Toll-Like Receptor-4 Dependent Inflammatory Responses Following Intestinal Colonization of Secondary Abiotic IL10-Deficient Mice with Multidrug-Resistant Pseudomonas Aeruginosa

Abstract

The rising incidences of infections with multidrug-resistant (MDR) Gram-negative bacteria including Pseudomonas aeruginosa (PA) have gained increasing attention in medicine, but also in the general public and global health politics. The mechanisms underlying opportunistic pathogen–host interactions are unclear, however. To address this, we challenged secondary abiotic IL10 ^–/– mice deficient for Toll-like receptor-4 (TLR4 ^–/– × IL10 ^–/–), the main receptor of the Gram-negative cell wall constituent lipopolysaccharide, with a clinical MDR PA isolate. Despite higher intestinal colonization densities, apoptotic colonic epithelial cell numbers were lower in TLR4 ^–/– × IL10 ^–/– mice as compared to IL10 ^–/– controls at day 14 postinfection (p.i.), whereas proliferating/regenerating cells had increased in the latter only. Furthermore, PA-colonized TLR4 ^–/– × IL10 ^–/– mice displayed less distinct innate and adaptive immune cell responses in the colon as compared to IL10 ^–/– counterparts that were accompanied by lower nitric oxide concentrations in mesenteric lymph nodes in the former at day 14 p.i. Conversely, splenic NO levels were higher in both naive and PA-colonized TLR4-deficient IL10 ^–/– mice versus IL10 ^–/– controls. Remarkably, intestinal MDR PA was able to translocate to extra-intestinal including systemic compartments of TLR4 ^–/– × IL10 ^–/– mice only. Hence, MDR PA-induced intestinal and systemic immune responses observed in secondary abiotic IL10 ^–/– mice are TLR4-dependent.