The Major Cellular Sterol Regulatory Pathway Is Required for Andes Virus Infection

Abstract

The Bunyaviridae comprise a large family of RNA viruses with worldwide distribution and includes the pathogenic New World hantavirus, Andes virus (ANDV). Host factors needed for hantavirus entry remain largely enigmatic and therapeutics are unavailable. To identify cellular requirements for ANDV infection, we performed two parallel genetic screens. Analysis of a large library of insertionally mutagenized human haploid cells and a siRNA genomic screen converged on components (SREBP-2, SCAP, S1P and S2P) of the sterol regulatory pathway as critically important for infection by ANDV. The significance of this pathway was confirmed using functionally deficient cells, TALEN-mediated gene disruption, RNA interference and pharmacologic inhibition. Disruption of sterol regulatory complex function impaired ANDV internalization without affecting virus binding. Pharmacologic manipulation of cholesterol levels demonstrated that ANDV entry is sensitive to changes in cellular cholesterol and raises the possibility that clinically approved regulators of sterol synthesis may prove useful for combating ANDV infection.

Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling

“…While it remains mechanistically unclear as to how each invading pathogen subverts host lipid metabolism, it has been proposed that co-opting of host metabolism is a general strategy employed by pathogens to meet the anabolic requirements of pathogen lifecycle, and facilitate evasion from host defense (Cui et al, 2014; Greseth and Traktman, 2014; Heaton et al, 2010; Herker and Ott, 2011; Kapadia and Chisari, 2005; Ouellet et al, 2011). Consistent with this concept, genetic or pharmacologic inhibition of host lipid metabolism has been shown to attenuate pathogenesis of both viral and microbial infections in a number of model systems (Gilbert et al, 2005; Herker and Ott, 2011; Liu et al, 2008; Munger et al, 2008; Parihar et al, 2014; Petersen et al, 2014; Rzouq et al, 2014). …”

The Envelope Proteins of the Bunyavirales

“…The Hantaan virus hGc ectodomain was shown to require cholesterol (Guardado-Calvo et al, 2016). Similarly, disruption of the membrane-bound host enzyme S1P (for "transcription factor peptidase/site-1"), which causes a modest cholesterol depletion in target cells, led to an important reduction of infectivity levels by Hantaan virus and by Andes virus in haploid human (HAP1) cells (Kleinfelter et al, 2015;Petersen et al, 2014), reflecting the importance of high cholesterol levels for hGc insertion to target membranes. For phleboviruses, cholesterol was shown to play a role in viral entry for the mosquito-borne RVFV (Harmon et al, 2012), but not for the tickborne UUKV, for which the membrane fusion reaction requires the presence of anionic lipids in the target membrane, but not cholesterol (Bitto et al, 2016).…”

Cholesterol is required for stability and infectivity of influenza A and respiratory syncytial viruses

“…Importantly, the antiviral effect of statins and fibrates is not restricted to respiratory RNA viruses. These agents are also effective in controlling hepatitis C virus (Ikeda et al, 2006), Andes virus (Petersen et al, 2014), HIV (del Real et al, 2004), and Ebola virus infections (Fedson, 2016). Overall, these studies suggest that cholesterol could be an attractive target for broad-spectrum antivirals against clinically important enveloped viruses.…”