Polyamine Depletion Inhibits Bunyavirus Infection via Generation of Noninfectious Interfering Virions

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 depletion 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 noninfectious 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 depletion but that a nonenveloped enterovirus is not. We posit that polyamines are required 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.

Targeting Polyamines Inhibits Coronavirus Infection by Reducing Cellular Attachment and Entry

“…Using the data from infectious titers ( Figure 1 E) and viral genomes ( Figure 1 I), we calculated the specific infectivity (genomes per PFU) and observed that DFMO treatment increased the ratio of genomes to titer ( Figure 1 J), similar to previous findings with bunyaviruses and polyamine depletion. 23 Thus, polyamines enhance coronavirus infection and maintain a specific infectivity of MHV.…”

Polyamine regulation of porcine reproductive and respiratory syndrome virus infection depends on spermidine-spermine acetyltransferase 1

“…Because polyamines perform vital roles in viral infections, their depletion disrupts the proliferation of numerous viruses from different families, such as Herpesviridae (HSV-1 and HCMV), Togaviridae (Semliki forest virus, Sindbis virus, and CHIKV), Flaviviridae (dengue virus serotype 1, Japanese encephalitis virus, Yellow fever virus, and ZIKV), Picornaviridae (enterovirus A71, poliovirus, and CVB3), Bunyaviridae (Rift Valley fever virus and La Crosse virus), Rhabdoviridae (rabies virus and Vesicular stomatitis virus) and Coronaviridae (Middle East respiratory syndrome coronavirus [MERS-CoV]) ( Mastrodomenico et al, 2019 ; Mounce et al, 2016a ; Mounce et al, 2016b ; Tuomi et al, 1980 ; Tyms and Williamson, 1982 ). Here, we investigated the impact of polyamines on PRRSV, an Arteriviridae family member.…”

Diverse Functions of Polyamines in Virus Infection

“…HSV-1 was shown to produce comparable amounts of viral particles in cells depleted of polyamines with the specific ODC1 inhibitor DFMO and control cells, but those produced from polyamine-deficient cells had different abundance of DNA fragments [38] and DFMO-treated cells produced lower viral titers [39]. Similarly, the bunyaviruses, Rift Valley Fever virus, and Lacrosse virus produced non-infectious particles in polyamine-depleted cells [40]. Polyamines are present to varying degrees in capsids of diverse viruses.…”