The antiviral potential of the antiandrogen enzalutamide and the viral-androgen signaling interplay in seasonal coronaviruses.

The sex disparity in COVID-19 outcomes with males generally faring worse than females has been associated with the androgen-regulated expression of the protease TMPRSS2 and the cell receptor ACE2 in the lung and fueled interest in antiandrogens as potential antivirals. In this study, we explored enzalutamide, an antiandrogen used commonly to treat prostate cancer, as a potential antiviral against the human coronaviruses which cause seasonal respiratory infections (HCoV-NL63, -229E, and -OC43). Using lentivirus-pseudotyped and authentic HCoV, we report that enzalutamide reduced 229E and NL63 entry and infection in both TMPRSS2- and nonexpressing immortalized cells, suggesting a TMPRSS2-independent mechanism. However, no effect was observed against OC43. To decipher this distinction, we performed RNA-sequencing analysis on 229E- and OC43-infected primary human airway cells. Our results show a significant induction of androgen-responsive genes by 229E compared to OC43 at 24 and 72 h postinfection. The virus-mediated effect on AR-signaling was further confirmed with a consensus androgen response element-driven luciferase assay in androgen-depleted MRC-5 cells. Specifically, 229E induced luciferase-reporter activity in the presence and absence of the synthetic androgen mibolerone, while OC43 inhibited induction. These findings highlight a complex interplay between viral infections and androgen-signaling, offering insights for disparities in viral outcomes and antiviral interventions.

Seasonal coronaviruses and SARS-CoV-2: effects of preexisting immunity during the COVID-19 pandemic / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Although the coronavirus disease 2019 (COVID-19) epidemic is still ongoing, vaccination rates are rising slowly and related treatments and drugs are being developed. At the same time, there is increasing evidence of preexisting immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans, mainly consisting of preexisting antibodies and immune cells (including T cells and B cells). The presence of these antibodies is mainly due to the seasonal prevalence of four common coronavirus types, especially OC43 and HKU1. The accumulated relevant evidence has suggested that the target of antibodies is mainly the S2 subunit of S protein, followed by evolutionary conservative regions such as the nucleocapsid (N) protein. Additionally, preexisting memory T and B cells are also present in the population. Preexisting antibodies can help the body protect against SARS-CoV-2 infection, reduce the severity of COVID-19, and rapidly increase the immune response post-infection. These multiple effects can directly affect disease progression and even the likelihood of death in certain individuals. Besides the positive effects, preexisting immunity may also have negative consequences, such as antibody-dependent enhancement (ADE) and original antigenic sin (OAS), the prevalence of which needs to be further established. In the future, more research should be focused on evaluating the role of preexisting immunity in COVID-19 outcomes, adopting appropriate policies and strategies for fighting the pandemic, and vaccine development that considers preexisting immunity.