tacrolimus and Escherichia-coli-Infections

Calcineurin inhibitor Tacrolimus, is a potent immunosuppressive drug widely used in order to prevent acute graft rejection. Urinary tract infection (UTI) is the most frequent infectious complication in renal transplant patients and long-term use of Tacrolimus might be involved in higher susceptibility to bacterial infections. It remains largely unknown how Tacrolimus affects the host innate immune response against lower and upper UTI. To address this issue, we used experimental UTI model by intravesical inoculation of uropathogenic E.coli in female wild-type mice pre-treated with Tacrolimus or solvent (CTR). We found that Tacrolimus pre-treated mice displayed higher bacterial loads (cystitis, pyelonephritis and bacteremia) than CTR mice. Granulocytes from Tacrolimus pre-treated mice phagocytized less E. coli, released less MPO and expressed decreased levels of CXCR2 receptor upon infection. Moreover, Tacrolimus reduced TLR5 expression in bladder macrophages during UTI. This immunosuppressive state can be explained by the upregulation of TLR-signaling negative regulators (A20, ATF3, IRAK-M and SOCS1) and parallel downregulation of TLR5 as observed in Tacrolimus treated granulocytes and macrophages. We conclude that Tacrolimus impairs host innate immune responses against UTI.

Topics: Animals; Bacterial Load; Calcineurin Inhibitors; Disease Models, Animal; Escherichia coli Infections; Female; Granulocytes; Immunologic Factors; Immunosuppressive Agents; Mice; Peroxidase; Phagocytosis; Tacrolimus; Urinary Tract Infections; Uropathogenic Escherichia coli

Transplant recipients are treated with immunosuppressive (IS) therapies, which impact host-microbial interactions. We examined the impact of IS drugs on gut microbiota and on the expression of ileal antimicrobial peptides.. Mice were treated for 14 days with prednisolone, mycophenolate mofetil, tacrolimus, a combination of these 3 drugs, everolimus, or water. Feces were collected before and after treatment initiation. Ileal samples were collected after sacrifice. Fecal and ileal microbiota were analyzed by pyrosequencing of 16S rRNA genes and enumeration of selected bacteria by culture, and C-type lectins were assessed in ileal tissues by reverse transcriptase-quantitative polymerase chain reaction.. Prednisolone disrupted fecal microbiota community structure, decreased Bacteroidetes, and increased Firmicutes in the feces. Prednisolone, tacrolimus, and mycophenolate mofetil modified fecal microbiota at the family level in each experimental replicate, but changes were not consistent between the replicates. In ileal samples, the genus Clostridium sensu stricto was dramatically reduced in the prednisolone and combined IS drug groups. These modifications corresponded to an altered ileal expression of C-type lectins Reg3γ and Reg3β, and of interleukin 22. Interestingly, the combined IS treatment enabled a commensal Escherichia coli to flourish, and dramatically increased colonization by uropathogenic E. coli strain 536.. IS treatment alters innate antimicrobial defenses and disrupts the gut microbiota, which leads to overgrowth of indigenous E. coli and facilitates colonization by opportunistic pathogens.

Topics: Animals; Antimicrobial Cationic Peptides; Drug Therapy, Combination; Escherichia coli Infections; Feces; Gastrointestinal Microbiome; Host-Pathogen Interactions; Ileum; Immunocompromised Host; Immunosuppressive Agents; Lectins, C-Type; Mice, Inbred C57BL; Models, Animal; Mycophenolic Acid; Opportunistic Infections; Prednisolone; Reverse Transcriptase Polymerase Chain Reaction; Ribotyping; Tacrolimus; Time Factors; Urinary Tract Infections; Uropathogenic Escherichia coli

Topics: Anti-Bacterial Agents; Biological Availability; Drug Interactions; Escherichia coli Infections; Female; Humans; Immunosuppressive Agents; Injections, Intravenous; Kidney Transplantation; Middle Aged; Minocycline; Tacrolimus; Tigecycline

Topics: Child; Cholangitis, Sclerosing; Escherichia coli Infections; Esophageal and Gastric Varices; Female; Gastritis; Gastrointestinal Hemorrhage; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Postoperative Complications; Tacrolimus

An enterohemorrhagic Escherichia coli (EHEC) O157 oral infection murine model was established to examine the potentiating activity of drugs on mucosal immune responses. Groups of ICR mice inoculated intragastrically with 10(11) CFU/kg EHEC O157 showed chronic intestinal infection with the pathogen that persisted over 3 weeks and resulted in the synthesis of relatively high levels of antigen specific fecal IgA antibody. Intraperitoneal administration of 80 NU/kg Neurotropin, an immunopotentiator, augmented the antigen specific mucosal immune responses to EHEC O157. On the other hand, FK506 clearly suppressed the response. To further document the augmenting effect of Neurotropin on mucosal immune responses, mice were immunized intranasally with a mixture of ovalbumin and cholera toxin. Co-administration of 80 NU/kg Neurotropin significantly potentiated the synthesis of fecal IgA and serum IgG antibodies. These results suggest that Neurotropin has potential as a mucosal adjuvant to promote secretory IgA antibody production and that the mice model of oral infection with EHEC O157 is useful for immunopharmacological studies of bacterial infection-defensive mucosal immune responses.

Topics: Adjuvants, Immunologic; Administration, Intranasal; Animals; Antibodies, Bacterial; Antibody Formation; Disease Models, Animal; Enterotoxins; Escherichia coli Infections; Escherichia coli O157; Feces; Female; Gastric Mucosa; Immunity, Mucosal; Immunoglobulin A; Immunoglobulin G; Injections, Intraperitoneal; Mice; Mice, Inbred ICR; Ovalbumin; Polysaccharides; Tacrolimus