Suppression of monkeypox virus by downregulation of fatty acid synthase
and upregulation of cholesterol-25 hydroxylase
Abstract
The re-emergence of the monkeypox virus (MPXV) three years after the
start of the SARS-CoV-2 epidemic further emphasizes the need to develop
broad spectrum antivirals (BSAs) that might control the spread of poorly
understood pathogens. The induction of innate immune responses to a
viral infection triggers rapid expression of type-I-interferon (IFN-I),
which subsequently results in the differential expression of more than
300 genes that foster an antiviral state. Whereas the expression of a
majority of these “interferon-stimulated genes” (ISGs) are enhanced, ,
other ISGs’ expression are suppressed, including some involved in lipid
metabolism which is hijacked to promote viral growth. Herein, we report
that the expression of fatty acid synthase (FASN), an enzyme involved in
de novo biosynthesis of fatty acids, was significantly reduced
upon MPXV infection. Moreover, MPXV infection was impaired in FASN
knockout cells, and biological inhibitors of FASN significantly
inhibited MPXV. Interestingly, the ISG chosterol-25-hydroxylase was
induced in MPXV-infected cells, and its enzymatic product,
25-hydroxychlosterol (25HC), blocked MPXV infection. Overall, this study
indicates that 25HC and FASN inhibitors are highly potent BSAs and may
have therapeutic applications in combating understudied infectious
diseases in early outbreak settings when targeted therapies have not yet
been developed.