Polyamine Depletion Inhibits Bunyavirus Infection via Generation of Noninfectious Interfering Virions Vincent Mastrodomenico, a Jeremy J. Esin, a,b Marion L. Graham, a Patrick M. Tate, a Grant M. Hawkins, a Zachary J. Sandler, a,b David J. Rademacher, a,c Thomas M. Kicmal, a,b Courtney N. Dial, a,b Bryan C. Mounce a,b a Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA b Infectious Disease and Immunology Research Institute, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA c Core Imaging Facility, Loyola University Chicago, Maywood, Illinois, USA ABSTRACT Several host and viral processes contribute to forming infectious virions. Polyamines are small host molecules that play diverse roles in viral replication. We previously demonstrated that polyamines are crucial for RNA viruses; however, the mechanisms by which polyamines function remain unknown. Here, we investigated the role of polyamines in the replication of the bunyaviruses Rift Valley fever virus (vaccine strain MP-12) and La Crosse virus (LACV). We found that polyamine deple- tion did not impact viral RNA or protein accumulation, despite significant decreases in titer. Viral particles demonstrated no change in morphology, size, or density. Thus, polyamine depletion promotes the formation of noninfectious particles. These particles interfere with virus replication and stimulate innate immune responses. We extended this phenotype to Zika virus; however, coxsackievirus did not similarly produce noninfec- tious particles. In sum, polyamine depletion results in the accumulation of noninfectious particles that interfere with replication and stimulate immune signaling, with important implications for targeting polyamines therapeutically, as well as for vaccine strategies. IMPORTANCE Bunyaviruses are emerging viral pathogens that cause encephalitis, hemorrhagic fevers, and meningitis. We have uncovered that diverse bunyaviruses require polyamines for productive infection. Polyamines are small, positively charged host-derived molecules that play diverse roles in human cells and in infection. In polyamine-depleted cells, bunyaviruses produce an overabundance of noninfectious particles that are indistinguishable from infectious particles. However, these particles interfere with productive infection and stimulate antiviral signaling pathways. We further find that additional enveloped viruses are similarly sensitive to polyamine de- pletion but that a nonenveloped enterovirus is not. We posit that polyamines are re- quired to maintain bunyavirus infectivity and that polyamine depletion results in the accumulation of interfering noninfectious particles that limit infectivity. These results highlight a novel means by which bunyaviruses use polyamines for replication and suggest promising means to target host polyamines to reduce virus replication. KEYWORDS bunyaviruses, noninfectious particles, polyamines B unyaviruses such as Rift Valley fever virus (RVFV) and La Crosse virus (LACV) are emerging arthropod-borne pathogens that cause significant disease. RVFV, which is currently restricted to Africa and the Middle East, can cause encephalitis and hemorrhagic fever in humans, as well as spontaneous abortion in domesticated animals (1). Thus, RVFV infection has significant economic and human health costs. Distantly related to RVFV, LACV can cause encephalitis following infection transmitted by mos- quito bite and is localized primarily to midwestern and mid-Atlantic states of the United States (2, 3). These as well as other bunyaviruses pose significant threats to human health. Further, the rapid dissemination of several other arthropod-borne viruses Citation Mastrodomenico V, Esin JJ, Graham ML, Tate PM, Hawkins GM, Sandler ZJ, Rademacher DJ, Kicmal TM, Dial CN, Mounce BC. 2019. Polyamine depletion inhibits bunyavirus infection via generation of noninfectious interfering virions. J Virol 93:e00530-19. https://doi.org/10.1128/JVI .00530-19. Editor Mark T. Heise, University of North Carolina at Chapel Hill Copyright © 2019 American Society for Microbiology. All Rights Reserved. Address correspondence to Bryan C. Mounce, [email protected]. Received 2 April 2019 Accepted 28 April 2019 Accepted manuscript posted online 1 May 2019 Published VIRUS-CELL INTERACTIONS crossm July 2019 Volume 93 Issue 14 e00530-19 jvi.asm.org 1 Journal of Virology 28 June 2019 Downloaded from https://journals.asm.org/journal/jvi on 27 July 2023 by 171.243.71.223.
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