The COVID-19 pandemic continues to spread in many parts of the world, and resurgences are occurring in some countries where the virus was thought to be successfully contained. A recent paper published in the preprint server bioRxiv* in September 2020 discusses the “clinically relevant variation in the expression of COVID-19-related genes”, which is associated with the host and environmental factors, as well as host genetic factors.
Some of these factors which predispose to severe COVID-19 include advanced age, male sex, being Black American, smoking, and chronic conditions such as hypertension, obesity, diabetes, cardiovascular disease, and chronic airway diseases as well as host genetic factors.
The researchers used bronchial epithelium brushing samples to carry out RNA sequencing since this is the target tissue for the virus. The brushings came from three cohorts of healthy individuals.
Transmission electron micrograph of SARS-CoV-2 virus particles, isolated from a patient. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID
Smoking, Obesity, and Hypertension Increase ACE2 Levels
They found that the presence of active smoking, obesity, and hypertension was related to higher levels of the angiotensin-converting enzyme 2 (ACE2) that is the host cell receptor for the virus. These are known to exacerbate the severity of COVID-19, and, they say, “current smoking, when compared to non-smoking, had the largest overall effect on ACE2 expression of any phenotypic feature.”
Chronic obstructive pulmonary disease (COPD) was not found to be associated with higher ACE2 levels, and neither was the Black American race independent of the higher occurrence of comorbidities in this group. Both obesity and hypertension were linked to higher ACE2 expression, but this was reduced in the case of the latter condition by the use of medications to bring down the blood pressure. The use of angiotensin receptor blockers (ARBs) and diuretics was specifically linked to this phenomenon, but not ACE inhibitors or calcium channel blockers. This was partly an effect of smoking.
Suppressed Airway Immunity in Chronic Illness
Inflammation is often found in many airway diseases, and this can contribute to gene expression levels. The researchers found that the presence of obesity, hypertension, and cardiovascular disease produces a pattern of gene expression that indicates a lessened ability to mount innate and adaptive airway immune responses in the early phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that is not seen with other viruses. This could be the reason for the increased viral load and long pre-symptomatic period in this infection.
This immunosuppressive state may mediate increased susceptibility to the virus and the increased risk of severe COVID-19 in these conditions.
The presence of a shortened form of the ACE2 molecule, which fails to bind to the virus but activates interferon pathways, was found to be linked to the induction of one type of inflammation in COVID-19. IL-17 inflammation was also linked to higher ACE2 levels. Older patients and men had a small reduction in ACE2 expression. Overall, however, the truncated ACE2 isoform does not seem to be related to the higher risk of severe COVID-19 in individuals with these conditions.
Host Genetic Factors
The researchers found that ACE2 and TMPRSS2 were not significantly regulated and probably did not contribute to the genetic effect of the host on COVID-19. The expression of TMPRSS2 was only slightly affected by current smoking, and was higher in asthmatics but not in COPD, and went down in individuals who used steroids for control.
Several other variants of regulatory genes that may play an important role in COVID-19 were found to be associated with immune response or respiratory illness, and their interactions with other factors could play a role in this disease.
The researchers thus conclude that the variations in the clinical presentation of COVID-19 are caused by complex interactions of host and environmental factors, rather than simply being driven by elevated expression of ACE2.
Current smoking, hypertension, and cardiovascular disease, and advancing age, are linked to reduced mucosal immunity, which creates “an airway microenvironment in which SARS-CoV-2 can gain a foothold before an effective host response is mounted,” by increasing the susceptibility of the patient to the virus and the severity of the clinical phenotype.
On the other hand, inflammatory conditions of the airway like COPD typically trigger airway immunity and thus help prevent the worsening of the underlying airway disease when exposed to other viruses. However, this response is not seen in SARS-CoV-2.
The genetic make-up of the host also plays a role in the expression of many genes potentially involved in COVID-19. Many genes that interact with this condition have regulatory variants that are linked to both immunological and airway-related outcomes. This genetic profile may affect the risk of the infection as well as its clinical course. This knowledge could help identify relevant targets for the therapy of the disease.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.