Host Cathelicidin Exacerbates Group BStreptococcusUrinary Tract Infection

Abstract

Group B Streptococcus (GBS) causes frequent urinary tract infection (UTI) in susceptible populations, including individuals with type 2 diabetes and pregnant women; however, specific host factors responsible for increased GBS susceptibility in these populations are not well characterized. Here, we investigate cathelicidin, a cationic antimicrobial peptide, known to be critical for defense during UTI with uropathogenic Escherichia coli (UPEC). We observed a loss of antimicrobial activity of human and mouse cathelicidins against GBS and UPEC in synthetic urine and no evidence for increased cathelicidin resistance in GBS urinary isolates. Furthermore, we found that GBS degrades cathelicidin in a protease-dependent manner. Surprisingly, in a UTI model, cathelicidin-deficient (Camp−/−) mice showed decreased GBS burdens and mast cell recruitment in the bladder compared to levels in wild-type (WT) mice. Pharmacologic inhibition of mast cells reduced GBS burdens and histamine release in WT but not Camp−/− mice. Streptozotocin-induced diabetic mice had increased bladder cathelicidin production and mast cell recruitment at 24 h postinfection with GBS compared to levels in nondiabetic controls. We propose that cathelicidin is an important immune regulator but ineffective antimicrobial peptide against GBS in urine. Combined, our findings may in part explain the increased frequency of GBS UTI in diabetic and pregnant individuals. IMPORTANCE Certain populations such as diabetic individuals are at increased risk for developing urinary tract infections (UTI), although the underlying reasons for this susceptibility are not fully known. Additionally, diabetics are more likely to become infected with certain types of bacteria, such as group B Streptococcus (GBS). In this study, we find that an antimicrobial peptide called cathelicidin, which is thought to protect the bladder from infection, is ineffective in controlling GBS and alters the type of immune cells that migrate to the bladder during infection. Using a mouse model of diabetes, we observe that diabetic mice are more susceptible to GBS infection even though they also have more infiltrating immune cells and increased production of cathelicidin. Taken together, our findings identify this antimicrobial peptide as a potential contributor to increased susceptibility of diabetic individuals to GBS UTI.

Group B streptococcal infection of the genitourinary tract in pregnant and non‐pregnant patients with diabetes mellitus: An immunocompromised host or something more?

“…94 Recent studies have tried to model how changes in available glucose within patients with DM might alter the pathogenesis of GBS. 95,103 While more work is needed to fully understand how host metabolic disease might impact host-pathogen interactions, these studies suggest that both local immune responses 103 and GBS virulence regulation 95 are affected. These environmental changes may induce other changes in bacterial physiology, leading to upregulation of adhesion proteins and biofilm production, which may promote vaginal colonization.…”

“…95 Patras et al examined the role of LL-37, a cathelicidin antimicrobial peptide expressed in the setting of UTIs, on GBS infections in a streptozotocin-induced diabetic mouse model of ascending UTI resulting in hyperglycemia and glucosuria. 103 They found that streptozotocin-induced diabetic mice had higher GBS burdens in the bladder than mock-treated control mice. When the authors examined the immune cell populations responding to infection, they found similar numbers of neutrophils and monocytes, but higher populations of mast cells in diabetic mice, suggesting differences in immune responses may also contribute to the increased susceptibility of UTIs experienced by diabetic patients.…”

Novel Models of Streptococcus canis Colonization and Disease Reveal Modest Contributions of M-Like (SCM) Protein

“…Vaginal swab samples obtained during swabbing for bacterial colonization were subjected to flow cytometry as adapted from previous work [ 36 , 41 ]. Vaginal lumen cells were released from vaginal swabs by vortexing for 2–3 s, passed through a 40-μm-pore-size filter, and pelleted at 500× g for 5 min.…”

Streptococcus pyogenes upregulates arginine catabolism to exert its pathogenesis on the skin surface

“…To induce diabetes mellitus, C57BL/6 male mice (4-week-old) were injected i.p. with streptozotocin (Adipogen, San Diego, CA, USA) at 80 mg/kg/dose in 200 mL of 0.1 M citrate buffer daily for 4 days (Patras et al, 2020). Control mice received 4 daily treatments of 200 mL of 0.1 M citrate buffer.…”