We read the article “Neutralizing antibody-mediated response and risk of BK virus–associated nephropathy” by Solis et al.1 with great interest. Although a cell-mediated immune response is crucial for overcoming and clearing polyoma-BK virus infections and polyoma virus nephropathy (PVN),2,3 the significance of antibodies in extenuating polyoma virus infections is poorly understood.4 In their study, Solis et al.1 were able to shed new light on the protective role of strain-specific neutralizing antibodies in preventing the onset of PVN. We made similar observations in newborn mice, typically permissive to productive murine polyomavirus infections (MPyV)/PVN but protected by maternally transmitted antibodies.
Three breeding mice (Charles River Laboratories; MPyV negative, including undetectable antibodies) were exposed to MPyV by either intraperitoneal injection (n=1) or direct body contact (n=2) with other infected study animals. Regardless of exposure route, all exposed breeders developed circulating IgG anti-MPyV antibodies (titers 1:1280–1:5120), had no IgM response, and showed no morphologic evidence of a productive MPyV infection/no PVN. Newborns from these three exposed breeders had measurable anti-MPyV IgG (titer 1:40) and no IgM at birth/day 0. Pups in this study cohort (n=12; “passive immunity group”) were injected with MPyV on day 0 and euthanized at weeks 1, 2, 4, and 6. During follow-up, all animals lacked morphologic signs of PVN, failed to mount an IgM response, and developed a rapid rise of IgG at weeks 1 and 2 (peaking at 1:2000; n=9 animals). PCR analyses showed molecular evidence of MPyV in the plasma (1.4×103 MPyV copies per milliliter, median; 25th percentile: 2.6×102; pooled time points weeks 1–6) and kidneys (9.9×103 MPyV copies per milligram wet, median; 25th percentile: 4.2×101) accompanied by only very sporadic MPyV shedding in the urine (median 0 MPyV copies per milliliter).
In comparison, a cohort of unexposed breeders with pups infected with MPyV on day 0 and followed for 6 weeks (n=19; “naïve group”) showed very striking morphologic evidence of a productive MPyV infection/PVN at all time points starting at week 1. PCR assays showed very high MPyV loads in the plasma (1.6×108 MPyV copies per milliliter, median; 25th percentile: 6.2×107; pooled time points weeks 1–6), kidney (4.5×109 MPyV copies per milligram wet, median; 25th percentile: 8.8×108), and urine (3.3×109 MPyV copies per milliliter, median; 25th percentile: 2.8×107). Comparison of “naïve” with “passive immunity” groups for kidneys/urine/plasma showed P<0.001 for each site. In the naïve cohort, both IgG and IgM anti-MPyV antibody titers remained undetectable until day 8, when they started progressively rising.
Our observations support the data from Solis et al.1 on the protective role that neutralizing antibodies can play in preventing the onset of PVN with virally induced renal injury as well as extenuating the overall polyoma virus burden in tissue. Testing for strain-specific antibodies against polyoma-BK virus might help with stratifying kidney transplant recipients into high- and low-risk PVN groups. In addition, studies on “boosting” BK virus antibody titers as preemptive therapeutic intervention strategies after kidney transplantation deserve further consideration. New paradigms for PVN are on the horizon!5
All mouse experiments were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (University of North Carolina study number 14-040.0-C).
This study was supported by internal UNC-DPLM funds.
1. Solis M, Velay A, Porcher R, Domingo-Calap P, Soulier E, Joly M, et al.: Neutralizing antibody-mediated response and risk of BK virus–associated nephropathy. J Am Soc Nephrol 29: 326–334, 2018
2. Leboeuf C, Wilk S, Achermann R, Binet I, Golshayan D, Hadaya K, et al.; Swiss Transplant Cohort Study: BK polyomavirus-specific 9mer CD8 T cell responses correlate with clearance of BK Viremia in kidney transplant recipients: First report from the Swiss Transplant Cohort Study. Am J Transplant 17: 2591–2600, 2017
3. Menter T, Mayr M, Schaub S, Mihatsch MJ, Hirsch HH, Hopfer H: Pathology of resolving polyomavirus-associated nephropathy. Am J Transplant 13: 1474–1483, 2013
4. Pastrana DV, Brennan DC, Cuburu N, Storch GA, Viscidi RP, Randhawa PS, et al.: Neutralization serotyping of BK polyomavirus infection in kidney transplant recipients. PLoS Pathog 8: e1002650, 2012
5. Nickeleit V, Singh HK: Polyomaviruses and disease: Is there more to know than viremia and viruria? Curr Opin Organ Transplant 20: 348–358, 2015