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. 2021 Feb 25;16(2):e0246266.
doi: 10.1371/journal.pone.0246266. eCollection 2021.

A multi-omic investigation of male lower urinary tract symptoms: Potential role for JC virus

Samuel Thomas  1 , Christopher D Dunn  2 , Lewis J Campbell  2 , Douglas W Strand  3 , Chad M Vezina  4 , Dale E Bjorling  4 , Kristina L Penniston  5 , Lingjun Li  1   6 , William A Ricke  1   4 , Tony L Goldberg  2   7
Affiliations

A multi-omic investigation of male lower urinary tract symptoms: Potential role for JC virus

Samuel Thomas et al. PLoS One. .

Abstract

Male lower urinary tract symptoms (LUTS) comprise a common syndrome of aging that negatively impacts quality of life. The etiology of LUTS is multifactorial, involving benign prostatic hyperplasia, smooth muscle and neurologic dysfunction, inflammation, sexually transmitted infections, fibrosis, and potentially dysbiosis, but this aspect remains poorly explored. We investigated whether the presence of infectious agents in urine might be associated with LUTS by combining next-generation DNA sequencing for virus discovery, microbiome analysis for characterization of bacterial communities, and mass spectrometry-based metabolomics. In urine from 29 LUTS cases and 9 controls from Wisconsin, we found a statistically significant association between a diagnosis of LUTS and the presence of JC virus (JCV), a common neurotropic human polyomavirus (Polyomaviridae, Betapolyomavirus) linked to severe neurologic disease in rare cases. This association (based on metagenomics) was not borne out when specific polymerase chain reaction (PCR) testing was applied to this set of samples, likely due to the greater sensitivity of PCR. Interestingly, urine metabolomics analysis identified dysregulation of metabolites associated with key LUTS processes. Microbiome analysis found no evidence of microbial community dysbiosis in LUTS cases, but JCV-positive samples contained more Anaerococcus species, which are involved in polymicrobial infections of the urinary tract. Neither age nor body mass index were significantly associated with the presence of urinary JCV-in the initial group or in an additional, regionally distinct group. These data provide preliminary support the hypothesis that viruses such as JCV may play a role in the development or progression of LUTS, together with other infectious agents and host metabolic responses.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Experimental design and workflow.
A: Next-generation sequencing to investigate viral associations with LUTS and microbiome and mass spectrometry-based metabolomics for molecular associations with virome in Wisconsin study. B: PCR for candidate virus in Wisconsin and Texas sample groups.
Fig 2
Fig 2. Urine microbiomes: comparisons of bacterial communities observed in LUTS+ vs LUTS- samples and JCV+ vs JCV- samples.
A: alpha diversity–the number of species present regardless of community structure or taxonomy. The effective number of species (ENS; y-axis) of each sample (points) is displayed over a box and whisker plot showing the distribution of the ENS values for each comparison group. Statistical analysis showed no significant differences in either LUTS+/- or JCV+/- comparisons (Wilcoxon test, p = 0.78 and p = 0.87, respectively), and B: beta diversity–differences in community structure between LUTS+/- and JCV+/- comparison groups. Plots show a non-metric multi-dimensional scaling based on Bray-Curtis dissimilarity distances between samples: statistical comparison of group centroids using permutational analysis of variance (PERMANOVA) showed no significant differences in LUTS+/- or JCV+/- comparison groups (PERMANOVA, p = 0.11 and p = 0.67, respectively).
Fig 3
Fig 3. Urine microbiomes: Unique bacterial genera found to be biomarkers of either member of a comparison group are shown on the y-axis and the number of sequence variants belonging to each genera on the x-axis; summary of results from linear discriminant effect size analysis (LEfSe).
A: LUTS positive and negative, and B: JC virus positive and negative. Note increased Streptococcus and Enterococcus sequence variants in LUTS+ samples and increased Anaerococcus sequence variants in JCV+ samples.
Fig 4
Fig 4
Urine metabolomes of JC virus in A: all samples and B: LUTS samples only. Volcano plots show 3079 and 2658 total m/z features, respectively; enlarged dots indicate significantly modulated features (Student’s t-test p-value < 0.05 and fold-change ≥ 50%); red indicates increase with JC virus, green indicates decrease with JC virus. C: Venn diagram of significantly modulated features shows the urine metabolome of JC virus in LUTS patients is larger and represents more roles, including neurologic, fungal, oxidative stress, and innate immune system (filtered by known compounds with known roles).
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