A rare opportunist,Morganella morganii, decreases severity of polymicrobial catheter-associated urinary tract infection

Abstract

26Catheter-associated urinary tract infections (CAUTIs) are common hospital-acquired infections 27 and frequently polymicrobial, which complicates effective treatment. However, few studies 28 experimentally address the consequences of polymicrobial interactions within the urinary tract, 29 and the clinical significance of polymicrobial bacteriuria is not fully understood. Proteus 30 mirabilis is one of the most common causes of monomicrobial and polymicrobial CAUTI, and 31 frequently co-colonizes with Enterococcus faecalis, Escherichia coli, Providencia stuartii, and 32 Morganella morganii. P. mirabilis infections are particularly challenging due to its potent urease 33 enzyme, which facilitates formations of struvite crystals, catheter encrustation, blockage, and 34 formation of urinary stones. We previously determined that interactions between P. mirabilis and 35 other uropathogens can enhance P. mirabilis urease activity, resulting in greater disease severity 36 during experimental polymicrobial infection. Our present work reveals that M. morganii acts on 37 P. mirabilis in a contact-independent manner to decrease urease activity. Furthermore, M. 38 morganii actively prevents urease enhancement by E. faecalis, P. stuartii, and E. coli. 39 Importantly, these interactions translate to modulation of disease severity during experimental 40 CAUTI, predominantly through a urease-dependent mechanism. Thus, products secreted by 41 multiple bacterial species in the milieu of the catheterized urinary tract can directly impact 42 prognosis. 43 urolithiasis; urease 46 47Urinary catheters are common in health care settings, estimated to be utilized in ~60% of 48 critically ill patients, 20% of surgical unit patients, and 10% of nursing homes residents (1-3). 49The vast majority of individuals with an indwelling urinary catheter will experience bacteriuria 50 and may progress to catheter-associated urinary tract infection (CAUTI) (1). CAUTI is the most 51 common healthcare-associated condition in the United States, and carries an estimated economic 52 burden approaching $1.7 billion annually (4). 53 Bacteriuria in catheterized individuals rapidly becomes polymicrobial, involving 54 combinations of Proteus mirabilis, Enterococcus faecalis, Escherichia coli, Pseudomonas 55 aeruginosa, Klebsiella pneumoniae, Providencia stuartii, Morganella morganii, Citrobacter 56 species, Staphylococcus species, and Streptococcus species (1, 2, 5). It is estimated that 31-86% 57 of CAUTIs are also polymicrobial (6-14); however, urine specimens are often suspected of 58 harboring periurethral or vaginal microbiota if multiple colony types are observed, particularly if 59Gram-positive organisms are present, and are therefore often dismissed as "contamination" (15, 60 16). Thus, the clinical significance of polymicrobial bacteriuria is not fully understood. 61 There are numerous experimental and clinical examples of polymicrobial colonization 62 causing more severe disease than infection with a single bacterial species (monomicro...

Enterococcus faecalis Polymicrobial Interactions Facilitate Biofilm Formation, Antibiotic Recalcitrance, and Persistent Colonization of the Catheterized Urinary Tract

“…Single-species infections of P. mirabilis HI4320 alone and E. faecalis 3143 alone exhibited comparable catheter, bladder, and kidney colonization, although only P. mirabilis was capable of disseminating to the bloodstream to colonize the spleen and heart ( Figure 2 A). Both species were also capable of co-colonizing the catheter segment and bladder during co-infection ( Figure 2 B–D), and co-infection also appeared to facilitate dissemination of E. faecalis to the spleen by 24 hpi ( Figure 2 C), which is consistent with our prior observations at 96 hpi in CBA/J mice [ 34 ]. Notably, E. faecalis strain 3143 exhibited similar colonization patterns as the well-characterized strain OG1RF ( Figure 2 A,D).…”

“…We previously determined that E. faecalis and P. mirabilis strains isolated from catheterized human subjects can establish polymicrobial colonization in a murine model of CAUTI [ 34 ]. However, co-localization during infection was not directly assessed.…”

“…To explore the significance of enhanced biofilm formation during co-culture, we first sought to determine the source of the increased biomass. We previously demonstrated that broth co-culture of E. faecalis and P. mirabilis does not impact the viability or growth of either species in vitro [ 34 ]. However, enhanced biomass during stationary incubation could be a result of increased bacterial viability within the biofilm.…”

“…We previously determined that P. mirabilis isolates respond to E. faecalis secreted factors, resulting in increased urease activity and cytotoxicity to host cells [ 34 ]. To determine whether the increase in biofilm biomass is similarly mediated by secreted factors, crystal violet biofilm quantification was conducted using a transwell system in which P. mirabilis and E. faecalis were physically separated by a permeable polycarbonate membrane ( Figure 4 C).…”

“…In the context of urinary tract infection, only a handful of studies have explored the consequences of polymicrobial colonization, the majority of which have indicated that polymicrobial interactions increase colonization and persistence [ 11 , 28 , 29 , 30 , 31 , 32 , 33 ]. We recently determined that factors secreted by E. faecalis can enhance the pathogenic potential of P. mirabilis by promoting urease activity and cytotoxicity, and that co-infection of E. faecalis with P. mirabilis increases tissue damage and the incidence of urolithiasis and bacteremia during experimental CAUTI [ 34 ]. Thus, the presence of both E. faecalis and P. mirabilis at a high bacterial burden can be detrimental to the host, and further exploration of the factors that promote colonization by these species may elucidate new targets for reducing the risk of developing CAUTI and severe sequelae.…”