26 August Genetic susceptibility, immunology, review on rapid tests and provocative interview

Dear colleagues,

Genetic susceptibility to the SARS-CoV2  infection and COVID-19 disease

1. ACE2 and TMPRSS2 polymorphism (Hou et al. BMC Medicine) shows that there is a number of SNPs in both human proteins that may limit their functionality. 

• Some variants in ACE decrease the interaction with SARS-CoV2 spike, hence might limit infection.  Moreover, ACE2 polymorphisms were more likely to be associated with cardiovascular and pulmonary conditions by altering the angiotensinogen-ACE2 interactions.

• The protease TMPRSS2 has two functions: it activates the SARS-CoV-2 spike, but it also activates the receptor ACE2.  The first function may be diminished by some mutations in TMPRSS2, the second by mutations in ACE2. 

Clearly all these SNPs have a different distribution amongst ethnic groups.  In addition there is a potential link with gender, as the ACE2 gene is located on the x-chromosome and with Down as the TMPRSS2 gene is on chromosome 21q. 

The authors also speculate how interfering with TMPRSS2 function and endosomal acidification could be used as a treatment, but the drugs they propose (chloroquine, Camostat and E64D) are unlikely to enter the clinic for this indication. 

2.   The theme of susceptibility to  disease is further broadened and elaborated by Gemmati et al. In J Mol Sciences:

• Role of ACE1/ACE2 activity: ACE2 counteracts the deleterious effects of ACE1, including vasoconstriction, fibrosis, apoptosis, thrombosis, lung edema, inflammation, tissue damage… (see Fig 1 p. 3 and Fig 2 p. 5). Therefore, polymorphisms in a number of genes might influence this balance:
  • those of the RAS system itself: renin, angiotensinogen, ACE1, ACE2, Angiotensin II receptor 1 and 2 (AT1, AT2) and MAS1
  • modulators s such as ADAM 17 (shedding of ACE2); SRY (upregulates REN promoter; SOX3 (downregulates REN promoter); ABO polymorphism influences ACE treatment and group O has lower susceptibility to infection. 

Note that several of these factors are X linked, including ACE2 (Xp22.2); AT2 (Xq23); SOX3 on X, while SRY is on Y chromosome.

•    In fact there is a lot of evidence on sex differences:
  • ACE1 activity is higher in males in general and the D allele leads to even higher expression of ACE1 in males
  • ACE2 8790 G-allele polymorphism, associated with lower expression, cannot be compensated by the normal allele in men (since only 1 X chromosome)
  • ACE2 repression induced by SARS-CoV2 might be counteracted by high basal levels of ACE2 induced by higher levels of sex hormones (which decrease with age) and reduced by systemic inflammation.
  • Across pathologies, males tend to experience the worst prognosis in acute inflammatory settings (e.g., sepsis)
  • X-chromosome carries about 1,200 genes including cytokines/cytokines receptors, toll-like receptor (TLR)-mediated signaling pathway genes, NF-kB and MAPK signaling genes, genes involved in apoptosis, genes involved in redox balance and other immune-modulators such as CD40 ligand and FOXP3.

• Some conclusions:
  • An overly activated RAS-system, mainly due to local ACE1/ACE2 unbalancing, might be crucial in determining specific vulnerability/receptivity and in giving indicators of the local balanced inflammation, blood coagulation, and fibrinolysis
  • Although  higher expression of ACE2 in females, the inverse age-dependent ACE2 expression significantly reduced by the presence of diabetes, and the strong repression of ACE2 by inflammatory cytokines, confirm an inverse correlation between ACE2 levels and SARS-CoV-2 prognosis.
  • SARS-CoV-2 mediated repression of ACE2 is
    • counteracted by sex hormone inducible mechanisms (though unfortunately sex-hormones decrease with age)
    • exacerbated by systemic inflammation (which unfortunately increases with age and chronic diseases)

A nice overview of immunology, providing a lot of didactic figures.

A Cochrane review on rapid tests (provided by colleague Tine Verdonck)

Conclusions: This review identifies early-stage evaluations of point-of-care tests for detecting SARS-CoV-2 infection, largely based on remnant laboratory samples. The findings currently have limited applicability, as we are uncertain whether tests will perform in the same way in clinical practice, and according to symptoms of COVID-19, duration of symptoms, or in asymptomatic people.

Rapid tests have the potential to be used to inform triage of RT-PCR use, allowing earlier detection of those testing positive, but the evidence currently is not strong enough to determine how useful they are in clinical practice.

Prospective and comparative evaluations of rapid tests for COVID-19 infection in clinically relevant settings are urgently needed.

• Studies should recruit consecutive series of eligible participants, including both those presenting for testing due to symptoms and asymptomatic people who may have come into contact with confirmed cases.
• Studies should clearly describe symptomatic status and document time from symptom onset or time since exposure. Point-of-care tests must be conducted on samples according to manufacturer instructions for use and be conducted at the point of care.
• Any future research study report should conform to the Standards for Reporting of Diagnostic Accuracy (STARD) guideline.”

Finally, a slightly provoking interview with our colleague Hans Nauwynck (also reader of this blog) in the e-journal “Doorbraak” (in Dutch).  Short summary:

• Hans is expecting an evolution of SARS-CoV-2 towards lower virulence and adaptation to the receptors in nasal mucosa, as is the case with the “older” human Coronaviruses, resulting in simple rhinitis only 
• In this scenario, vaccination would only be needed in the first time period, until the virus has adapted and is no longer a threat for public health (of elderly adults).  In that case, further vaccination of the new generations will no longer be needed, as children will get immunized by infection and the virus will no longer cause lung disease.
• Hans is also pleading for more diagnostic efforts to find bacterial co-infections with SARS-CoV-2, which could be treated with antibiotics and thus may save lives of people.  At present, performing multiple diagnostic PCR is discouraged by RIZIV (the health insurance), which may lead to underdiagnosis of these treatable, but potentially lethal  co-infections.   

I might not be easy to reach in the next few days by e-mail.

Best wishes,

Guido