A Mouse Model for "Definitive" Polyomavirus Nephropathy with End-Organ Injury.

Abstract

Mouse models for "definitive" polyomavirus nephropathy with lytic viral replication and end-organ disease (PyVN) do not exist. We aimed at defining a PyVN model in Black-Swiss mice (n = 126) by injecting newborn animals with murine polyomavirus (strain A2; 1 × 10plaque forming units) that led in all mice to a productive intrarenal infection with genetically stable, episomal MuPyV lacking latency. Animals were monitored and morphologic, immunohistochemical, molecular, genetic, and immunological analyses were conducted. Results: Within 3-6 weeks peak PyVN developed characterized by acute tubular injury, lytic replication in up to 14% of tubules (mainly collecting ducts/distal nephrons), high viral gene coverage (up to 3589 viral DNA reads/cell equivalent) and RNA expression (up to 9317 VP1-RNA reads/10RNA reads), inflammation, DNAemia, and-uria. MuPyV doubling times were high early post-infection (urine: 0.17 day-1.61 day) followed by steady slow viral clearance post day 28 (urine, half-life: 9.90 days). By 54 weeks PyVN had morphologically cleared (no chronic tissue injury) with only qPCR evidence of residual MuPyV in 17% of kidneys/mice. Infection induced an IgM/IgG response (peak plasma IgG titer at 7-30 weeks 1:20,480; low IgG titers in 92% of mice at end of follow-up after one year). During infection, episomal MuPyV remained genetically stable, without significant alterations that could have modified the course of PyVN. The mouse model resembles "definitive" PyVN in humans. It is suited for research on the pathogenesis of PyVN including virally induced tubular injury and immunologic interactions. It facilitates in vivo studies of therapeutic interventions aimed at blocking lytic intrarenalPyV replication.