Advancing Research in COVID-19: One of Our Own

Written by Kaylee Stella Harris MBChB III and Mayuri Ramnarain MBChB IV

Figure 1⁽¹⁾

Professor Robert Millar, is one of our own! He is the Director of the Centre for Neuroendocrinology at the University of Pretoria’s Faculty of Health Sciences and was recently featured on the University of Pretoria’s Research Matters page. Prof. Millar is a highly rated academic who holds an H-index (the productivity and citation metric of a scientist) of above 70 (which is extraordinary), has published over 400 peer reviewed articles and is, amongst others, also a Research Fellow of the University of Edinburgh and an Emeritus Professor at the University of St Andrews, Scotland. He attained his Master’s degree in biology from London and his PhD on reproductive biology from Liverpool. In addition, he has been awarded many major accolades including the Harry Oppenheimer Fellowship, the John F Herschel Medal of the Royal Society of South Africa, the Kwame Nkrumah Continental Award of the African Union and the MRC South Africa Platinum Medal. In one of his most recent articles in the Journal of Neuroendocrinology, Prof Millar alongside his Italian colleagues, presented an argument about the severity of COVID-19 in male versus female patients.⁽²⁾

Prof Millar explains that there is no difference in the incidence of COVID-19 in male and females, but there is a significant difference in the severity of the cases and the mortality rate. The mortality rate for men during the first Italian epidemiological peak of COVID-19 in March 2020 was 13.3% as opposed to 7.4% in females.⁽¹⁴⁾ It is suspected that sex hormones have a role to play in the entry of the virus into the cells of the body, the inflammatory and immune response and, lastly, the thrombosis diathesis and coagulation. Furthermore, elderly males display an increased susceptibility to COVID-19 infection as they have a more severely weakened immune system and are more prone to thrombosis.^{(3, 4)}

Mechanism of increased severity

According to Prof Millar, there are two main mechanisms that lead to this difference in severity between males and females. They are, firstly, differences in the way the virus enters into the body’s cells and, secondly, the capability of the virus to replicate itself within the cells to increase its viral load to amplify the amount of damage the virus can have on the body.^{(3, 5)} There are two molecules that have an influence on this, namely ACE2 (angiotensin-converting enzyme 2) which is involved in blood pressure regulation and has been coopted by the virus for cell entry, and TMPRSS2 (transmembrane protease, serine 2).⁽²⁾ ACE2 is involved in the RAAS (renin angiotensin-aldosterone system), which is responsible for regulating blood pressure, directing inflammation and wound repair.  ACE2 is found in the lungs, kidneys, heart, blood vessels, GIT (gastrointestinal system) and liver.⁽⁶⁾ TMPRSS2 is found on the endothelial cells of the lungs and the GIT. TMPRSS2 cleaves peptide bonds of cells with serine within their active sites and is associated with other pathologies such as prostate cancer.⁽⁷⁾

The key point is that the distribution of these two molecules in the body differs between males and females. In males, an abundance is found on the cells of the lungs, blood vessels and the GIT; whereas in females the abundance is found in the pancreas and adipose tissue.⁽³⁾ COVID-19 uses its spike proteins to attach to ACE2 and uses TMPRSS2 to cleave the spike protein and the amino terminus of ACE2 to facilitate the induction of COVID-19 into the cell. Both molecules are needed for entry into the cell.⁽³⁾

Studies have shown that androgens increase the expression of these molecules, whereas oestrogen decreases the expression.⁽³⁾

Figure 2: The differences between COVID-19 infections in males and females⁽³⁾

Other factors that influence the severity

In addition to the effect of androgens on the expression of ACE2 and TMPRSS2, it is of note that male patterns of lifestyle put them at a greater disposition for contracting COVID-19 and have a detrimental influence on disease severity. These factors include smoking, alcohol consumption and  general hygiene routines. Comorbidities commonly found in men such as cardiovascular and respiratory diseases are also contributing factors.⁽⁴⁾ A US study reported that men are more likely to downplay the severity of the virus’s potential to harm them and fewer men than women have reported that they avoid large public gatherings or comply with social distancing.⁽⁸⁾

Females genetically have a more efficient immune response than males. The genes which influence the positive regulation of the innate immune system are located on the X chromosome. Females have two X chromosomes, so if a mutation occurs on one of their X chromosomes their entire innate immune system will not be implicated (because the other X chromosome provides protection). However, males have 1 X and 1 Y chromosome. Therefore, males only need one recessive harmful mutation on their X chromosome to result in the functional loss of an important part of the immune system.⁽⁴⁾

Figure 3: Chromosome differences associated with COVID-19 susceptibility⁽⁴⁾

It has been reported that men experience neutrophil infiltration into their lungs resulting in respiratory inflammatory syndrome as well as an increased production of pro-inflammatory cytokines, due to the enhanced pro-inflammatory ability of macrophages, further contributing to the aggravation of COVID-19 symptoms. This is in contrast to women who display increased phagocytic activity and increased production of interferon (IFN), which triggers an anti-viral defence resulting in a more favourable approach to combatting COVID-19.⁽⁴⁾

Figure 4: Differences in the innate and adaptive immune systems in males and females⁽⁴⁾

Conclusion

Prof. Millar and his fellow researchers suggest that it may be of interest to use short term oestrogen patches on male COVID-19 patients to induce better outcomes and increase overall survival. They note that this treatment is already used, along with androgen antagonists and androgen inhibitors, to effectively treat those suffering from prostate cancer.⁽³⁾ However, regardless of male or female sex, there are a number of lifestyle changes we all must abide by, including regular hand hygiene, the wearing of face masks and social distancing to reduce the risk of contracting COVID-19.

Use the following link to read the full article:https://www.karger.com/Article/FullText/513346

Bibliography

1. Ramesh M. COVID-19 Killing More Men Than Women – What Numbers, Studies Say [Internet]. TheQuint. 2020 [cited 2021 May 16]. Available from: https://www.thequint.com/neon/gender/why-is-coronavirus-killing-more-men-than-women
2. Riekert C. About the Director | Article | University of Pretoria [Internet]. www.up.ac.za. [cited 2021 May 16]. Available from: https://www.up.ac.za/centre-for-neuroendocrinology/article/2626228/about-the-director-
3. Millar R. COVID-19: Are men the weaker sex? | University of Pretoria [Internet]. www.up.ac.za. 2021 [cited 2021 May 16]. Available from: https://www.up.ac.za/research-matters/news/post_2968510-covid-19-are-men-the-weaker-sex-
4. Pivonello R, Auriemma RS, Pivonello C, Isidori AM, Corona G, Colao A, et al. Sex Disparities in COVID-19 Severity and Outcome: Are Men Weaker or Women Stronger? Neuroendocrinology [Internet]. 2020 Nov 26; Available from: https://www.karger.com/Article/FullText/513346#f03
5. Mandal A. Does high COVID-19 viral load mean more risk of infection? [Internet]. News-Medical.net. 2020 [cited 2021 May 16]. Available from: https://www.news-medical.ne/news/20200421/Does-high-COVID-19-viral-load-mean-more-risk-of-infection.aspx
6. Sriram K, Insel P, Loomba R. What is the ACE2 receptor, how is it connected to coronavirus and why might it be key to treating COVID-19? The experts explain [Internet]. The Conversaton. 2020. Available from: https://theconversation.com/what-is-the-ace2-receptor-how-is-it-connected-to-coronavirus-and-why-might-it-be-key-to-treating-covid-19-the-experts-explain-136928
7. Shabir O. What is TMPRSS2? [Internet]. News-Medical.net. 2020 [cited 2020 Aug 16]. Available from: https://www.news-medical.net/health/What-is-TMPRSS2.aspx
8. Griffith DM, Sharma G, Holliday CS, Enyia OK, Valliere M, Semlow AR, et al. Men and COVID-19: A Biopsychosocial Approach to Understanding Sex Differences in Mortality and Recommendations for Practice and Policy Interventions. Prev Chronic Dis 2020;17:200247.