Confounding Virus in Mouse Facilities

Abstract

A new member of the Parvoviridae genus causes kidney pathology in immunosuppressed mice resembling BK virus in humans, is transmitted horizontally, and needs to be screened for to prevent confounding results in murine models of kidney transplantation. A new member of the Parvoviridae genus causes kidney pathology in immunosuppressed mice resembling BK virus in humans, is transmitted horizontally, and needs to be screened for to prevent confounding results in murine models of kidney transplantation. CITATION Roediger B, Lee Q, Tikoo S, et al. An atypical parvovirus drives chronic tubulointerstitial nephropathy and kidney fibrosis. Cell. 2018;175:530-543. Chasing the long-puzzling occurrence of spontaneous nephropathy observed predominantly in aged, immunocompromised mice, Roediger and colleagues identified a new member of the Parvoviridae family termed “mouse kidney parvovirus” (MKPV) as the culprit in causing inclusion body nephropathy, kidney fibrosis and ultimately kidney failure in infected mice. The authors showed that MKPV, a single-stranded (ss) DNA virus, was widely distributed among immunodeficient mice from various facilities in Australia and North America. Histopathology and in situ hybridization revealed its tropism to kidney epithelial cells. Co-housing experiments demonstrated that MKPV can horizontally transmit between individuals via either a fecal (or urinary) oral route, and can infect both immunodeficient and immunocompetent mice. However, severe tubulointerstitial nephropathy leading to kidney fibrosis and eventual morbidity and mortality occurred predominantly in immunodeficient mice. Chronological studies revealed that prior to 60 days of age, viral DNA could only be detected in the kidney; however, at later time points (>100 days of age), viral load increased significantly in the kidney and could also be detected in blood, urine and feces. Beyond 200 days of age, kidneys of infected mice became shrunken and pale, and blood urea nitrogen and creatinine levels were elevated, indicating renal dysfunction. Importantly, flow cytometric analysis revealed that MKPV infection was accompanied by a significantly increased infiltration of activated macrophages, together with the development of fibroblast activation protein (FAP)+CD24+ myofibroblasts and a loss of epithelial cells within the fibrotic kidney. The identification of MKPV in mice has two immediate implications for researchers using mouse models of kidney transplantation, particularly in the context of immunosuppression. First, how MKPV infection of kidney epithelial cells in the donor kidney may alter the recipient alloimmune response and consequently graft outcome of the transplanted kidney warrants investigation. Similar to other parvoviruses, it is likely that MKPV infection in immunocompetent kidney donors results in viral latency. The virus may subsequently reactivate once the latently infected kidney is transplanted to a recipient, particularly when the recipient is treated with immunosuppression. Even if the donor kidney is not latently infected with MKPV, recipient prior infection may still result in de novo infection of the transplanted kidney, particularly if the viral-tropic kidneys of the recipients are not removed prior to implantation of the donor kidney. Either way, MKPV infection of the transplanted kidney may exacerbate the initial innate immune response and the subsequent adaptive immune response. For the time being, it is necessary that researchers studying kidney transplant immunobiology in mouse models determine whether the facilities housing their experimental animals carry MKPV or are free of the virus. This can be achieved with validated methods for MKPV detection. Based on the data for MKPV horizontal transmission, this is likely to be an “all or none” phenomenon. If the facility is deemed MKPV positive, then interpretation of any data generated on kidney transplantation would need to carefully take into consideration the confounding effect of MKPV on kidney allograft health. If the facility is deemed MKPV free, then any animal imports for future experiments also need to be from MKPV-free facilities or vendors. A second potentially interesting implication lies in the pathological similarity between MKPV-induced kidney fibrosis in mice and the kidney fibrosis induced by another kidney-tropic virus, the polyoma virus BK (BKV) in humans, both of which manifest renal pathology only under immunosuppression. Several in vitro and in vivo mouse models have been developed to study BKV-induced nephropathy, but none of them are clinically relevant due to various limitations. Despite differences in MKPV (ssDNA virus) and BKV (double-stranded DNA virus), the MKPV mouse model may represent the best model currently available for studying the BKV-induced nephropathy and kidney fibrosis seen in human kidney transplant recipients. A transcriptomic comparison of MKPV-infected kidneys with kidneys following unilateral ureteral obstruction revealed 60 to 70% similarity in gene expression, including downregulation of the epidermal growth factor gene. These data were consistent with those for human patients with chronic kidney diseases. Therefore, the MKPV mouse model may also be suitable for examining therapeutic interventions aiming at preventing or retarding kidney fibrosis and kidney failure in the setting of BKV-induced nephropathy.