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Thanks very much to Melisa Eraslan for submitting her MIMM 214 assignment to post on The Turret. This guest post will explain why older people are more vulnerable to COVID-19.

We are currently facing one of the biggest pandemics seen in history: coronavirus disease (COVID-19), an infectious disease caused by the coronavirus named SARS-CoV-2. Thus far, it has afflicted over 100 million people worldwide and taken the life of 2 million. (1) There is a vast heterogeneity in COVID-19 disease severity; the spectrum of infection ranges from mild to fatal outcomes. Amid various risk factors for severe infection, age is the largest one; older adults (aged above 60 years) are disproportionately afflicted, with the highest number of infections, complications, hospitalizations and deaths. (2) Although research is still underway, scientists have unveiled certain reasons why this age group is particularly vulnerable to COVID-19.

The heightened COVID-19 risk in the elderly is multifactorial. One contributing factor involves enhanced exposure to the coronavirus because of increased shedding from infected cells into the environment, atypical disease manifestation, and difficulty quarantining. (3) Moreover, increased frailty due to preexisting conditions (comorbidities) and the decline in organs’ physiological capabilities, also increase elders’ susceptibility to the virus. (4) Equally important, as age advances, the immune system weakens, which is called “immunosenescence.” (3)

The human immune system is composed of many cells, molecules, tissues and organs. Under normal circumstances, our immune system orchestrates a complex response, referred to as inflammation, which protects us of harm from small disease-causing infectious agents referred to as germs or pathogens. The immune system is separated into the innate immune system, our body’s first line of defense, and the adaptive immune system, our second-line force of acquired immunity against specific pathogens. Pathogens – namely, viruses – gain a foothold in humans by evading our built-in immune mechanisms to cause disease.

When encountered with a virus, innate immune cells secrete messenger molecules called type 1 interferons, which are warning signals prompting protective antiviral activity. (5) In older patients, SARS-CoV-2 is particularly stealthy in its strategy in bypassing our innate immune defenses, specifically, the triggering of these warning signals, which results in a delay in the innate immune response. (6) Furthermore, with aging comes chronic inflammation, referred to as “inflammaging.” (3) This is a baseline continual production of messenger molecules promoting inflammation (such as IL-6 and TNF-α). Although inflammation normally protects us, when triggered without appropriate stimulation from pathogens, or when overstimulated, it can be detrimental. Inflammaging compounded with the coronavirus can cause the aged innate immune response to flare out of control, exacerbating COVID-19’s impact on the elderly. (7)

On the other hand, the adaptive immune system surges into the battle field soon after the innate response. The adaptive system’s main fighters are T and B cells: immune cells specialized in defending against specific pathogens upon their activation. T and B cells are able to respond to new pathogens by directly and indirectly killing infected cells, and by secreting germ-neutralizing proteins called antibodies.  Prior to their activation, these cells exist as “naïve” cells, not yet programmed to fight, but eagerly waiting to. In a recent study, Moderbacher et al. shows that this quantity of “naïve” T cells in our body dwindles with age, leaving elders depleted of T cells able to fight against new pathogens. (8) Fewer soldier cells dealing with never-before seen attackers, such as the coronavirus, increases disease severity in older adults.

Research continues unabated as scientists scramble to elucidate the full story behind COVID-19’s lethality for the elderly. What we do know is that the weakened and dysfunctional immune system in elders is a key part of the story, since it responds to the virus inadequately. On the bright side, the advent of COVID-19 vaccines is encouraging news for populations at risk, as vaccination is able to boost the weakened aging immune system. Needless to say, it is vital to follow pandemic regulations to protect our vulnerable populations from this disastrous virus.

References

1. BBC News. Covid map: Coronavirus cases, deaths, vaccinations by country [Internet]. London ENG: BBC News; 2021 [updated 2021 Feb 6; cited 2021 Feb 7]. Available from:  www.bbc.com/news/world-51235105

2. Ottawa Public Health. Older Adults & COVID-19 [Internet]. Ottawa CAN: Ottawa Public Health; 2021 [updated 2021 Feb 5; cited 2021 Feb 7]. Available from: www.ottawapublichealth.ca/en/public-health-topics/Older_Adults_and_COVID-19.aspx

3. Smorenberg AN, Peters ED, Daele PA, Nossent ES, Muller MA. How does SARS-CoV-2 target the elderly patients? A review on potential mechanisms increasing disease severity. Eur. J. Intern. Med. [Internet]. 2020 Nov 30 [cited 2021 Feb 6]; 83(1):1-2. Available from: doi.org/10.1016/j.ejim.2020.11.024

4. Begley SH. What explains Covid-19’s lethality for the elderly? Scientists look to ‘twilight’ of the immune system [Internet]. STAT News; 2020 Mar 30 [updated 2020 Apr 1; cited 2021 Feb 7]. Available from: www.statnews.com/2020/03/30/what-explains-coronavirus-lethality-for-elderly/

5. Murphy KE, Weaver, C. Janeway’s Immunobiology. 9th edition. Washington: WW Norton & Co; 2016 Jun 13.

6. Sette AL, Crotty SH. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell [Internet]. 2021 [cited 2021 Feb 6];1(6):10-11. Available from: doi.org/10.1016/j.cell.2021.01.007

7. Nidadavolu LO, Walston JE. Underlying Vulnerabilities to the Cytokine Storm and Adverse COVID-19 Outcomes in the Aging Immune System. J. Gerontol. [Internet]. 2020 Aug 25 [cites 2021 Feb 5];1(209): 2-4. Available from: doi.org/10.1093/gerona/glaa209

8. Moderbacher CA, Ramirez SY, Dan JE, Grifoni AL, Hastie KA, Weiskopf, Belanger SI. Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity. ScienceDirect [Internet]. 2020 Nov 12 [cited 2021 Feb 6];183(4):996-1012 Available from: doi.org/10.1016/j.cell.2020.09.038

Thank you very much to Cyril Kazan for letting us post his MIMM 214 assignment on The Turret. In this post, Cyril talks about an interesting aspect of our immune system.

Memory is an essential element of everyday life. Without it, learning would not be possible. Similarly, when it comes to your immune system, memory is priceless. Vaccines, for instance,would never work without your immunological memory. After being exposed to a pathogen, which is a term used to describe infectious agents like bacteria and viruses, your immune system will remember it. This way, the next time it encounters this same pathogen, it will eliminate it much faster. This concept, termed adaptive memory, has been well understood for decades. It is associated exclusively to a part of your immune system called adaptive immunity. The other part, innate immunity, has always been known to be non-specific and non-adaptive, meaning that it cannot remember a pathogen and will have the exact same response if it re-encounters it in the future.

Recently, a growing body of research is challenging what has always been thought of as true. Greater protection against re-infection has been reported in plants and invertebrates, which lack an adaptive immune system. Furthermore, certain infections and vaccinations can induce broad protection against other pathogens through innate immune mechanisms. This has led researchers to hypothesize the presence of an innate immune memory they coined “trained immunity”. In a review paper published in Nature, scientists explain what has recently been discovered about this intriguing mechanism.

How Trained Immunity Works
Unlike adaptive memory, which works by keeping a reserve of memory cells specific to the pathogen previously encountered; trained immunity is thought to function through epigenetic reprogramming, which is a change in the expression levels of genes. Adaptive memory and trained immunity are therefore fundamentally different mechanisms.

During a typical immune response, genes coding for proteins called cytokines are expressed. These proteins play a broad range of key roles in the immune response including inflammation and recruitment of immune cells. Research findings have shown that the expression of these genes leaves behind an “epigenetic scar”. This leads to an easier expression of these genes on the following infection, resulting in a greater and faster production of cytokines on the next contact with a pathogen, and to a more efficient immune response overall. Notice that it will lead to a more ample production of cytokines regardless of the identity of the pathogen. Trained immunity is therefore non-specific.

But it is not so simple. A reprogramming of the cell’s metabolism, the series of biochemical reactions occurring inside of it, also takes place and affects how efficiently cytokine genes will be expressed. It is also important to keep in mind that these are relatively recent discoveries and that the exact mechanism behind trained immunity is not yet fully understood.

Why It’s Important
Armed with this fair understanding of how trained immunity works, you may now be wondering why you should care. First of all, trained immunity plays a critical role in humans. Interestingly, more and more evidence is showing that live vaccines such as the smallpox vaccine, measles vaccine, and the BCG vaccine for tuberculosis, which normally provide specific immunity through adaptive immune cells actually have a broad beneficial effect against infection by other pathogens as well.

This occurs through non-specific activation of innate immune mechanisms. In addition, although trained immunity has evolved as a beneficial mechanism that makes our response to pathogens more effective, studies are pointing out the potential harmful effects it can have. These effects have been especially observed in the context of sterile inflammation, inflammation that does not result from a pathogen, but from food for example. It is becoming increasingly evident that sterile inflammation, boosted by trained immunity, in response to diet and lifestyle changes, forms the basis on which chronic inflammatory diseases develop. These augmented immune functions can lead to tissue damage in some instances.

Last but certainly not least, trained immunity can be critically important in the context of the interplay between innate immune cells and tumour cells. It can be either beneficial or detrimental. A stronger and more efficient innate immune response is helpful in the fight against cancer cells. Nonetheless, excessive or prolonged inflammatory responses can also contribute to the progression of the tumour. For instance, an increased cytokine release by innate immune cells that infiltrated the micro-environment of the tumour is associated with an enhanced growth of the tumour and its spread to other parts of the body.

References
Mihai G. Netea et al.. Defining trained immunity and its role in health and disease. Nature Reviews Immunology [Internet]. 2020 March 04. Available from: https://www.nature.com/articles/s41577-020-0285-6

Janeway CA Jr, Travers P, Walport M, et al. Immunological Memory. Immunobiology: the immune system in health and disease, 5th edition. [Internet]. New York, 2001. 10-21;10-24. Available from: https://www.ncbi.nlm.nih.gov/books/NBK27158/

Molnar C, Gair J. Adaptive Immune Response. Concepts of Biology, 1st Canadian Edition [Internet]. 2012. 23.2. Available from: https://opentextbc.ca/biology/chapter/23-2-adaptive-immune-response/University of Pennsylvania.

By altering bone marrow, ‘training’ can prepare innate immune system for future challenges. Science Daily [Internet]. 2018 January 11. Available from:
https://www.sciencedaily.com/releases/2018/01/180111141646.htm

Namrata Rana. Trained immunity: the immunologic memory that humans have always had. The McGill Tribune [Internet]. 2021 January 26. Available from: http://www.mcgilltribune.com/sci-tech/trained-immunity-the-immunologic-memory-that-humans-have-always-had-01262021/