Which of the following is a similarity between the central nervous system and the immune system?

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The emergence of new pathogens in humans, that originated in animals, has been a disturbing trend. Disruption in wildlife habitat and changes in human behaviour are significant contributors to pathogens crossing the species barrier, with globalization an accelerant. Disease-causing microorganisms, that once infected only animals, have enhanced their infective repertoire to accommodate humans.

The 2019 SARS-CoV-2 outbreak is reported to have originated in a wet animal market, reliant on poaching and the trafficking and trade of wildlife. The demand for wild animals, which are used as exotic foods and in traditional forms of medicine spurs trade in wildlife. Within these markets live animals and humans come in close contact. Such situations can create a breeding ground for zoonotic viruses to jump from animals to humans through mutations.

The consensus among scientists is that SARS-CoV-2 was transmitted from bats to humans, with pangolins acting as the link. This however is not a simple process. Coronaviruses interchange between cycles of active virus production and inactive quiescence during persistent virus infections in bats. The latter acts as a means to avoid detection by the bat immune system, whilst the former trig-gers immune responses against the virus. Such responses include the production of reactive oxygen species, such as superoxide and hydrogen peroxide, which, in turn induce mutations in the SARS-CoV-2 genome. This virus-host interaction generates quasi-species pools of virus, with adaptive potential, including the ability to infect humans.

Despite there being regulations overseeing international wildlife trade, sceptics argue that CITES (Convention on International Trade in Endangered Species of Wild Flora and Fauna) is simply an agreement between nations and call instead for a complete ban on illegal trade of wildlife. There was a failure to heed the warnings of the emergence and spread of influenza and coronaviruses more than a decade ago, particularly during the 2009 H1N1 swine flu pandemic and during the SARS-CoV and MERS-CoV outbreaks of 2002 and 2012. Many bodies have been calling for a ban on wildlife trade ever since.

Dangerous liaisons

Viruses are thrifty organisms; they possess only two major biological molecules, protein and nucleic acids, and yet can do enormous harm. The proteins carry out the processes of infecting cells and diverting the cell’s resources to its own requirements, while the genetic material replicates, producing more virus particles. SARS-CoV-2 possesses a large RNA genome, which shares significant similarity with that of SARS-CoV. This explains the similarity between the two viruses in infection pattern and their disease outcome in humans.

Transmission of SARS-CoV-2 from humans to humans is through direct contact or through respiratory droplets transmitted from infected individuals. SARS-CoV-2 enters into the respiratory tract and lungs through the mucosal membranes of the nasal passage and larynx. It is not yet clear whether it can be transmitted through the oral-faecal route, and uncertainty remains over its infectious potential on inanimate objects.

Target practice

Viruses possess specific proteins, such as the spike protein in the case of SARS-CoV-2, that recognize and target specific types of host cells, thereby helping viral entry into the cell. SARS-CoV-2 targets a protein on human cells, namely angiotensin converting enzyme 2 (ACE2). It is expressed primarily in lung tissue, kidneys and the gastrointestinal tract. The function of this important enzyme whose function is to regulate blood pressure and protect the host from worsening of lung injury. On entry into the cell, the virus is able to hijack the host cell’s machinery for its own needs.

Despite the unknowns around this novel coronavirus, scientists and clinicians have elucidated three stages of the SARS-CoV-2 infection cycle: the asymptomatic stage with detectable or undetectable viral loads, non-severe symptomatic stage with detectable viral load, and severe disease with high viral load. Onset of symptoms takes place five to six days after infection, but studies have reported incubation periods varying from 14-30 days in some individuals. Symptoms range from mild fever, sore throat, cough, myalgia, fatigue, lymphocytopenia and radiographic signs of pneumonia. Mild cold and flu-like symptoms, along with reports of afebrile cases, had initially pointed at a broader spectrum of causative agents, such as dengue infection. This in turn, had delayed diagnoses in the early days of the pandemic. However, when the severe disease stage emerged, the fine line between ‘flu-like’ and severe became unclear. Severe disease can lead to shock, acute respiratory distress syndrome, acute cardiac injury, acute kidney injury, and death.

Fighting back

Infected people recover when their immune system elicits a directed and durable response during the first two stages of SARS-CoV-2 infection. It is hypothesized that this protective anti-viral immunity mainly occurs under the setting of overall good health, in the absence of underlying diseases, and in the presence of an appropriate genetic background.

SARS-CoV-2 infection results in severe disease and fatality when there is an imbalance in the immune response: a tug of war between a protective immune response and a dysregulated inflammatory response ensues. The former induces protective anti-viral immunity, while a dysregulated inflammatory response leads to cell death and tissue damage.

Such an inflammatory response occurs when there is uncontrolled viral replication, a delay in the production of immunomodulators, an increased infiltration of neutrophils, and an increased influx of pro-inflammatory mediators. The respiratory tract is a major site of viral attack and this is supported by the observation of high ACE2 expression in the lungs. Oxygen transfer between the tiny air sacs (alveoli) and the capillaries that line the alveoli is impeded due to an influx of inflammatory mediators and cells.

This results in the formation of dead cells along with pus, which contributes to the clinical presentation of coughing, fever and shallow breathing, leading to pneumonia. Oxygen therapy alleviates symptoms for some patients, who are able to recover, while others struggle, a fall in blood pressure ensues, vascular leakage occurs, blood clots form, and organ failure sets in. This immunological cascade of events results in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Ultimately, pulmonary infiltration of inflammatory cells and mediators is the major cause of fatality in severe SARS-CoV-2 infections.SARS-CoV-2 may also be striking the cardiovascular system: there have been reports of heart attacks and ischemia (blood vessel constriction) in fingers and toes.

It is suggested that the virus attacks blood vessels and cardiac muscle, with reports identifying blood clots lodged in the lungs and brain. This leads to pulmonary embolism and stroke, respectively, which have been one of the major causes of morbidity in critical patients. It is thought that there are other targets on the cardiovascular system, which are yet to be identified. This is of importance in the case of patients suffering from hypertension, diabetes, and chronic lung disease, as they are considered to be more vulnerable to such attack.

The kidney is another target of SARS-CoV-2, where there is a high expression of ACE2. Patients suffering from kidney failure are more susceptible to acute kidney injury (AKI) as a result of infection.

Another worrying target is the central nervous system (CNS); some patients have reported loss of smell and developed strokes or seizures. These symptoms suggest the virus has penetrative power into the brain and spinal cord or these symptoms manifest as a result of the dysregulated immune response. A combination of both would most likely be the case as SARS-CoV was able to enter the CNS and cause encephalitis.

Patients have also reported diarrhoea, vomiting and abdominal pain, which was most often diagnosed as a stomach bug, but when coughing was also reported, SARS-CoV-2 was found to be the culprit. Endoscopic images show that gastrointestinal tract injury occurs as a result of viral replication. This does pose the question of oral-faecal route of transmission, but studies have not confirmed this.

Hospitalized patients have also reported conjunctivitis of the eye and have been observed to suffer liver damage, the latter is most likely due to an overworked immune system and the effect of xenobiotic administration during the course of treatment.

These observations suggest the need for therapeutic interventions for varying effects. Initially, administration of an agent that can boost the natural host immune response in patients who are undergoing mild infections, and in patients with severe infection, the administration of a therapeutic modulator of host inflammatory responses.

The conundrums

An alarming observation is the presence of the virus in patients who have recovered from SARS-CoV-2. This reappearance of the virus suggests that the host immune response may be partial or the virus has found a mechanism to remain hidden and escape detection, possibly reactivating later on.

Another difficulty in combating SARS-CoV-2 is the presence of viral mutant strains. Several lines of thought have delved into the possibility of multiple SARS-CoV-2 strains in circulation, this suggests that the viral genome may be unstable and may diversify to infect different populations or it may alter its virulence.

Owing to a contrast in the incidence of disease in different regions of the world, a predisposition to severe forms of disease or an inherent resistance to virulent forms have also been taken into consideration. Genome-wide studies are indicative of this, but require a deeper understanding. This could lead to the development of targeted vaccines to specific groups of individuals. Collectively, these anomalies point to the challenges to vaccine design and therapeutic interventions.

Tackled to the ground

Prevention is the only response in the current situation. Physical distancing, the approach used by public health agencies, is highly relevant considering that airborne transmission, i.e. transmission of the virus while talking or breathing, has not been completely ruled out and the infectious dose has not been deter-mined. Researchers suggest increased ventilation indoors and reduced recirculation of air can keep the virus at bay. Use of masks is discouraged in some countries owing to increased demand in healthcare settings, while some countries believe their use adds an extra layer of protection. Encouragement of proper personal hygiene and respiratory etiquette is the dominant approach currently in play.

A strategy several European countries have set out to implement is the phenomenon of herd immunity, a concept that suggests that if a significant proportion of the population is immunized with a specific pathogen, for instance, by a vaccine, then the remaining unvaccinated individuals are unlikely to become infected, owing to a decrease in the spread of the disease. Proponents of herd immunity are relying on natural immunity to kick in and provide an indirect blanket of immunity to the rest of the population. Considering the enormity of the unknown facts about this virus, it is a huge gamble.

The last few months have forcefully stifled society and halted the consumption of the fruits of globalization. There is uncertainty about what lies ahead, but this period serves as a time for introspection and evaluation. Despite advances in science, technology and medicine, we are in uncharted territory.

[Nature India Special Issue: COVID-19 Crisis]

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