SARS Cov 2 molecular mimicry
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. This over time creates a series of waves of resources inside the cell. Framing a viral infection as a resource optimization problem then a virus will have seasons with low and high resource availability. 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.
However, the similarity between the viral components and the host cell is necessary to hijack the cellular molecular machinery. Mapping similar genes could point toward the specific pathway followed during the infection. This could be used to fast-track the characterization of a novel pathogen as well as to provide some insight into the kind of dysregulation resulting from the acute phase infection. Highly similar genes could be downregulated as a starvation strategy or could point to possible drivers of autoimmunity.
The following will be a long evolving post of previously selected genes with high similarity to the SARS-Cov2 genome. This is not medical advice, it's just an effort to broaden the discussion regarding post-acute sequelae and long covid. A complete list of similar genes can be found by clicking here.
CLOCK
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.
https://www.genecards.org/cgi-bin/carddisp.pl?gene=CLOCK
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.
https://en.wikipedia.org/wiki/Delayed_sleep_phase_disorder
Involvement between SARSCov2 and the circadian rhythm has been proposed before.
https://onlinelibrary.wiley.com/doi/full/10.1002/ctm2.949
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.
https://www.sciencedirect.com/science/article/pii/S2589004221011123
And either pharmacological or genetic targeting of BMAL1 reduces SARSCov2 replication. 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.
https://www.sciencedirect.com/science/article/pii/S075333222200261X
As well as a faster recovery rate, lowering the days with lymphopenia in a randomized clinical trial setting.
https://www.frontiersin.org/articles/10.3389/fphar.2022.850583/full
Also, electronic health records showed a lower incidence of COVID-19 cases in subjects with therapeutic levels of lithium in their blood.
https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/abs/association-between-serum-lithium-level-and-incidence-of-covid19-infection/C10A4E115ECCB30AA8FAC30220D1E240
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.
https://buffalohealthyliving.com/long-covid-symptoms-low-dose-lithium-may-help-call-716-829-5454/
CALM2
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).
https://en.wikipedia.org/wiki/Catecholaminergic_polymorphic_ventricular_tachycardia
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.
https://pubmed.ncbi.nlm.nih.gov/25557436/
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.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153851
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.
https://link.springer.com/article/10.1007/s00228-020-02963-4
AGL
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.
https://www.ncbi.nlm.nih.gov/books/NBK26372/
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.
https://pubmed.ncbi.nlm.nih.gov/23507172/
Direct involvement of AGL with SARSCov2 infection has not been found, however pharmacological treatments aiming at AGL have been found to inhibit viral replication.
https://academic.oup.com/glycob/article/31/4/378/5911971?login=false
While Duvoglustat, another molecule that targets AGL only has been proposed as a treatment for viral infections.
https://pubs.acs.org/doi/full/10.1021/acs.jnatprod.0c00968
SLC2A2
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.
https://www.malacards.org/card/fanconi_bickel_syndrome
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.
https://www.thelancet.com/journals/landia/article/PIIS2213-8587(22)00044-4/fulltext
Specific dysregulation of GLUT2 due to SARSCov2 infection results in altered expression patterns of GLUT2 in the pancreas, altering its function.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037197/
It has also been suggested as a possible target for dysregulation by SARSCov2 infection in the intestine leading to diarrhea.
https://journals.physiology.org/doi/full/10.1152/ajpgi.00021.2023
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.
https://www.nature.com/articles/s41598-022-09639-2
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.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9810227/
PIK3C3
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.
https://www.genecards.org/cgi-bin/carddisp.pl?gene=PIK3C3
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"
https://www.malacards.org/card/neurodegeneration_with_brain_iron_accumulation
Iron accumulation has been suggested as a consequence of covid-19 by multiple studies.
https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.066865
However, a direct measurement of iron accumulation in the brain remains to be assessed.
https://www.degruyter.com/document/doi/10.1515/nipt-2022-0016/html
PIK3C3 has been involved in the early steps of viral infection, particularly due to its involvement in endosome recycling.
https://www.sciencedirect.com/science/article/pii/S0092867420313945#sec4
Multiple studies have shown that PIK3 inhibitors inhibit SARS Cov2 viral replication in cell culture.
https://www.nature.com/articles/s41588-021-00805-2
Exvivo analysis showed that inhibitors of PIK3 inhibited SARS Cov2 infection in ex vivo lung tissue cultures.
https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.26583
Clinically PIK3 inhibitors have shown decreased rates of COVID-19 in cancer patients.
https://jamanetwork.com/journals/jamaoncology/article-abstract/2783284
Quercetin, another PIK3 inhibitor has also shown faster recovery rates when used with antiviral drugs in a clinical trial setting.
https://www.sciencedirect.com/science/article/pii/S0014299921007718
BCAT1
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.
https://www.malacards.org/card/hypervalinemia_and_hyperleucine_isoleucinemia
Abnormal levels of branch chains amino acids in plasma have been found in COVID-19 patients.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955102/
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.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9877759/
Also, a case report has shown that gabapentin can be used to manage the tinnitus that resulted from the COVID-19 infection
https://www.sciencedirect.com/science/article/pii/S0196070921003094
HDAC2
Mutations in HDAC2 can produce Chronic obstructive pulmonary disease, a disease characterized by shortness of breath, wheezing, productive cough, and chest tightness.
https://www.malacards.org/card/pulmonary_disease_chronic_obstructive
Specific manipulation of HDAC2 by SARS Cov 2 is regulated by NSP5, this manipulation results in the downregulation of MHCII.
https://www.biorxiv.org/content/10.1101/2023.02.10.528032v2.full.pdf
SARS Cov 2 main protease can also cleave HDAC2 and reduce the interferon response.
https://www.jbc.org/article/S0021-9258(23)00122-9/fulltext
ACE2 expression is regulated by different HDACs making them a target for COVID-19 treatment.
https://link.springer.com/content/pdf/10.1038/s41598-021-82970-2.pdf
Panobinostat an HDAC2 inhibitor showed a decrease of viral entry on cell culture.
https://pubs.acs.org/doi/full/10.1021/acsptsci.0c00163
While Theophylline, another HDAC2 inhibitor has been used to treat several post-acute sequelae symptoms such as sinus bradycardia.
https://www.mdpi.com/2039-7283/11/2/47
Atrioventricular block.
https://www.heartrhythmcasereports.com/article/S2214-0271(21)00258-X/fulltext
And the improvement of smell function over a randomized controlled trial.
https://jamanetwork.com/journals/jamaotolaryngology/article-abstract/2793987
PANK3
PANK3 is a gene related to Neurodegeneration with Brain Iron Accumulation 1 and Woodhouse-Sakati Syndrome.
https://www.genecards.org/cgi-bin/carddisp.pl?gene=PANK3#drugs_compounds
A target of PANK3 is Pantothenic acid or B5, and B5 offers a protective effect against COVID-19.
https://web.archive.org/web/20221117015610id_/https://www.cambridge.org/core/services/aop-cambridge-core/content/view/ABB34ACDBF78F044643BC6417F844AB1/S0007114522003075a.pdf/div-class-title-the-association-between-b-vitamins-and-the-risk-of-covid-19-div.pdf
CHN1
CHN1 is a gene related to Duane Retraction Syndrome 2 a condition with restricted horizontal eye movement.
https://www.malacards.org/card/duane_retraction_syndrome_2
Alterations in eye movement have been found as a post-acute of COVID-19.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8875414/
CHN1 plasma levels are correlated with inflammation and disease severity.
https://www.frontiersin.org/articles/10.3389/fimmu.2022.941663/full
INPP4B
INPP4B is differentially expressed in COVID-19 patients. Particularly had a negative correlation with disease severity.
https://www.sciencedirect.com/science/article/pii/S0009898121003892
DSC2
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.
https://medlineplus.gov/genetics/condition/arrhythmogenic-right-ventricular-cardiomyopathy/
SARS Cov 2 infected cardiomyocytes with mutations in the DSC2 gene showed an increased viral load in cell culture.
https://www.jacc.org/doi/full/10.1016/S0735-1097%2821%2904454-5
LAMP2
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.
https://www.malacards.org/card/left_ventricular_noncompaction
LAMP2 also has a role during SARS Cov 2 infection, as a specific spike mutation accumulates in LAMP2-positive membranes.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743070/
Furthermore, LAMP2 interacts with the 5' end of the SARS Cov 2 genome regulating the amount of viral RNA inside the infected cell.
https://journals.asm.org/doi/full/10.1128/mSystems.00643-21
AGPAT5
High expression of AGPAT5 in the livers of COVID-19 patients has been found.
https://www.nature.com/articles/s41392-020-00406-1
TLR3
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).
https://www.malacards.org/card/immunodeficiency_83_viral_infections
Also, mutations in TLR3 are markers of COVID-19 disease severity in males.
https://www.tandfonline.com/doi/full/10.1080/15548627.2021.1995152
TLR3 induces the innate immune response against the SARS-Cov2 infection.
https://www.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.
https://link.springer.com/article/10.1007/s10875-020-00933-0
ADAM10
ADAM10 is a gene related to the neurodegenerative Alzheimer's disease.
https://www.malacards.org/card/alzheimer_disease_18
Regarding SARS Cov2 infection ADAM10 mediates the priming of the spike protein and lung cell fusion.
https://www.embopress.org/doi/full/10.15252/embr.202154305
ADAM10 inhibition reduces the entry of viral particles in cell culture.
https://journals.asm.org/doi/full/10.1128/mbio.00519-22
ADAM10 inhibition by Disulfiram has shown positive effects, as it inhibits the interaction between ACE2 and the spike protein in cell culture.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9360250/
While patients treated with Disulfram for alcohol user disorder showed a reduced risk for COVID-19.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553043/
PDE4D
PDE4D is a gene related to Acrodysostosis 2 with or Without Hormone Resistance a condition with endocrine abnormalities and in females irregular menses.
https://www.malacards.org/card/acrodysostosis_2_with_or_without_hormone_resistance_2
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.
https://www.frontiersin.org/articles/10.3389/fimmu.2021.797390/full
While Dyphylline showed antiviral activity in cell culture, its effect is attributed to an off-target effect.
https://www.future-science.com/doi/full/10.4155/fmc-2021-0311
CAMK4
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"
https://www.malacards.org/card/cerebral_hypoxia
Clinical data shows elevated levels of CAMK4 in the kidneys of COVID-19 patients.
https://www.sciencedirect.com/science/article/pii/S1521661621001327
PPP1R12A
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.
https://www.sciencedirect.com/science/article/pii/S0092867422015057#sec4
Mutations in PPP1R12A can lead to a condition known as Coronary Artery Vasospasm, a condition related to angina pectoris and orthostatic intolerance.
https://www.malacards.org/card/coronary_artery_vasospasm#related_genes
Cases of coronary vasospasms have been reported in COVID-19 patients but in low numbers.
https://www.sciencedirect.com/science/article/pii/S1878540923000701
C9orf72
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.
https://www.malacards.org/card/frontotemporal_dementia_and_or_amyotrophic_lateral_sclerosis_1
Specific mutations in C9orf72 have been found to influence SARS Cov 2 infection and perhaps drive it toward a more pathogenic phenotype.
https://www.mdpi.com/1422-0067/22/13/6991
TRNT1
Mutations in TRNT1 can lead to Sideroblastic Anemia with B-Cell Immunodeficiency, Periodic Fevers, and Developmental Delay.
https://www.malacards.org/card/sideroblastic_anemia_with_b_cell_immunodeficiency_periodic_fevers_and_developmental_delay
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.
https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-020-05231-z
RORA
RORA is a gene related to Intellectual Developmental Disorder with or Without Epilepsy or Cerebellar Ataxia and Autism.
https://www.malacards.org/card/intellectual_developmental_disorder_with_or_without_epilepsy_or_cerebellar_ataxia
RORA SNPs have also been found to be differentially expressed in different COVID-19 phenotypes.
https://www.frontiersin.org/articles/10.3389/fgene.2021.698033/full
Also, RORA is differentially expressed in heart failure among other genes.
https://onlinelibrary.wiley.com/doi/full/10.1002/ehf2.14003