Nutritional Immunity and Antibiotic Drug Treatments Influence Microbial Composition but Fail to Eliminate Urethral Catheter Biofilms in Recurrently Catheterized Patients

Abstract

21Polymicrobial biofilms that form on indwelling urethral catheters used by neurogenic 22 bladder patients are known to recur following catheter replacements. Uropathogens dominate in 23 catheter biofilms (CBs), grow and disperse as multi-cellular aggregates. Their microbial 24 complexity, the characteristics of host immune responses and the molecular crosstalk in this 25 ecosystem are incompletely understood. By surveying eight patients over up to six months with 26 meta-omics analysis methods, we shed new light on the longitudinal microbial dynamics in CBs 27 and the microbial-host crosstalk. There was evidence of chronic innate immune responses in all 28 patients. Pathogens dominated the microbial contents. Proteus mirabilis often out-competed other 29 species in cases of salt encrustation of catheters. The examination of proteomes in CBs and 30 associated urinary pellets revealed many abundant bacterial systems for transition metal ion (TMI) 31 acquisition. TMIs are sequestered by effector proteins released by activated neutrophils and 32 urothelial cells, such as lactotransferrin and calgranulins, which were abundant in the host 33 proteomes. We identified positive quantitative correlations among systems responsible for 34 siderophore biosynthesis, TMI/siderophore uptake and TMI cellular import in bacterial species, 35 suggesting competition for TMIs to support their metabolism and growth in CBs. Enterococcus 36 faecalis was prevalent as a cohabitant of CBs and expressed three lipoproteins with apparent TMI 37 acquisition functions. Fastidious anaerobic bacteria such as Veillonella, Actinobaculum, and 38 Bifidobacterium grew in CB communities that appeared to be oxygen starved. Finally, antibiotic 39 drug treatments were shown to influence microbial composition of CBs but failed to prevent re-40 colonization of urethral catheters with persisting and/or drug-resistant newly emerging pathogens. 41 42 43 44 45 46 Urethral catheter-associated urinary tract infection (CAUTI) is the most common type of 47 complicated UTI. CAUTIs have a higher risk of recurrence, pyelonephritis and bacteremia than 48 uncomplicated UTIs in nosocomial environments (1-3). Asymptomatic cases are usually 49 diagnosed as catheter-associated asymptomatic bacteriuria (CAASB). The use of nearly 100 50 million urethral catheters per year worldwide, the 3% to 10% incidence of bacteriuria over 24 51 hours following patient catheterization and an average bladder catheter insertion time of 72 h (2) 52 suggest an estimated 9 to 27 million CAUTI cases per year globally. Among the most common 53 causes are Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, 54 Enterococcus and Candida spp. (1, 3, 4). Indwelling Foley catheters are often used by patients 55 with anatomical urinary tract abnormalities and neurogenic bladder syndrome and retained in the 56 urinary tract for one week or longer. Microbial colonization is difficult to avoid even when catheters 57 are regularly replaced, and antibi...