The Murine Polyomavirus MicroRNA Locus Is Required To Promote Viruria during the Acute Phase of Infection

Abstract

Polyomaviruses (PyVs) can cause serious disease in immunosuppressed hosts. Several pathogenic PyVs encode microRNAs (miRNAs), small RNAs that regulate gene expression via RNA silencing. Despite recent advances in understanding the activities of PyV miRNAs, the biological functions of PyV miRNAs during infections are mostly unknown. The studies presented here used murine polyomavirus (MuPyV) as a model to assess the roles of the PyV miRNAs in a natural host. This analysis revealed that a MuPyV mutant that is unable to express miRNAs has enhanced viral DNA loads in select tissues at late times after infection. This is consistent with the PyV miRNAs functioning to reduce viral replication during the persistent phase of infection in a natural host. Additionally, the MuPyV miRNA locus promotes viruria during the acute phase of infection as evidenced by a defect in shedding during infection with the miRNA mutant virus. The viruria defect of the miRNA mutant virus could be rescued by infecting mice. These findings implicate the miRNA locus as functioning in both the persistent and acute phases of infection and suggest a role for MuPyV miRNA in evading the adaptive immune response. MicroRNAs are expressed by diverse viruses, but for only a few is there any understanding of their function. PyVs can cause serious disease in immunocompromised hosts. Therefore, increased knowledge of how these viruses interact with the immune response is of clinical relevance. Here we show a novel activity for a viral miRNA locus in promoting virus shedding. This work indicates that in addition to any role for the PyV miRNA locus in long-term persistence, it also has biological activity during the acute phase. As this mutant phenotype is alleviated by infection of mice lacking an adaptive immune response, our work also connects the activity of the PyV miRNA locus to the immune response. Given that PyV-associated disease is associated with alterations in the immune response, our findings help to better understand how the balance between PyVs and the immune response becomes altered in pathogenic states.

Test sensitivity is secondary to frequency and turnaround time for COVID-19 surveillance

“…Latent periods prior to symptoms have been estimated to be around 5 days [40]. Latent periods prior to detection via virological tests at secondary sites of replication or shedding have been estimated to be up to 4 days [41], corresponding to a latent or eclipse phase observed with other viruses [42]. Viral load appears to peak prior to symptom onset [21], and peaks within 2 days of challenge in a macaque model [43, 44], though it should be noted that macaque challenge doses were high.…”

Control of archetype BK polyomavirus miRNA expression

“…However, a mutant MuPyV virus that does not express the miRNA exhibited the same infection and transformation phenotypes as wild type MuPyV, and the mutant induced an indistinguishable immune response as the wild type virus in mice (24). On the other hand, the MuPyV miRNA seems to control viruria in acutely-infected animals (36). It has also been reported that the BKPyV and JCPyV miRNAs target the cellular stress-induced ligand ULBP3 to allow the virus to escape detection by the immune system (38).…”

“…Although it is well known that the miRNA from different polyomaviruses share the common ability to regulate expression of viral TAg, which has been proposed to modulate persistent infection (23,34,36,37), the miRNAs may also harbor distinct functions. The SV40 miRNA has been shown to downregulate TAg expression as a means of immune evasion, reducing cytotoxic T lymphocyte susceptibility of infected cells (26).…”

JCPyV VP1 Mutations in Progressive Multifocal Leukoencephalopathy: Altering Tropism or Mediating Immune Evasion?

“…LT binds to NCCR sites as hexameric complexes, where it engages its helicase activity to drive viral genomic DNA synthesis. By eliminating LT transcripts, microRNAs act to reduce viral genome replication and concomitantly remove/reduce epitope targets for virus-specific T-cells [ 37 , 38 , 39 ]. Alternatively, the concept of “proteostatic viral latency” has been advanced by Kwun, Moore, and coworkers whereby particular host cell E3 ubiquitin ligases instigate proteasome-mediated degradation of LT in MCPyV-infected cells [ 40 , 41 , 42 ].…”