title: Treatment of Experimental Candida Sepsis with a Janus Kinase Inhibitor Controls Inflammation and Prolongs Survival.
abstract: Janus kinases (JAK) are intracellular tyrosine kinases that transduce cytokine-mediated signals to the nucleus, promoting gene expression. Cytokines play a major role in microbial sepsis, which is often associated with uncontrolled inflammation leading to death. JAK inhibitors have been used for the treatment of several autoimmune diseases by modulating immune response, but they have never been tested against microbial sepsis. Ruxolitinib is a small-molecule inhibitor of JAK1/2 proteins, which are involved in the downstream signaling pathway of the vast majority of proinflammatory and anti-inflammatory cytokines. We therefore studied the effect of ruxolitinib in a mouse model of sepsis due to Candida albicans. When ruxolitinib therapy (50 mg/kg [of body weight]/day) was started 1 day before infection, the median survival time was reduced by 3 days, the fungal loads in all organs were higher, the inflammation was significantly less, and serum tumor necrosis factor alpha (TNF-α) and interleukin 10 (IL-10) levels and IL-10/TNF-α ratios were higher than in controls. When ruxolitinib therapy (50 to 1.5 mg/kg/day) was started 1 day after infection, an inverted-U relationship was found, with 6.25 mg/kg/day prolonging median survival time by 6 days, resulting in similar fungal loads, less inflammation, and similar cytokine levels but higher IL-10/TNF-α ratios than the controls. The optimal dose of ruxolitinib controlled infection and prolonged survival with less inflammation than in control animals. Administration of JAK inhibitors may be a promising therapeutic adjunct that needs further investigation.
authors.affiliation: Second Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: P
authors.initials: P
authors.lastname: Tsirigotis
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: N
authors.initials: N
authors.lastname: Papanikolaou
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: A
authors.initials: A
authors.lastname: Elefanti
authors.affiliation: Department of Pathology, Evaggelismos General Hospital, Athens, Greece.
authors.forename: P
authors.initials: P
authors.lastname: Konstantinou
authors.affiliation: Second Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: K
authors.initials: K
authors.lastname: Gkirkas
authors.affiliation: Department of Pathology, Evaggelismos General Hospital, Athens, Greece.
authors.forename: D
authors.initials: D
authors.lastname: Rontogianni
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: N
authors.initials: N
authors.lastname: Siafakas
authors.affiliation: Department of Cytopathology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: P
authors.initials: P
authors.lastname: Karakitsos
authors.affiliation: Infectious Diseases Unit, Third Department of Pediatrics, Aristotle University School of Medicine, Hippokration Hospital, Thessaloniki, Greece.
authors.forename: E
authors.initials: E
authors.lastname: Roilides
authors.affiliation: Second Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: G
authors.initials: G
authors.lastname: Dimitriadis
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: L
authors.initials: L
authors.lastname: Zerva
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece jmeletiadis@med.uoa.gr.
authors.forename: J
authors.initials: J
authors.lastname: Meletiadis
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000302:isolation & purification; D058387:Candidemia / Q000188:drug therapy* / Q000401:mortality; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000382:microbiology; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D008815:Mice, Inbred Strains; D009570:Nitriles; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality
chemical_list: D000935:Antifungal Agents; D016207:Cytokines; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; D053612:Janus Kinases