlm.nih.gov/pmc/articles/

While patients treated with Disulfram for alcohol user disorder showed a reduced risk for COVID-19.
ncbi.nlm.nih.gov/pmc/articles/

PDE4D is a gene related to Acrodysostosis 2 with or Without Hormone Resistance a condition with endocrine abnormalities and in females irregular menses.
malacards.org/card/acrodysosto

Although there's no information linking PDE4D and some SARS Cov 2 components, targeting it has been successful.

Tanimilast regulates the immune activation derived from SARS Cov 2 ssRNA. .
frontiersin.org/articles/10.33

While Dyphylline showed antiviral activity in cell culture, its effect is attributed to an off-target effect.
future-science.com/doi/full/10

CAMK4 is a gene related to autism and Cerebral hypoxia disease. A disease characterized by "Having a hard time paying attention * Poor judgment and decision making * Memory loss * Having a hard time controlling movement"
malacards.org/card/cerebral_hy

Clinical data shows elevated levels of CAMK4 in the kidneys of COVID-19
patients.
sciencedirect.com/science/arti

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Tavo

PPP1R12A is a gene involved in the regulation of microvilli in nasal epithelial cells. This pathway has been suggested as a target for SARS Cov 2 infection. .
sciencedirect.com/science/arti

Mutations in PPP1R12A can lead to a condition known as Coronary Artery Vasospasm, a condition related to angina pectoris and orthostatic intolerance. .
malacards.org/card/coronary_ar

Cases of coronary vasospasms have been reported in COVID-19 patients but in low numbers.
sciencedirect.com/science/arti

C9orf72 is a gene related to Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis a neurodegenerative disease. Patients with mutations on C9orf72 have a propensity toward psychosis or hallucinations.
malacards.org/card/frontotempo

Specific mutations in C9orf72 have been found to influence SARS Cov 2 infection and perhaps drive it toward a more pathogenic phenotype.
mdpi.com/1422-0067/22/13/6991

Mutations in TRNT1 can lead to Sideroblastic Anemia with B-Cell Immunodeficiency, Periodic Fevers, and Developmental Delay.
malacards.org/card/sideroblast

Mutations in TRNT1 could also be used as a risk factor for COVID-19. A case report study shows recurrent infections in patients with such mutations.
bmcinfectdis.biomedcentral.com

RORA is a gene related to Intellectual Developmental Disorder with or Without Epilepsy or Cerebellar Ataxia and Autism.
malacards.org/card/intellectua

RORA SNPs have also been found to be differentially expressed in different COVID-19 phenotypes. frontiersin.org/articles/10.33

Also, RORA is differentially expressed in heart failure among other genes. .
onlinelibrary.wiley.com/doi/fu

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Trinsec @Qoto

@tavoglc Just as an aside, unrelated to your topic: You know you can type longer messages here? Having a chain of short messages isn't really comfortable to read. And yes, people will see the full posts, it's not like they get cut off or anything.

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