MECHANISMS OF SARS-COV-2 INFECTION, TRANSMISSION AND SURVIVAL

Since its sudden outbreak and discovery, SARS-COV-2 has taken the world by storm. In an effort to control the current pandemic, insights on the infectious strategies of the virus are being uncovered at a furious pace. A better understanding of the virus has emerged that has allowed for the rapid development of treatment options[1] [2].

The below article discusses a few currently known aspects of SARS-COV-2 infection and transmissibility. Highlights include its entry into cells, replication, immune evasion tactics, routes of exposure and environmental conditions affecting its success as a pathogen.

SARS-COV-2 Structure and Cellular Invasion Strategy

All pathogens have unique infection strategies that serve to improve the chances of survival and evade immune tactics. Their shape, structure, and genetic constituents all contribute towards this purpose.

The shape and structure of SARS-COV-2 is similar to that of other coronaviruses. These are complex viruses that have a large surface area. They consist of round lipid membranes that house viral RNA, covered in a viral envelope that has many protrusions. The protrusions contain spike proteins that allow for viral adhesion and entry to cell receptors, as well as modulation of cellular DNA.

The virus has been shown to integrate its own genetic code into the genome of the infected cell, using the cell as a means of replication for its own material, including spike proteins.

Viral Entry

The virus and its spike proteins mainly bind to ACE2 (angiotensin-converting enzyme II) receptors to enter and infect a cell.[3] Other binding receptors have also been discovered that allow for viral and spike protein entry, including surface membrane proteins and the receptors CD147 and CD26 in red blood cells.

Current findings regarding viral entry include the following:

• ACE2 Receptor Binding

ACE2 is a zinc metallopeptidase, meaning that it is a zinc-bearing enzyme that cleaves proteins, in this case angiotensin II. It has been shown to be critical to regulating cardiovascular function by converting angiotensin II into seven other homologues and tempering the potential adverse effects of angiotensin II.

Angiotensin II is a potent vasoconstrictor and in high amounts, it is associated with vascular fibrosis, capillary damage, heightened blood pressure, reduced cardiac contractility and kidney damage[4]. As these features overlap with COVID-19 symptoms, it is possible that SARS-COV-2 causes an increase in ACE2 through interfering with ACE2 receptors.[5]

• Protein-Cleaving Enzymes

Intercellular proteases such as furin, cathepsin L and transmembrane serine protease 2[6] are required for viral entry at ACE2 receptor sites and replication. A preliminary study reveals that inhibiting proteases may reduce risk of infection due to preventing viral entry into cells.[7] More trials are required to test the safety and efficacy of protease inhibitors.

• Efficient Evasion Mutation

There are more than 45 000 recorded SARS-COV-2 genomic sequences to-date, highlighting the potential for the virus to mutate[8]. Many strains appear to have mutated in a way that makes them potentially less infectious. However, the spike protein adaptations in several new variant strains pose increased immune evasion challenges, combined with increased ACE2 receptor affinity. These SARS-COV-2 strains are better at infecting cells, making them far more contagious and reclassified as ‘variants of concern.’

• Systemic Potential

The respiratory tract has a high humidity and is an area in the body that has some of the highest ACE2 receptor expression, making it an obvious hotspot for viral invasion. ACE2 receptors are however found on the cell membranes of many cells across all tissues[9], suggesting that an infection may be able to spread systemically. CD147 receptors are also found on the surfaces of multiple cells across the whole body, adding to this observation. A few patient reports support this notion, revealing SARS-COV-2 may induce hemolytic anemia by infecting red blood cells.[10]

• Red Blood Cell Entry

The virus is able to infect red blood cells and their stem cell precursors via ACE2, CD147 and CD26 cell membrane receptors[11].

Hypoxia (cellular oxygen deficit) has been associated with hemolytic anemia and worse disease outcomes, including potential fatality. ACE2 receptors are likely downregulated in those with hypoxia[12], while CD147 receptors are upregulated; suggesting an increased risk of systemic infection, cardiovascular damage, and more.

• COVID-19 Vascular Damage

CD147 receptor expression increases on the membrane of many cell types following injury and inflammation[13]. Increased vascular and blood platelet expression of this receptor is associated with a few health conditions including thrombosis, atherosclerosis and coronary artery diseases. Those with these conditions may be more susceptible to contracting severe manifestations of COVID-19.

Spike proteins may potentially activate CD147 receptors and release inflammatory cytokines that have also been associated with vascular damage and abnormalities in COVID-19 patients[14]. In light of this information, scientists speculate that COVID-19 is likely to be reclassified as an inflammatory vascular disease with systemic implications.[15] [16]

• Immune Cell Entry and Viral Lymphopenia

Via CD147 and ACE2 receptors, SARS-COV-2 may infect macrophages, dendritic cells, monocytes and T lymphocytes[17]. As seen in other severe infections, this may predispose susceptible individuals to autoimmune complications. Autoimmune symptoms have been shown to increase or newly emerge in those with moderate to severe COVID-19[18] [19].

Later studies reveal that roughly 10% of monocytes become infected and die off[20]; suggesting the virus may decrease white blood cell count and contribute towards immune deficiency. Low lymphocyte levels are observed in many cases of COVID, with the elderly at a higher risk.[21] Autoimmune and immune compromised individuals are likely to be at a higher risk of severe outcomes.

Viral Replication

SARS-COV-2 replicates in a similar fashion to other coronaviruses. After entering the cell, the virus releases its genetic material into the cell and starts to manipulate parts of the cell in order to produce copies of itself. Eventually, viral RNA integrates structural proteins into the cell’s genetic code that allows for it to instruct other organelles to produce the virus. Other than this, little is known on the specifics of viral replication.

Interaction of the virus and its proteins within the cell suggest that it interrupts multiple cellular pathways that would otherwise be conducive to optimal immunity and cellular metabolism.

Aside from making use of proteases, other interrupted pathways that are implicated in SARS-COV-2 infection include:

• Metalloprotein Balance

Infection appears to deregulate cellular zinc signaling, and disturb magnesium levels. Manganese, copper and iron revealed minor perturbations at the cellular level[22]. ACE2 is a zinc metalloenzyme and ACE2 receptors therefore depend on zinc for activation, displaying a higher affinity for zinc than other ions. Spike protein binding to CD147 receptors may further serve to disturb metalloprotein balance, as this receptor induces metalloprotein production and expression.

• Electrolyte Depletion

Electrolyte disturbances are common in COVID-19 patients. Hypokalemia (severe potassium deficiency) has been reported in many hospitalized cases, suspected to be related to ACE2 receptor disruption and the renin-angiotensin system[23].

• Low Oxygen Status

SARS-COV-2 spike proteins are able to infect red blood cells, which may cause them to die off due to inflammation. It is possible for the virus to move from the lungs and into the bloodstream in severely infected persons, due to viral actions that may enhance blood barrier permeability (e.g. zinc deficits, excessive inflammation, tissue damage, etc).

Another observation is that the spike proteins appear to mimic hepcidin, a major cellular peptide required for regulating iron metabolism and heme protein. It is hypothesized that through binding with heme protein, hemoglobin can become dysfunctional and no longer take up oxygen. Furthermore, the cell would register an increase in hepcidin content when exposed to spike proteins, which may lead to an increase in iron uptake resulting in cell death. Due to limited available evidence, this view remains to be proven.

Both outcomes may provoke anemia or hypoxia (low cell oxygen), as well as the respiratory and systemic damage observed in COVID cases.

• Blood Clotting Factors

Blood cell and vascular damage as a result of systemic infection has been shown to increase blood clotting factors, worsening disease severity for those with coronary heart disease and other vascular conditions.

• Microcirculation Deficits

Fibrosis, reduced tissue oxygenation and impaired vascular function are common outcomes in those with COVID-19[24]. This may be related to low oxygen levels and/or ACE2 receptor takeover by the virus.

How Does COVID-19 Spread? Favorable Conditions, Survivability and Routes of Exposure

The virus is airborne and highly infectious. Currently known routes of exposure include:

• Infected People. Just like the common cold and other flus, the virus is transmitted through moisture droplets that are exhaled from the infected, via coughing, breathing, etc.
• Infected Animals. COVID-19 may also be passed on through animals or consuming infected animal products. This is how the outbreak was believed to have initially started.
• Points of Contact. The uninfected can contract the virus by inhaling infectious particles, or by coming into contact with a surface containing active viral particles. The hands tend to pick viral particles up and transmit the virus to a person when they touch their face or food prior to eating.

Environmental Factors Affecting SARS-COV-2 Replication and Infectivity

Viral particles are more active in certain conditions and are less active in others. Understanding factors in the environment that influence the behavior of the virus can help in slowing its spread.

How long does COVID-19 Survive on Surfaces?

SARS-COV-2 fragments remain stable for varying lengths of time on different surfaces. The time depends on the surface material and environment. Infectivity of viral particles on surfaces can range anywhere between a few hours to 14 days, according to current data.

The virus appears more stable on smoother surfaces and on surfaces exhibiting favorable conditions. These include:

1. Temperature

The virus appears very stable at 4˚C (39.2˚F), showing signs of infectivity even up to 14 days after culturing. Heat makes it less stable, with a temperature of over 70˚C (158˚F) reducing viral particles to undetectable levels within 5mins.[25]

Body temperature proved to lower levels of infectious particles to undetectable levels within 2 days at a humidity of 65%[26]. This implies that keeping one’s temperature stable may help to lower the spread.

Washing linen and clothing at higher temperatures may help to degrade active viral particles faster.

Interestingly, temperature has a minor role in the efficacy of handwashing as a pathogen prevention measure. Studies prior to the pandemic highlight that the quality of soap or disinfectant, whether one scrubbed vigorously or not and the time it takes are more important factors to consider.[27]

2. Humidity and Moisture

SARS-COV-2 does better in moisture-rich conditions that have high humidity. Reducing moisture in one’s immediate environment may lower the level of potentially infectious particles.

One experiment[28] revealed that at 40% humidity and 21-23˚C (69.8-73.4˚F), viral particles remained viable for up to:

• 3 days on plastic
• 2 days on stainless steel
• 1 day on cardboard
• 4 hours on copper

At a temperature of 22˚C (71.6˚F) with a higher humidity of 65%, active viral particles were found up to:

• 7 days on stainless steel, plastic and the outer layer of surgical masks
• 4 days on glass and banknotes
• 2 days on treated wood and cloth
• 3hours on tissue paper and printing paper

More than half of those with COVID-19 viral infections sweated profusely. As sweating increases bodily moisture and is one potential avenue of viral shedding, those prone to sweats should change as frequently as required to keep clothing and linen clean and dry. This is especially important in cold environments.

3. Disinfectant

Optimal hand hygiene and disinfectants are key to stopping the spread of the current pandemic.

Disinfecting surfaces proved to greatly reduce active viral load (from 47.8% to 8.7%) in samples collected from the apartment of an infected person in quarantine.[29]

Many disinfectants were quickly approved by EPA authorities based on their ability to destroy other coronaviruses or viruses that are more resilient than SARS-COV-2.[30] Chlorine-based disinfectants (0.1% sodium hypochlorite), alcohol-based disinfectants (62-71% ethanol) and other pro-oxidant compounds such as hydrogen peroxide (0.5%) were shown to denature SARS-COV-2 viral particles and reduce infectivity within 1min[31].

Potential Disinfectant Risks

While the above products may be excellent for disinfecting contaminated surfaces, many of them are known to cause skin irritation. Formaldehyde and chlorine-based products should potentially be avoided as they are known to be more corrosive than other disinfectants as well as a danger to health and the environment.[32]

Disinfecting Sensitive Skin

Soap is a far gentler disinfecting agent. In prior studies from the last two decades, the quality of soap one uses determines how effective it is against bacteria and viruses. Those with chemical sensitivity or sensitive skin may benefit from employing gloves when leaving the house and using soap at home.

Inefficient Environmental Disinfectant Practices

Some countries have taken to spraying disinfectants in outdoor environments to protect the public from infection. Disinfecting the environment (i.e. pavements, highways, parks, etc) is not recommended by WHO officials as dirt and debris are known to inactivate disinfectants, lowering their efficacy against pathogens. Furthermore, it risks severe environmental pollution.

4. UV and Sun Exposure

It has long been understood that sunlight and other high-intensity light will do a lot for viral control.

In 1903, Niels Finsen won the Nobel Prize in Medicine for his work on the treatment of infectious diseases using visible light. Since the 1930’s, light-based technologies were sold to hospitals and labs in order to sterilize surfaces and equipment.

UV technology employed by hospitals is likely to contribute substantially to disinfectant measures against SARS-COV-2, given current evidence. These include blue light technology and ultraviolet radiation devices, which require special handling due to potential consequences on health. [33]

For members of the general public, sunlight is the most affordable light-based prevention option. Artificial light sources in homes may also provide a fractional degree of viral inhibition due to the spectrum emitted, however this remains to be proven.

How Effective is Sunlight Against SARS-COV-2?

Sunlight increases the ambient temperature and consists of a spectrum of UV radiation that is capable of obliterating exposed viral particles. Nevertheless, natural UV is not nearly as effective as light-based technologies and is not deemed as effective enough to use in clinical settings[34].

Only 5% of sunlight comprises of UV radiation. 95% of this radiation is UVA, which appears to have little to no effect on virions. UV-B radiation exerts a significant antiviral effect, and comprises most of the remaining 5%. [35]

Of all the radiation sunlight harbors, the smallest fraction comprising of UV-C radiation proved to be the most effective[36]. Unfortunately this type of radiation is associated with sunburn and skin cancer, being equally detrimental to our DNA as it is to viral DNA. Furthermore, it only makes up a fraction of sunlight and is largely blocked by the ozone layer.

There are numerous factors that also decrease the predictability and effectiveness of sunlight, including:

• Pollution
• Cloud cover
• Distance from the equator
• Time of day
• Season
• Non-reflective environments
• Decreases in altitude

A higher intensity or longer duration of UV radiation is required to be effective when the relative humidity is higher. Experiments reveal that virions have substantial protection when grouped together and housed inside water droplets or other biologic material[37]. The moment the water evaporates, UV-C radiation works quickly to nuke viral particles with approximate 99.99% effectiveness.[38]

In this regard, sunlight may serve to effectively destroy viral particles on warm and dry surfaces in non-polluted areas over the course of a few days. In large metropolitan areas and regions with high humidity, the effectiveness of sunlight is likely to be greatly reduced.

Photobiomodulation therapies such as ultrafast laser irradiation and infrared light treatment may also prove to be useful complementary treatment options for patients with COVID-19. In spite of being approved for promoting general health and well-being, more research is required to verify their effectiveness.

Other Potential Exposure Routes

Other routes of exposure being investigated include the following:

The Eyes

Media coverage from the initial outbreak in Wuhan warned that the virus may be contagious through the eyes as well, as even doctors wearing hazmat suits are becoming infected in hospitals.

A few findings from clinical studies suggest these observations are true:

• SARS-COV-2 is capable of replicating in the eyes, including in the cornea and conjunctiva which make up the first two layers of the eye.[39]
• A small percentage of patients with COVID develop ocular symptoms such as eye itching, redness, pain and watering.[40]
• A review of 172 studies from 16 countries highlight how wearing a face shield or protective eyewear significantly decreased COVID-19 infectivity amongst healthcare workers. According to this study, the risk of infection was three times less likely when wearing protective eyewear.
• Another large study revealed that 19% of healthcare workers got infected, despite wearing triple layered masks, gloves and shoe covers. Face shields prevented these infections when added to the equation[41].

In this context, healthcare workers may benefit from wearing protective eyewear. Nevertheless, the chances of getting infected with COVID-19 through the eyes are far less than that of the nose or mouth.

Refraining from touching one’s face may help to reduce viral transmission through the eyes, nose or mouth.

Skin and Sweat

Another route of viral transmission being investigated would be the skin and sweat. Highlights of current evidence include[42]:

• Receptors that the virus could potentially bind to and infect are known to reside in cells of the skin, sweat glands and skin pores. This implies that the virus may directly infect people through exposure to the skin, but is as of yet unconfirmed.
• COVID-19 has been found in the sweat glands of deceased COVID patients.
• Other viruses that are similar to COVID-19 have been found active in sweat glands and have shown to be potentially transmissible via sweat.
• A study including 212 COVID-19 patients revealed that more than half of those infected sweated profusely while running a fever. Many of these patients also experienced night sweats.

This suggests that infected sweat may be a route of transmission, particularly within households. Further research is required to verify whether COVID-19 may be transmissible via sweat and skin.

Human Waste

Active COVID-19 RNA has been found in many samples of patient feces, with a very low occurrence in urine samples (4.5%[43]). This implies that transmission may be possible through fecal exposure and very unlikely due to urinary exposure.

Infectivity of COVID-19 in fecal samples was varied. Some studies indicated that fecal samples held infectious material for between 17 and 31 days at 20˚C.[44]

Wastewater

Thorough analysis of an apartment of a quarantined infected person revealed the highest quantity of active viral fragments resided in the toilet bowel and sewer inlet[45]. COVID outbreaks within apartment buildings have been attributed to poor plumbing systems and a close proximity to wastewater.

Wastewater, sewage and river water has shown positive for COVID-19 in many countries around the world. Viral particles found in wastewater and contaminated river water failed to be actively infectious when tested[46]. The results may be due to the chemical treatment of waste water and/or the natural decomposition of sewage[47].

Treated water showed the least infectious viral fragments while viral load in wastewater proved to lower over time, possibly due to natural degradation.

Can COVID-19 survive in drinking water?

There have been no studies yet to prove whether SARS-COV-2 may survive in drinking water. The COVID-19 virus has as of yet not been found in non-polluted natural waters and drinking water. According to WHO assessments, the risk of infected drinking water and water supplies is very low[48].

Furthermore, most viruses in the coronavirus family, including SARS-COV-2, are hydrophobic with a lipid membrane that makes them more susceptible to oxidants like chlorine, UV exposure, soap and disinfectant.[49] This is likely to make it more difficult for the virus to be infectious in drinking, pool and bath water. More research is required to confirm this for SARS-COV-2, yet preliminary evidence supports this notion.

Conclusion

SARS-COV-2 is a rapidly mutating virus with the potential for systemic complication and fatality. The current understanding of the virus has evolved beyond a simplistic respiratory pathogen, confirming the urgent need to adhere to prevention measures.

Moisture and low temperatures can help the virus to survive for longer in the environment. Heat and intense UV radiation may inhibit viral particles, however sunlight is likely to be ineffective in most conditions.

Multiple detergents and disinfectants are able to inhibit the virus and slow its spread, as are chemicals used to treat water. Wastewater systems, drains and smooth surfaces should be paid special attention with regard to sanitation.

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