PPEs For the Immune System to Win the COVID-19 Battle
In the absence of a vaccine, we need to boost the body’s immune system to fight against any pandemic
The history of infections and pandemics is as ancient as that of human civilisation. Since ages, viral and bacterial infectious diseases like plague, cholera, smallpox, and influenza have posed a tremendous threat to humans claiming millions of lives. We are now in 2020, and we have the novel coronavirus. But in spite of human history being replete of so many such devastating outbreaks, till today, the world is not armed and equipped appropriately to fight these battles. We are not able to defeat and overpower the ‘virus’. Is this because we are seeking cures only after the monster is out of the dungeon?
After every viral pandemic, along with public health measures to contain the viral spread, all over the globe, scientists begin working strenuously to come up with anti-viral drugs and vaccines, both of which are based on thorough understanding of the viral components.
Whereas anti-viral drugs usually block the entry of viruses or block their replication in host cells, vaccines are weakened strains of virus that boost and prepare our immune system to tackle the virus.
In comparison to bacterial diseases, viral spreads are difficult to target. The answers lie in the biology of viruses. Viruses are not made of cells, they dwell in grey areas between the living and the non-living. Intriguingly, Wendell M. Stanley from Rockefeller University who first crystallised a virus received the Nobel Prize in 1946 in chemistry and not in physiology or medicine!
Viruses take charge of their host cells in order to survive and grow, making it difficult to target them, which means, when you are attacking a virus, you are actually damaging its host. Viruses are much smaller than bacteria and hence have smaller genomes. So the number of viral genes/proteins that can be utilised as drug targets are severely limited as compared to bacteria. Viruses (especially RNA viruses like coronaviruses) also mutate much more quickly than bacteria. When COVID-19 knocked our doors, it presented itself with an altogether different biology than its previous relatives, SARS-CoV1 and MERS-CoV (which caused the pandemics in 2002-2003 and 2012) and intriguingly, till date we already have more than 800 different genome sequences of COVID-19.
Due to all reasons stated above, undoubtedly, antiviral therapeutics are tough nuts to crack, may take years for development and one antiviral drug/vaccine may not work for future viral outbreaks. We still don’t have any vaccine for SARS-CoV1. Although many people are talking about herd immunity as one of the solutions to COVID-19, it’s still a far-fetched dream and would come into existence only after we have an effective vaccine in hand.
Immune Response and COVID-19
With no vaccines in place, the need of the hour is to protect the vulnerable and to mitigate the casualties as far as possible. We need to think of solutions beyond preventive measures and lock-downs. We need to sincerely redirect our efforts to delineate and work on the other component of the viral infection, the host cells and here specifically human lung cells/tissues, the preferred dwelling site of coronaviruses.
‘Our first line of defense towards any microbe is the ‘innate immune system’.
The system is comprised of several specialised cells and proteins that are present in or on the cells to capture and defend us against the microbes. We have specific pattern recognition receptors on several lung cells to recognise patterns on different microbes including viruses. These receptors are sensors that sense and bind to viruses and then facilitate activation of downstream signalling soluble proteins to stimulate expression of antiviral defense proteins such as types I and III interferons and other pro-inflammatory cytokines that effectively help in curbing the further spread of the virus.
These initial sentinels of immunity also trigger the second and specific line of defense, termed as ‘adaptive immune system’, against the virus that in most cases eventually clears the virus from the infected cells. There are several studies that demonstrate that functional differences in innate and adaptive immune sensors and their downstream signalling components are strongly associated with variable outcomes of the disease, particularly those with heterogeneous manifestations.
Even in case of COVID-19, large variabilities in clinical outcomes have been reported. There have been critically severe infections of COVID-19 in apparently healthy subjects with no underlying disease like diabetes, heart or lung disease. Differences in immune responses may definitely be playing a determinant role in these diverse clinical responses and a dismal outcome may be a result of the malfunction of immune machinery. Now the next obvious question that comes: Are these immune differences controlled by our genes or in other words, is our immune system regulated genetically? Definitely, our immune system is not solely governed by genetics. Differential immunological responses towards microbes and vaccines in twins, aged and diseased individuals bear a testimony to the fact that the environmental cues do nurture and modulate our immune system more than the genes.
When we know that our immunity can be wilfully tempered, our future strategies to curb COVID-19 and in fact any viral pandemics should be based on enhancing the protective immune responses against a pathogen, and/or on restraining its exuberant activation or inflammation. While enhancing the protective immunity would be advantageous to fight the virus in the early phases of infection, inhibiting the excess activation of immune responses would be favourable in severe infection cases.
Due to its immune-inhibitory features, hydroxychloroquine has become the most sought after drug for the prophylaxis and treatment of COVID-19. The potential protective effects of the Bacille Calmette-Guerin (BCG) vaccine, a vaccine used against tuberculosis, may also be attributed to its non-specific immune-boosting effects. BCG vaccine is already an immunotherapeutic drug for patients with bladder cancer. However, we still need more evidence-based studies to ascertain the efficacy of both hydroxychloroquine and BCG vaccine against COVID-19.
Enhancing Lung Immunity
The COVID-19 hue and cry is far from over and an effective vaccine may take its own course. It is imperative to study immunological differences between the COVID-19 patients who recover and those who do not, to identify and investigate novel immune-signatures which can be then utilized to design new therapies, especially for critically ill patients. As most of these immune pathways are already discerned, along with searching for newer drugs and vaccines, scientists are also involved in repurposing of already approved drugs and initiate efficacy studies of these drugs with suitable animal models and then patients with COVID-19 and other viral infections.
Undoubtedly, repurposing of old drugs (with established safety) is far less expensive with shorter development timelines than testing the newer drugs.
Besides drugs and small molecules, cell-based therapies which are already known to contribute towards the repair of lung tissues should also be experimented with.
Although, a healthy diet and regular light exercise, are enough to maintain an immunological homeostasis, food supplements such as vitamin B3 and herbal medicines which have proven roles in preventing lung tissue damage and fortify our immune system may be investigated as another choice for enhancing lung immunity.
A crucial point to ponder here is that the above approaches are not virus-specific and can be applied to a spectrum of viral and bacterial infections. For developing these treatments, we do not need a complete understanding of the virus itself but viral-specific immune responses in general. Such strategies can be investigated with consistent and concerted research efforts and programs well before we are inflicted with catastrophic viral outbreaks and pandemics. These immune-modulating drugs can be used as sole or and as adjunctive therapies in combination with more selective viral vaccines and drugs and most importantly they can serve to reduce infection-induced mortalities. Another advantage of using these therapies is that whereas the use of anti-viral or anti-bacterial drugs may create drug-resistant strains, these therapies would not lead to more mutated versions.
As an old saying goes: ‘An inefficient virus kills its host while a clever virus stays with it’. And COVID-19 is definitely not a fool, it is here to exist, rather co-exist with its host. This may also be gauged by the fact that most of the patients inflicted with viral infections including COVID-19 are asymptomatic or mildly symptomatic. What seems inefficient and hence requires some tweaking is the host’s immune system. So, along with the expansion of personal protective equipment for our frontline workers, there is a dire need to develop a suitable protective armour for our patients’ so that they can confront any foreign invader today or in the years to come.
(Dr Savneet Kaur is the assistant professor and principal investigator, Liver Physiology Lab, Scientist-in-charge, Animal House Facility, Department of Molecular and Cellular Medicine at Institute of Liver and Biliary Sciences (ILBS))
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