Sex differences in severity and mortality from COVID-19: are males more vulnerable?

Abstract

Coronavirus disease 2019 (COVID-19) has shown high infection and mortality rates all over the world, and despite the global efforts, there is so far no specific therapy available for COVID-19. Interestingly, while the severity and mortality of COVID-19 are higher in males than in females, the underlying molecular mechanisms are unclear. In this review, we explore sex-related differences that may be contributing factors to the observed male-biased mortality from COVID-19. Males are considered the weaker sex in aspects related to endurance and infection control. Studies show that viral RNA clearance is delayed in males with COVID-19. A recent study has indicated that the testis can harbor coronavirus, and consequently, males show delayed viral clearance. However, the role of testis involvement in COVID-19 severity and mortality needs further research. Males and females show a distinct difference in immune system responses with females eliciting stronger immune responses to pathogens. This difference in immune system responses may be a major contributing factor to viral load, disease severity, and mortality. In addition, differences in sex hormone milieus could also be a determinant of viral infections as estrogen has immunoenhancing effects while testosterone has immunosuppressive effects. The sex-specific severity of COVID-19 infections indicates that further research on understanding the sex differences is needed. Inclusion of both males and females in basic research and clinical trials is required to provide critical information on sex-related differences that may help to better understand disease outcome and therapy.

Keywords: Coronavirus; Gender; Immune system; Pathogenesis; Sex hormones.

Fig. 1

Sex-biased mortality from COVID-19. The data from different countries show that male mortality is higher than females. The data for Peru, Italy, Spain, England, France, USA, and Mexico was obtained from Global Health 50/50 which was updated July 12. The mortality data as of July 24 for Sweden was taken from the Swedish Public Health Agency

Fig. 2

Coronavirus entry into cell. Coronavirus spike protein binds to ACE2 on the human cell surface. TMPRSS2 cleaves spike protein to help virus fusion and entry inside the target cell. ADAM17 can cleave ACE2 and release the ectodomain as a soluble form. The soluble form can bind to virus and can help to prevent infection

Fig. 3

Spike protein of coronavirus. The schematic diagram shows the coronavirus structure (a). The spike protein (S) has S1 and S2 domains. The S protein has receptor binding domain (RBD) and the receptor binding motif (RBM) and within RBD binds ACE2. S1/S2 and S2′cleavage sites are acted by protease to assist viral fusion. RBM sequence between SARS-CoV and SARS-CoV-2 showed 46.5% identity, and the nine residues that increase RBM affinity to ACE2 are indicated in red (b). NTD, N-terminal domain; RBD, receptor binding domain; RBM, receptor binding motif; FP, fusion protein; HR1, heptad repeat 1; HR2, heptad repeat 2; TM, transmembrane domain; CT, cytoplasmic tail

Fig. 4

Differential expression of ACE2 and TMPRSS2. The RNA sequencing data was obtained from the NCBI database (Bioproject, PRJEB4337) submitted by a previous study [96]. The raw reads were aligned to the human genome, and differential gene expression was determined using Partek Flow Software. The parameters were as follows: p value 0.05, false discovery rate 0.05, and fold change ± 2

Fig. 5

The possible factors in sex-biased mortality from COVID-19. COVID-19 has shown sex-biased mortality with higher death rate in males. This difference could be due to testosterone and estrogen differential effect on the immune system. Since females have two X chromosome, they have higher copy number of immune-related genes which provides a stronger immune response. The robust immune system in females better regulates viral infections, and consequently, lower mortality is observed. The stress endurance level is low in males compared with females, and this could also be a contributing factor for the sex-specific pathogenesis from COVID-19