COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-Chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males?

Abstract

In December 2019, a novel severe acute respiratory syndrome (SARS) from a new coronavirus (SARS-CoV-2) was recognized in the city of Wuhan, China. Rapidly, it became an epidemic in China and has now spread throughout the world reaching pandemic proportions. High mortality rates characterize SARS-CoV-2 disease (COVID-19), which mainly affects the elderly, causing unrestrained cytokines-storm and subsequent pulmonary shutdown, also suspected micro thromboembolism events. At the present time, no specific and dedicated treatments, nor approved vaccines, are available, though very promising data come from the use of anti-inflammatory, anti-malaria, and anti-coagulant drugs. In addition, it seems that males are more susceptible to SARS-CoV-2 than females, with males 65% more likely to die from the infection than females. Data from the World Health Organization (WHO) and Chinese scientists show that of all cases about 1.7% of women who contract the virus will die compared with 2.8% of men, and data from Hong Kong hospitals state that 32% of male and 15% of female COVID-19 patients required intensive care or died. On the other hand, the long-term fallout of coronavirus may be worse for women than for men due to social and psychosocial reasons. Regardless of sex- or gender-biased data obtained from WHO and those gathered from sometimes controversial scientific journals, some central points should be considered. Firstly, SARS-CoV-2 has a strong interaction with the human ACE2 receptor, which plays an essential role in cell entry together with transmembrane serine protease 2 (TMPRSS2); it is interesting to note that the ACE2 gene lays on the X-chromosome, thus allowing females to be potentially heterozygous and differently assorted compared to men who are definitely hemizygous. Secondly, the higher ACE2 expression rate in females, though controversial, might ascribe them the worst prognosis, in contrast with worldwide epidemiological data. Finally, several genes involved in inflammation are located on the X-chromosome, which also contains high number of immune-related genes responsible for innate and adaptive immune responses to infection. Other genes, out from the RAS-pathway, might directly or indirectly impact on the ACE1/ACE2 balance by influencing its main actors (e.g., ABO locus, SRY, SOX3, ADAM17). Unexpectedly, the higher levels of ACE2 or ACE1/ACE2 rebalancing might improve the outcome of COVID-19 in both sexes by reducing inflammation, thrombosis, and death. Moreover, X-heterozygous females might also activate a mosaic advantage and show more pronounced sex-related differences resulting in a sex dimorphism, further favoring them in counteracting the progression of the SARS-CoV-2 infection.

Assessment of the potential role of PM2.5/PM10 particles in intensifying the pandemic spread of SARS-CoV-2/COVID-19 in Northern Italy

“…In the present paper we report a statistical analysis correlating SARS-CoV-2/COVID-19 epidemiologic parameters to PM10 particle concentration measurements. In a recent paper by Borro et al (2020), the variability of the infection rate, the mortality rate and the case fatality rate as a function of particle concentration was estimated for PM2.5 particles only, recognizing a primary role of these smaller particles in inducing an over-expression of the angiotensin conversion enzyme 2 (ACE-2) in the human respiratory system (among others, see papers by Gemmati et al, 2020;Devaux et al, 2020;Bunyavanich et al, 2020;Leung et al, 2020), and consequently in enhancing COVID-19 epidemiologic impact. In the present paper we extend the analysis to PM10 particles.…”

“…More speci cally, atmospheric aerosols were demonstrated to play an important role in triggering pro-in ammation and oxidation processes in the lungs. Prolonged exposure to PM2.5/PM10 has been found to induce acute respiratory in ammation and immunological alterations (among others, Gemmati et al, 2020;Leung et al, 2020). A mortality analysis carried out by Cui et al (2003) for the previous coronavirus SARS (SARS-CoV-1) in China pointed out that patients in regions with moderated air pollution levels were more likely to die than those living in regions with low air pollution levels.…”

“…High concentrations of PM particles have been documented to lead to an over-expression of the viral receptor ACE-2 in the human respiratory system (among others, see papers by Borro et al, 2020;Gemmati et al, 2020;Devaux et al, 2020;Bunyavanich et al, 2020;Leung et al, 2020). It was speculated that the presence of an elevated number of viral receptors in the host cells may increase the susceptibility to SARS-CoV-2 infection.…”

“…In a previous paper by Borro et al (2020) the variability of the infection rate, the mortality rate and the case fatality rate as a function of particle concentration was estimated for PM2.5 particles only, recognizing a primary role of these particles in inducing an over-expression of ACE-2 in the human respiratory system (among others, see papers by Gemmati et al, 2020;Devaux et al, 2020;Bunyavanich et al, 2020;Leung et al, 2020). In the present section we extend the analysis to PM10 particles, thus assessing the incidence of this additional pollution source on epidemiologic parameters.…”

COVID-19 and Sex-/Gender-Specific Differences: Understanding the Discrimination

“…61 The gene for ACE2 is located on the X chromosome, 62 which means that the double X chromosome in females may be protective, as heterozygous females can have a mosaic advantage while males are hemizygous. 63 Furthermore, animal studies have revealed sexual dimorphism in ACE2 activity. 64 However, data from human studies on whether higher or lower levels of ACE2 are more protective are conflicting, and controversy persists regarding expression of ACE2 in different subpopulations.…”