Virion-Associated Polyamines Transmit with Bunyaviruses to Maintain Infectivity and Promote Entry

Abstract

Viruses require host cell metabolites to productively infect, and the mechanisms by which viruses usurp these molecules are diverse. One group of cellular metabolites important in virus infection is the polyamines, small positively charged molecules involved in cell cycle, translation, and nucleic acid metabolism, among other cellular functions. Polyamines support replication of diverse viruses, and they are important for processes such as transcription, translation, and viral protein enzymatic activity. Rift Valley fever virus (RVFV) is a negative and ambisense RNA virus that requires polyamines to produce infectious particles. In polyamine depleted conditions, noninfectious particles are produced that interfere with virus replication and stimulate immune signaling. Here, we find that RVFV relies on virion-associated polyamines to maintain infectivity and enhance viral entry. We show that RVFV replication is facilitated by a limited set of polyamines and that spermidine and closely related molecules associate with purified virions and transmit from cell to cell during infection. Virion-associated spermidine maintains virion infectivity, as virions devoid of polyamines rapidly lose infectivity and are temperature sensitive. Further, virions without polyamines bind to cells but exhibit a defect in entry, requiring more acidic conditions than virions containing spermidine. These data highlight a unique role for polyamines, and spermidine particularly, to maintain virus infectivity. Further, these studies are the first to identify polyamines associated with RVFV virions. Targeting polyamines represents a promising antiviral strategy, and this work highlights a new mechanism by which we can inhibit virus replication through FDA-approved polyamine depleting pharmaceuticals.

Polyamine Analog Diethylnorspermidine Restricts Coxsackievirus B3 and Is Overcome by 2A Protease Mutation In Vitro

“…Polyamines are essential for some viruses and their successful replication as well and have even been shown to be incorporated into the virions by some DNA and RNA viruses [9][10][11][12]. They are necessary for many stages in viral replication cycles, and the polyamine biosynthesis pathway has been effectively targeted for parasite and cancer treatments [13][14][15].…”

Sex-biased proteomic response to tomato spotted wilt virus infection of the salivary glands of Frankliniella occidentalis, the western flower thrips

“…CC-BY-NC-ND 4.0 International license available under a was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made spermidine associated directly and transmitted cell-to-cell with the virion, serving an essential role in infectivity (Mastrodomenico et al, 2020). Diverse plant viruses, including turnip yellow mosaic virus (TYMV) and Belladonna mosaic virus (BDMV) likewise incorporate host polyamines (spermidine or putrescine) in the virion (Balint and Cohen, 1985;Beer and Kosuge, 1970;Johnson and Markham, 1962;Virudachalam et al, 1983b), with some evidence suggesting a role in virion stability (Savithri et al, 1987;Virudachalam et al, 1983a).…”

Targeting Polyamines Inhibits Coronavirus Infection by Reducing Cellular Attachment and Entry

“…These data suggest that coronaviruses require a low concentration of polyamines for robust replication. In fact, bunyaviruses and alphaviruses replicate with supplementation of 100 nM polyamines in polyamine depleted cells. , Thus, these viruses may have evolved mechanisms to take advantage of polyamines even at low concentrations. This has implications for the molecular interactions between polyamines and coronaviruses, and perhaps coronaviruses evolved a strong affinity for polyamines.…”