SARS-CoV-2 cell entry leads to SARS-CoV-2 production

Sex

female sex (XX chromosomes)

ACE2 localizes to the X sex chromosome and displays a sex-dependent expression profile with higher expression in female than in male tissues [1,2]. Estradiol inhibits TMPRSS2, needed to facilitate SARS-CoV-2 entry into the cell [3]. Estrogen therapy has been shown to mitigate endoplasmic reticulum stress induced by SARS-CoV-2 invasion through activation of cellular unfold protein response and regulation of inositol triphosphate (IP3) and phospholipase C [4]. Different studies have also illustrated that estradiol increases the expression of ADAM17, leading to high-circulating soluble ACE2 potentially neutralizing SARS-CoV-2 and preventing its binding to mACE2 [5]. Thus, estradiol might reduce SARS-CoV-2 infectivity through modulation of cellular ACE2/TMPRSS2/ADAM17 axis expression.

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2. doi: 10.1016/j.mce.2015.11.004

3) doi: 10.1007/s11033-021-06390-1

4) doi: 10.1016/j.mehy.2020.110148

5) doi: 10.2217/pgs-2020-0092

6) doi: 10.1073/pnas.2021450118

1. 10.1016/j.exger.2021.111507

2. 10.1371/journal.pone.0247060

3. 10.15252/embr.202153658

Vitamin D

(high evidence)

Vitamin D administration enhanced mRNA expression of VDR and ACE2 in a rat model of acute lung injury [1]. In particular, vitamin D upregulates the sACE2 form [2]. Thus, low vitamin D status may impair the trapping protective mechanism of sACE2 [3]. Furthermore, vitamin D deficiency has been shown to reduce the expression of antimicrobial peptides (_-defensin, cathelicidin), which act against enveloped viruses [4,5]. Decreased sACE2 and cellular viral defense might be some mechanisms explaining how low vitamin D modulate SARS-CoV-2 infectibility.

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2. doi: 10.1152/ajplung.00071.2009

3. doi: 10.3390/ijms22105251

4. doi: 10.1007/s11154-021-09679-5

5. doi: 10.1080/14787210.2021.1941871

Gut microbiota

Gut dysbiosis (alteration of gut microbiota)

1. doi: 10.1002/path.1570

2. doi: 10.1038/s41575-021-00416-6

3.doi: 10.3390/genes1160645

4.doi: 10.1126/science.abc.1669

5.doi: 10.1126/sciimmunol.abc.3582

6. doi: 10.1038/s41467-021-25729-7

7.doi: 10.15252/embr.20139263

8.doi: 10.3390/jcm11195691

Is a prodrug of adenosine analogue, which binds to the viral RNA-dependent RNA polymerase (RdRp) and inhibits viral replication inside cells through premature termination of RNA transcription [1 – 4].

1) (EMA), E.M.A. Veklury. 2021.

Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/veklury (accessed on 12 May 2022)

2) 10.1038/s41467-020-20542-0

3) 10.1016/j.cegh.2020.07.011

4) 10.1038/s41586-020-2423-5

Is an isopropyl ester prodrug, which is cleaved in plasma by host esterases to an active nucleoside analog b-D-N4-hydroxycytidine (NHC) [1]. After entering host cells, it is intracellularly transformed into its active form, β-DN4- hydroxycytidine-triphosphate (NHC triphosphate) [2,3]. This then targets the RdRp, which is virally encoded and competitively inhibits the cytidine and uridine triphosphates and incorporates Molnupiravir instead. The RdRp (RNA-dependent RNA polymerase) enzyme of SARS-CoV-2 uses the NHC triphosphate as a substrate instead of the cytidine and uridine triphosphates and then incorporates either A or G in the RdRp active centres, forming stable complexes, thus escaping proof reading by the synthesis of a mutated RNA [4,5]. As a result, the virus can no longer reproduce. This mechanism of action (the accumulation of mutations) is referred to as viral error catastrophe [2].

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2) 10.1126/science.abb7498

3) 10.1128/AAC.00766-18

4) 10.1038/s41594-021-00651-0

5) 10.1016/j.jbc.2021.100770

Is an orally bioavailable 3C-like protease (3CL PRO) inhibitor that is the subject of phase 1 clinical trial NCT04756531 and the phase 2/3 clinical trials (NCT04960202 and NCT05011513, NCT04756531, NCT04960202 and NCT05011513). A 3CLpro antagonist will be highly specific to SARSCoV-2 and will have minimal side effects because 3Clpro shares no homology with human proteases [1,2]. The SARS-CoV-2 genome encodes two polyproteins (pp1a and pp1ab) and four structural proteins [3,4]. The polyproteins are cleaved by the critical SARSCoV-2 main protease (Mpro, also referred to as 3CL protease) at eleven different sites to yield shorter, non-structural proteins [5,6]. Without the activity of the 3CL PRO, nonstructural proteins cannot be released to perform their functions, inhibiting viral replication [7–9].

1) 10.1126/science.abb4489

2) 10.1007/s13238-013-2841-3

3) 10.1038/s41586-020-2008-3

4) 10.1038/s41586-020-2012-7

5) 10.1021/acs.jmedchem.5b01461

6) 10.1038/s41586-020-2223-y

7) 10.1007/s10930-020-09933-w

8) 10.1073/pnas.1601327113

9) 10.1002/med.21783  

 Air pollution

Air pollution induces increased expression of ACE2 which may result in increased viral entry and coronavirus production. 

Increased ACE2 expression has been reported in the respiratory system in response to air pollution exposure (1-4). Increased expression may affect susceptibility to SARS-CoV-2 infection. Similarly, some constituents of air pollution (PM, ozone) have been reported to increase the expression of TMPRSS2. (3, 5-6)

1) https://doi.org/10.1186/s12989-015-0094-4

2) 10.1016/j.burns.2015.04.010

3) 10.1016/j.envres.2021.110722

4) 10.3390/ijerph17155573

5) 10.1186/s12989-021-00404-3

6) https://doi.org/10.1038/s41598-022-04906-8

• Pelargonidin, found in red and black berries, was shown to dose-dependently block SARS-CoV-2 binding to ACE2, reduce SARS-CoV-2 replication in vitro and reduce ACE2 expression [213].

• Further evidence comes from SARS-CoV. Many plant-derived terpenoids and curcumin inhibited viral replication in vitro [218].

213: http://doi.org/10.1016/j.bcp.2021.114564

218: http://doi.org/10.1021/jm070295s