Pathogenesis of Streptococcus urinary tract infection depends on bacterial strain and β-hemolysin/cytolysin that mediates cytotoxicity, cytokine synthesis, inflammation and virulence

Abstract

Streptococcus agalactiae can cause urinary tract infection (UTI) including cystitis and asymptomatic bacteriuria (ABU). The early host-pathogen interactions that occur during S. agalactiae UTI and subsequent mechanisms of disease pathogenesis are poorly defined. Here, we define the early interactions between human bladder urothelial cells, monocyte-derived macrophages, and mouse bladder using uropathogenic S. agalactiae (UPSA) 807 and ABU-causing S. agalactiae (ABSA) 834 strains. UPSA 807 adhered, invaded and killed bladder urothelial cells more efficiently compared to ABSA 834 via mechanisms including low-level caspase-3 activation, and cytolysis, according to lactate dehydrogenase release measures and cell viability. Severe UPSA 807-induced cytotoxicity was mediated entirely by the bacterial β-hemolysin/cytolysin (β-H/C) because an β-H/C-deficient UPSA 807 isogenic mutant, UPSA 807ΔcylE, was not cytotoxic in vitro; the mutant was also significantly attenuated for colonization in the bladder in vivo. Analysis of infection-induced cytokines, including IL-8, IL-1β, IL-6 and TNF-α in vitro and in vivo revealed that cytokine and chemokine responses were dependent on expression of β-H/C that also elicited severe bladder neutrophilia. Thus, virulence of UPSA 807 encompasses adhesion to, invasion of and killing of bladder cells, pro-inflammatory cytokine/chemokine responses that elicit neutrophil infiltration, and β-H/C-mediated subversion of innate immune-mediated bacterial clearance from the bladder.

Histone deacetylase inhibitors mediate DNA damage repair in ameliorating hemorrhagic cystitis

“…Interestingly, those down stream of pyroptotic signaling (e.g. IL-6, IGF1, IL-1ß) are dependent on Ogg1 expression and documented to be consequential to the bladder pathology373839. Future studies could test if long-term prophylactic treatment with HDAC inhibitors following CPX/mesna treatment schedule could reduce the rates of hemorrhagic cystitis in this highly susceptible population.…”

Increased Age, but Not Parity Predisposes to Higher Bacteriuria Burdens Due to Streptococcus Urinary Tract Infection and Influences Bladder Cytokine Responses, Which Develop Independent of Tissue Bacterial Loads

“…Differences in the early steps in pathogenesis of S . agalactiae UTI have been reported related to strain differences [14]; some of these differences may relate to virulence factors such as the hemolysin [14, 57], or capsule, the sialic acids of which enhance the survival of S . agalactiae in the urinary tract [13] and augment the ability of E .…”

“…Several studies have demonstrated that the pathogenesis of S . agalactiae UTI encompasses binding of the bacteria to the bladder [11, 12], cytotoxicity in urothelial cells, and elicitation of pro- and anti-inflammatory cytokine and chemokine responses [13, 14], as well as growth of some ABU-causing S . agalactiae in human urine that may affect persistence [15].…”

Variation in hemolysin A expression between uropathogenic Escherichia coli isolates determines NLRP3‐dependent vs . ‐independent macrophage cell death and host colonization

“…For immune profiling of mouse bladders, tissues were collected and homogenized in protease inhibitor as described in ref. 32. Supernatants were frozen at 280°C until assay.…”