The coronavirus tightrope

May 10, 2020 0 By FM

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) is a virus that has spiralled the world as we know it into a frenzy with inexplicable consequences. The 2019 SARS-CoV 2 outbreak is reported to have originated from Huanan Wet Seafood Market in the Hubei province of China. It is speculated that SARS-CoV 2 was transmitted to humans from bats with pangolins acting as intermediary hosts. Coronaviruses are known to cause persistent virus infections in bats, where they alternate between cycles of active virus production and dormancy. The latter acts as a mechanism to avoid detection by the bat immune system, whilst the former causes immune responses against the virus. Such responses include the production of reactive oxygen species, which, in turn, cause mutations of the genetic material of SARS-CoV 2. This virus-host interaction generates quasi-species pools of the virus possessing advantageous mutations, which includes the potential to infect other species like humans.

Transmission of SARS-CoV 2 from humans to humans is thought to be through direct contact or through respiratory droplets transmitted from infected individuals. It enters into the respiratory tract and lungs through the mucosal membranes of the nasal passage and larynx. SARS-CoV 2 recognises and targets specific types of host cells, with the aid of a viral protein, SPIKE. It targets an enzyme on human cells, namely angiotensin converting enzyme 2 (ACE 2), which is expressed primarily in lung tissue, kidney and the gastrointestinal (GI) tract. ACE 2 is an important enzyme whose function is to regulate blood pressure and protect the host from worsening of lung injury.

Inflammatory influx 

Onset of symptoms take place 5-6 days after infection, but studies have reported incubation periods varying from 14-30 days in some individuals. Mild cold and flu-like symptoms have been widely reported, whilst severe disease can lead to shock, organ failure, and death.

Infected individuals recover when their immune system elicits a strong and appropriate immune response during the initial stage of infection. Observations suggest that this mainly occurs under the setting of good general health in the absence of underlying diseases and in the presence of an appropriate genetic background.

Severe disease and fatality as a result of SARS-CoV 2 infection results from an imbalance of the immunological tightrope between a protective immune response and a dysregulated inflammatory response. The former induces protective anti-viral immunity, whilst the latter leads to cell death and tissue damage. The latter occurs when there is uncontrolled viral replication, a delay in the production of immune response modulators, an increased infiltration of inflammatory cells, and an increased influx of inflammatory mediators. High levels of ACE 2 expression are found in the lungs, which indicates that the respiratory tract is a major site of viral attack. The underlying pathology is the development of pneumonia. Oxygen transfer is impeded due to an influx of inflammatory mediators and cells. This contributes to the clinical presentation of coughing, fever and shallow breathing. Some patients are able to recover from this stage with the aid of oxygen therapy, whilst others struggle. It is an immunological cascade of events that results in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).

Deep penetration

SARS-CoV 2 may also strike the cardiovascular system. It is hypothesised that the virus attacks blood vessels and cardiac muscle leading to pulmonary embolism and stroke. Studies suggest there are other targets of the cardiovascular system, which are yet to be identified. This is of importance in cases of patients suffering from underlying morbidity, as they are considered to be more vulnerable to such a targeted attack. 

The kidney is another target of SARS-CoV 2, because of the high expression of ACE 2. Patients suffering from kidney failure are more susceptible to acute kidney injury (AKI) as a result of the infection. Other SARS-CoV 2 targets include the central nervous system (CNS) and the GI tract, which suggests the virus has penetrative power into the CNS and may be transmitted via the oral-faecal route.

These observations suggest the need for therapeutic interventions that are administered in a two-step process: Initially boosting the natural immune response in patients who are undergoing mild infection, followed by the administration of a therapeutic modulator of inflammatory response in patients with severe infection.

Besides the present scientific literature available on SARS-CoV 2, several disconcerting questions have been raised. Reappearance of the virus in individuals who have recovered suggests that the immune response may not be complete or the virus is able to remain hidden, evade detection and reactivate later on. Additionally, the presence of mutant viral strains with differing virulence poses a huge challenge to vaccine development and the goal to achieve herd immunity. There is also a need to introduce genome-wide studies to address whether a predisposition to severe forms of the disease exists in different populations. Collectively, these research conundrums indicate the challenges to vaccine design and therapeutic interventions against SARS-CoV 2.