Why do we respond differently to the same virus infection?

By Yuchen Lin

No one is the same. This is not only true for our appearance and personalities but also for some invisible traits involving genetics. When confronting the same virus infection, such as SARS-CoV-2, different people respond with different symptoms. Lots of people show no or mild symptoms after infection, while others have severe reactions like a continuous high temperature and loss of the sense of smell or taste. Hence, what causes such different reactions among people?

SARS-CoV-2, an enveloped positive-sense single-stranded RNA virus with a large ~30kb genome, spreads broadly from avian and mammalian hosts to humans. Its high transmissibility made it a global concern and the pandemic it has caused is still a problem nearly two years. Multiple variants have emerged worldwide, some of which are virulent and became dominant this year. Before November 2021, more than 246 million cases and 5 million deaths had been detected.1  Although it is still not exactly clear why some people are asymptomatic whereas others develop life-threatening illness upon infection, the main reason is highly likely to be the uniqueness of each individual’s immune system.

After being infected by SARS-CoV-2 virus, there is an incubation period in which the symptoms do not appear and this can last up to 14 days. An individual’s immune system is critical for determining the path of the virus infection process. There are two lines of defence mechanisms. Physical barriers and innate immune systems are the first strategies utilized by our body. Our skin and mucous membranes such as the internal lining of the nose and throat block certain levels of viruses. Cell components of the innate immune system, including macrophages and Toll-like receptors, recognize molecules expressed by pathogens and lead to a cascade of proteolytic enzymes to promote inflammation and cytotoxicity. The membrane attack complex starts killing the invading virus. However, the recognition ability of everyone’s innate immune system varies, so not all can detect the invasion and kill a part of the viral load. A greater innate immune response enables individuals to have fewer viral particles inside the body, allowing quicker clearance. The adaptive immune system is the second line of defence. It requires a longer time to initiate and is primed by innate immune system mechanisms for ultimately clearing viruses. Once the system is established, lymphocytes with receptors that recognize the virus bind to the antigen, triggering the production of effector cells to terminate infection through efficient activation and production of B cells. Some individuals generate adaptive immune responses earlier, recognizing the antigens and fighting against them during the incubation period rapidly. Therefore, a strong immune response during the incubation period might prevent infection from taking place or reduce the quantity and power of the virus. In contrast, others with a weaker immune system are not able to start adaptive immune response early enough, resulting in symptom development.

The amounts of virus that survive and enter infection sites, such as down the respiratory tract into lungs in the case of SARS-CoV-2, are also important in determining the symptoms and the level of sickness. When the virus binds to the ACE2 receptor and starts viral replication, the immune system keeps producing effector cells to kill them. ACE2 receptor is critical in regulating immune response and the level of inflammation. If some individuals have fewer ACE2 receptors, they could have higher risk of severe infection. Larger numbers of viral replications cause the infected linings to produce higher amounts of fluid that fill air sacs. Therefore, the person will have the symptoms of pneumonia including cough, shortness of breath, and fever because the space for transferring O2 into the bloodstream and removing CO2 is reduced or blocked.

Sometimes people with prolonged or overactive immune responses also have serious illness as the cytokine storm is present. Huge amounts of cytokines, proteins that send signals to cellular components of the immune system, are produced to direct immune reactions. They induce excessive inflammation, leading to organ failure which is fatal. Younger people tend to have lighter symptoms while elder people have mild illness. This is largely because younger people, including teenagers and children, have a more active immune system and faster immune response. Some older people may even lack some ACE2 receptors, leading to a higher risk of cytokine storm and intense symptoms. Health conditions are also essential in a person’s ability to generate an appropriate amount of immune response. People with defective immune systems are not able to mount either innate or adaptive immune responses. In this case, they become more vulnerable to virus infection. Meanwhile, people that have previously been infected with other coronaviruses and are infected by SARS-CoV-2 again, are more likely to develop acute respiratory distress syndrome and fluid build-up in their lungs, causing breathing difficulty. Although their immune systems might be able to recognize and defend against the specific antigens, the battle between immune systems and viruses still causes fluid to accumulate and severe reactions to develop.

The genetic variation in HLA type, specifically the major histocompatibility complex (MHC) class I, affects individual susceptibility to the infection and the severity of the symptoms. Researchers have identified the HLA-B*46:01 allele to have the fewest predicted binding peptides for SARS-CoV-2 through in sillico analysis of all viral peptide and MHC class I binding affinity across HLA-A, HLA-B, and HLA-C genotypes.2 Therefore, people having this allele might be more vulnerable to the infection. It was also showed that HLA-B*15:03 has the greatest capacity to present viral peptides that are highly conserved among several coronaviruses. Thus, it might allow high protective T-cell based immunity, and people with this allele have a higher chance to be asymptomatic. Meanwhile, new variants with different genomes change their peptide-binding preference. A single mutation from the wildtype SARS-CoV-2 sequence alters viral peptide binding from MHC class I to MHC class II alleles.3 The selective pressure causes viruses to switch their binding and manipulate the quality of host immune responses.

Evolutionarily conserved sex differences occur in both innate and adaptive immune responses. Some differences last throughout life while others occurred after puberty, so genetic and hormonal reasons are involved. This leads to different susceptibilities to infections and responses to vaccinations. Acute HIV infections in females express 40% less viral RNA in blood, and 80% of autoimmune diseases are found in females. Males tend to have 2-fold lower antibody responses to seasonal influenza vaccines.4 Generally, there are stronger innate and adaptive immune responses in adult females, giving them faster virus clearance ability, lighter infection symptoms, and higher vaccine efficacy than males. However, this makes females more likely to suffer from inflammation caused by the immune system overreacting and autoimmune diseases.

Ethnicity alters individual responses to the same virus infection as well. UK statistics showed a disproportional death rate among African Americans in SARS-CoV-2 infection, which is ~2.6 times higher than other ethnic groups.5 The reason might be that the peripheral blood lymphocyte counts contain lower neutrophil counts and higher frequency of lymphocytes in African Americans compared to other groups. As a result, their immune responses are weaker in fighting against the infection. In some other infections and diseases, African Americans showed stronger immune responses. An example is bacterial infection with Salmonella, for which this group had higher expression of genes associated with inflammation than others, indicating a better ability at eliminating the bacterial invaders.6

In conclusion, with the same virus infection, HLA types, sex, ethnicity, power of the immune system, and pre-existing health conditions are all accountable for the symptoms that different individuals present. We cannot decide many of the factors, but we could improve our cellular immune defence by developing a healthier lifestyle. Give yourself some time to relax and exercise, you may find yourself stronger when facing viral infection.

References:

  1. COVID-19 pandemic cases, (2021) Wikipedia, The Free Encyclopedia. https://en.wikipedia.org/w/index.php?title=COVID-19_pandemic_cases&oldid=1052941692 [Accessed: 1st Nov 2021]
  2. Nguyen, A. et al., (2020) Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2. J Virol. 94(13):e00510-20. https://doi.org/10.1128/JVI.00510-20.
  3. De Sousa, E. et al., (2020) Mortality in COVID-19 disease patients correlating the association of major histocompatibility complex (MHC) with severe acute respiratory syndrome 2 (SARS-CoV-2) variants. Int J Infect Dis. 98: 454–459. https://doi.org/10.1016/j.ijid.2020.07.016 
  4. Klein, S.L. & Flanagan, K.L (2016) Sex differences in immune responses. Nat Rev Immunol. 16,626-638. https://doi.org/10.1038/nri.2016.90
  5. Khunti K. et al., (2020) Is ethnicity linked to incidence or outcomes of Covid-19? BMJ. 369:m1548. https://doi.org/10.1136/bmj.m1548 
  6. Eckwahl M., (2018) Evolution of the human immune response: Why infectious diseases affect us differently? UChicago Medicine. https://voices.uchicago.edu/dfiwellnews/2018/09/12/evolution-of-the-human-immune-response/ [Accessed: 31st Oct 2021]

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