A Multiomic Study Reveals Pilra, Monocytes and Interferons Put the “Itis” in BK Polyomavirus Cystitis

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Background BK polyomavirus (BKPyV) reactivation is nearly universal after pediatric hematopoietic stem cell transplant (HSCT); yet, only a quarter of patients develop BKPyV cystitis. We hypothesize that BKPyV reactivation alone is not sufficient for cystitis and that differential host immune responses to BKPyV are major determinants of disease. Objectives We assessed differences in cellular and soluble host factors that contribute to BKPyV cystitis after HSCT. Methods Plasma from 25 HSCT recipients underwent proteomics analysis (Somascan 7k platform) at 6 timepoints: baseline (pre-HSCT), day 7, 14, 30, 60 and 90. Paired immunoglobulin-like type 2 receptor alpha (PILRA) genotyping was performed on 112 consecutive patients at baseline. Single cell RNAseq was performed on day 60 peripheral blood mononuclear cells (PBMCs) from 12 HSCT recipients. Results We compared the plasma proteomes of patients with BKPyV viremia and cystitis (n=5) versus no cystitis (n=6). PILRA was a leading differentially expressed protein (DEP) at baseline (p=2.64e-2), day 7 (p=4.28e-2), day 14 (p=3e-3), day 30 (p=8.04e-3) and day 60 (p=5.09-3, Fig.1A). PILRA genotyping tested whether a known functional polymorphism (rs1859788) affects cystitis risk (Fig. 1B). Baseline heterozygotes (A/G, 12.5% cystitis rate) were significantly less likely to develop cystitis compared to homozygous (G/G, 39% cystitis rate; or A/A, 31% cystitis rate) patients (p=0.004). PBMC transcriptomes were compared between patients with BKPyV viremia and cystitis (n=3) versus BKPyV viremia and no cystitis (n=3). PILRA is predominantly expressed on monocytes and was a differentially expressed gene (DEG) in both CD16+ (q=4.6e-6) and CD14+ (q=2.6e-57) monocytes (Fig.2B). Pathway and upstream regulator analysis of CD14+ and CD16+ monocytes showed increased antiviral response (p=4.6e-19 and p=7.8e-23), interferon gamma (p=4e-17 and p=2.7e-12), and interferon alpha/beta (p=3.5e-15 and p=2.1e-11) enrichment in cystitis patients (Fig.2A). The interferon stimulated genes, interferon induced protein 44-like (IFI44L) and interferon induced protein 44 (IFI44), were leading DEGs in 9/11 cell types studied (Fig. 2C). Conclusions PILRA is a negative regulator of inflammatory processes and exists both in a membrane bound and soluble form. Baseline PILRA genotype was associated with cystitis risk in this study and the significantly lower soluble PILRA levels coupled with increased cellular PILRA expression support an increase in cell surface PILRA in cystitis patients. We conclude that soluble and monocytic PILRA differences contribute to a heightened interferon response to BKPyV that may cause inflammation and cystitis through interferon stimulated genes such as IFI44L and IFI44. Ongoing work aims to identify the mechanisms of PILRA-associated interferon production, as well as multiomic data analysis from BKPyV negative patients.

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