Abstract
ABSTRACTIn recent years, the clinical significance of Aerococcus urinae has been increasingly recognized. A. urinae has been implicated in cases of urinary tract infection (UTI; acute cystitis and pyelonephritis) in both male and female patients, ranging from children to older adults. Aerococcus urinae can also be invasive, causing urosepsis, endocarditis, and musculoskeletal infections. Mechanisms of pathogenesis in A. urinae infections are poorly understood, largely due to the lack of an animal model system. In response to this gap, we developed a model of A. urinae urinary tract infection in mice. We compared A. urinae UTI in female C3H/HeN and C57BL/6 mice and compared four clinical isolates of A. urinae isolated from patients with UTI, urgency urinary incontinence, and overactive bladder. Our data demonstrate that host genetic background modulates A. urinae UTI. Female C57BL/6 female mice rapidly cleared the infection. Female C3H/HeN mice, which have inherent vesicoureteral reflux that flushes urine from the bladder up into the kidneys, were susceptible to prolonged bacteriuria. This result is consistent with the fact that A. urinae infections most frequently occur in patients with underlying urinary tract abnormalities or disorders that make them susceptible to bacterial infection. Unlike uropathogens such as E. coli, which cause infection and inflammation both of the bladder and kidneys in C3H/HeN mice, A. urinae displayed tropism for the kidney, persisting in kidney tissue even after clearance of bacteria from the bladder. Aerococcus urinae strains from different genetic clades displayed varying propensities to cause persistent kidney infection. Aerococcus urinae infected kidneys displayed histological inflammation, neutrophil recruitment and increased pro-inflammatory cytokines. These results set the stage for future research that interrogates host-pathogen interactions between A. urinae and the urinary tract.
Highlights
These A. urinae strains comprised clinical isolates from cases of urinary tract infection (UTI), bacteremia, infective endocarditis (IE), overactive bladder (OAB), urgency urinary incontinence (UUI), and stress urinary incontinence (SUI), as well as two isolates from women with no urinary tract symptoms. While these strains clustered into five distinct clades based on their average nucleotide identity (ANI) values, there was no apparent relationship between host disease group (UTI, UUI, SUI, OAB, bacteremia, and IE) and clade (ANOVA P=0.24 by clade; P=0.22 by symptom group)
Experimental A. urinae urinary tract infection depends on mouse genetic background Using the data in Fig. 1, we chose four A. urinae strains from our collection to examine in the urinary tract of a mouse model
These strains were from three different clades and were isolated from patients with distinct clinical diagnoses: UMB80, isolated from a postmenopausal woman with OAB; UMB3669, isolated from a postmenopausal woman with UUI; UMB5628, isolated from a woman with a clinical UTI, where A. urinae was the predominant uropathogen identified by culture; and UMB722, isolated from a control woman with no lower urinary tract symptoms or other apparent urological conditions
Summary
Awareness of A. urinae as an emerging pathogen increased, especially following the advent of MALDI-TOF mass spectrometry techniques that allowed the organism to be discerned from staphylococci and streptococci (Meletis et al, 2017; Cattoir et al, 2010) Aerococcus urinae infects both males and females (Schuur et al, 1997), especially those with local or systemic predisposing conditions, such as elderly patients (Senneby et al, 2015) and those with urologic conditions (Sierra-Hoffman et al, 2005), prostatic diseases (Shelton-Dodge et al, 2011), urologic cancer (Higgins and Garg, 2017) or using urinary catheters (Sierra-Hoffman et al, 2005; Yu et al, 2019). The urinary tract is often implicated as the source of these disseminated infections because A. urinae is concurrently detected in urine (Senneby et al, 2016; Lyagoubi et al, 2020)
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