A plethora of earlier studies has reported on the differences between the sexes in susceptibility to the currently circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as its severity. A new preprint research paper posted to the bioRxiv* server extends this to the placenta in pregnancy.
Though over 82,000 pregnant women have contracted the infection in the USA so far, there is little evidence for vertical transmission, which may at most occur in 1-3% of cases. This may be mediated by placental infection.
The very low frequency of this complication reflects the low incidence of circulating virus in maternal blood, while the placenta may be protected by changes in the distribution and concentrations of viral entry receptors in this tissue.
Host cell receptors
There are two types of host cell receptors for the virus. One is the transmembrane receptor Angiotensin-Converting Enzyme 2 (ACE2) and the Type II Transmembrane Serine Protease (TMPRSS2. The first mediates viral attachment and the second primes the viral spike protein for ACE2 engagement.
In most cases, TMPRSS2 is found at low levels in placental tissue from infected mothers, mainly in the fetal endothelium, if present at all. ACE2 is strongly expressed throughout the placenta during the whole of pregnancy.
The study included 68 pregnant women, of whom 38 were tested positive for the virus by nasopharyngeal swabs tested by the reverse transcriptase-polymerase chain reaction (RT-PCR). The aim was to detect any existing difference in placental expression of ACE2 and TMPRSS2 in placental tissue, depending on the fetal sex and the presence of SARS-CoV-2 infection.
Women infected with the virus during pregnancy were more likely to be Hispanic, but otherwise, cases and controls were comparable.
What were the results?
The results showed that no placenta in the study showed the presence of SARS-CoV-2. However, the expression of one of the two crucial host cell receptors required for the attachment and cell entry of the virus showed sexual dimorphism.
TMPRSS2 was shown to be expressed at higher levels in the placenta of male fetuses compared to females in uninfected mothers. This difference was replicated at the translational level, with TMPRSS2 protein concentrations being higher in male placentas.
TMPRSS2 expression was markedly lower in male placentas relative to male controls at gene and protein levels among infected participants. However, this enzyme was increased in females following maternal SARS-CoV-2 infection.
ACE2 levels remained unchanged in placentas irrespective of sex or presence of maternal infection, with no evidence of any alteration in expression at gene and protein level.
However, in the placentas of male fetuses of an infected mother, there was a strong correlation between ACE2 and TMPRSS2 gene expression levels, but not in those of uninfected mothers. Female fetuses showed no such correlation, which was absent in controls as well.
It is possible that the correlation of ACE2 and TMPRSS2 exists in multiple human tissues and that they are both driven by androgens. In fact, the presence of androgen receptors and ACE2 expression is positively correlated in one study.
The methods used in this study, namely, qRT-PCR and Western blotting, may be more sensitive for TMPRSS2 expression in the placenta rather than the more commonly used immunohistochemical methods, which have consistently shown low levels of this protein.
Secondly, the reason for the lower TMPRSS2 levels in male placentas should be identified, whether it is a protective response to minimize the chance of infection for the more vulnerable male fetus. Some data exist to indicate this possibility, such as a somewhat lower rate of vertical transmission to male neonates, though the very small number of such cases makes further research mandatory.
TMPRSS2 is strongly expressed in the prostate and lung tissue and is under androgenic regulation, thus leading to the theory that it may underlie the marked predilection of the virus to cause severe disease in males. A rare allele that increases the expression of this enzyme has been found to be more common in a population with high COVID-19 mortality rates.
Moreover, androgen deprivation therapy, as in men with prostate cancer, as well as TMPRSS2 inhibitors, are being considered as potential therapies for this infection.
What are the implications?
“These findings may have implications for offspring vulnerability to placental infection and vertical transmission.”
Such differences in TMPRSS2 expression may impact diseases in which this gene is involved in the disease mechanism, including H1N1 influenza and adenocarcinoma of the prostate.
The study shows the importance of reporting placental infection or receptor expression, and neonatal outcomes, by sex, in this infection, and the need to probe the defensive potential of reduced TMPRSS2 expression in the placenta in maternal infection with SARS-CoV-2.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.