Effects of Drugs for the Treatment of Multiple Sclerosis in Severe Acute Respiratory Syndrome Coronavirus 2 Infection on the Expression of Angiotensin-converting Enzyme 2 in vitro.

BACKGROUND

Multiple sclerosis (MS) is an immune-mediated and demyelinating disease affecting oligodendrocytes, leading to neurodegeneration. Immunocompromised individuals may have a reduced antibody response after vaccination, and this insufficient immune response in COVID-19 individuals might contribute to the pathophysiology of MS. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds the angiotensin-converting enzyme 2 (ACE2) to entry into the host's cell and infect human cells.

OBJECTIVE

Evaluation of the effects of drugs for the treatment of MS, such as fingolimod, cladribine, dimethyl fumarate, and teriflunomide, on the expression of ACE2 in human lung carcinoma cell lines.

METHODS

We used Calu-3 human lung adenocarcinoma cells, physiologically expressing the ACE2 gene, and A549-hACE2-TMPRSS2 human lung carcinoma cells, overexpressing the human ACE2 gene, and challenged them with the pro-inflammatory interleukin-1β (IL-1β) in the presence or absence of MS drugs, and assessed ACE2 mRNA and protein levels.

RESULTS

MS drugs affected ACE2 mRNA and protein levels differently in Calu-3 and A549-hACE2-TMPRSS2 cells. Fingolimod (50 nM) significantly reduced ACE2 protein levels under inflammatory conditions in Calu-3 cells. Cladribine reduced ACE2 protein levels in A549-hACE2-TMPRSS2 cells. Dimethyl fumarate increased ACE2 protein levels in Calu-3 cells under both basal and pro-inflammatory conditions. Teriflunomide increased ACE2 protein levels in Calu-3 cells and ACE2 mRNA levels in A549-hACE2-TMPRSS2 cells, both in basal and pro-inflammatory conditions.

DISCUSSION: We incubated cells with drug concentrations similar to those found in the plasma of relapsing-remitting MS patients treated with disease-modifying drugs (DMD), although they act via different mechanisms. Fingolimod acts on sphingosine-1-phosphate receptors and inhibiting class 1 histone deacetylase could suppress ACE2 expression, independently of its immunosuppressive action, or might act at post-transcriptional levels. Fingolimod also stimulates the secretion of neurotrophic factors in the CNS and exerts neuroprotective effects.

CONCLUSION

Data suggest that drugs used in the treatment of MS can modify ACE2 expression; specifically, fingolimod reduces ACE2 expression and may have a protective role against SARS-CoV-2 infection.