A Mouse Model for "Definitive" Polyomavirus Nephropathy with Lytic Viral Replication

Background: A mouse model for polyomavirus nephropathy (PyVN) with lytic viral replication has not been described. Studies of PyVN based on observations in kidney transplants have limitations due to concurrent alloimmune injury. Aim: Characterization of a model of PyVN in native mouse kidneys. Methods: Black Swiss mice i.p. injected with murine strain A2 PyV (MUPyV; 1x107 PFU) reliably developed PyVN. Animals (n>100) were sacrificed at different intervals (end point 54 weeks). Testing performed: light microscopy (LM), electron microscopy (EM), immunohistochemistry (IHC), plasma anti-MUPyV antibody titers, PCR (kidney, plasma, urine), genetics on MUPyV stability. Results: PyVN with lytic replication occurred in all animals 2 weeks post infection. It peaked at 2-5 weeks (Fig: IHC for PyV-Capsid Protein-1; viral replication in 6.1% (median) of cortical tubules), subsequently decreased (weeks 6-30) and ultimately cleared by LM/IHC in all animals (weeks 47-54). At the end of follow-up subclinical infections (positivity in kidney/plasma/urine only by PCR; no changes by LM/IHC) were only seen in 15% of mice. Viral progeny were detected in the cytoplasm and nuclei of tubular and some mesenchymal cells by EM. Viral injury dominated in distal tubules and cortical collecting ducts. It was associated with inflammation rich in CD3+and CD4+ cells (75%) with fewer admixed myofibroblasts and F4/80+ histiocytes (20%-40%). Fibrosis did not occurr. During PyVN, MUPyV remained genetically stable. In week 3-5 post infection animals mounted a transient IgM reponse that disappeared during week 6-30 when IgG titers peaked. At the end of follow-up IgM was no longer detected while IgG titers were low positive in 92% of animals. Conclusion: Our PyVN mouse model in native kidneys is robust. Morphologic, molecular, genetic, and immunologic changes mimick human disease whereas scarring is absent. The model is well suited for targeted studies/ interventional drug trials. Funding: Clinical Revenue Support