title: Absence of kynurenine 3-monooxygenase reduces mortality of acute viral myocarditis in mice.
abstract: Infection of the encephalomyocarditis virus (EMCV) in mice is an established model for viral myocarditis. Previously, we have demonstrated that indoleamine 2,3-dioxygenase (IDO), an L-tryptophan - kynurenine pathway (KP) enzyme, affects acute viral myocarditis. However, the roles of KP metabolites in EMCV infection remain unclear. Kynurenine 3-monooxygenase (KMO) is one of the key regulatory enzymes, which metabolizes kynurenine to 3-hydroxykynurenine in the KP. Therefore, we examined the role of KMO in acute viral infection by comparing between KMO-/-mice and KMO+/+mice. KMO deficiency resulted in suppressed mortality after EMCV infection. The number of infiltrating cells and F4/80+cells in KMO-/-mice was suppressed compared with those in KMO+/+mice. KMO-/-mice showed significantly increased levels of serum KP metabolites, and induction of KMO expression upon EMCV infection was involved in its effect on mortality through EMCV suppression. Furthermore, KMO-/-mice showed significantly suppression of CCL2, CCL3 and CCL4 on day 2 and CXCL1 on day 4 after infection. These results suggest that increased KP metabolites reduced chemokine production, resulting in suppressed mortality upon KMO knockdown in EMCV infection. KP metabolites may thus provide an effective strategy for treating acute viral myocarditis.
authors.affiliation: Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan; Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi 470-1192, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Kubo
authors.affiliation: Department of Biochemical and Analytical Sciences, Fujita Health University Graduate School of Health Sciences, Aichi 470-1192, Japan. Electronic address: mhoshi@fujita-hu.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Hoshi
authors.affiliation: Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Sciences, Aichi 470-1192, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Mouri
authors.affiliation: Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi 470-1192, Japan; Department of Medical Technology, Gifu University of Medical Science, Gifu 501-3892, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Tashita
authors.affiliation: Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi 470-1192, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Sciences, Aichi 470-1192, Japan; Japanese Drug Organization of Appropriate Use and Research, Aichi 468-0069, Japan; Aino University, Osaka, Ibaragi 567-0012, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.affiliation: Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan; Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi 470-1192, Japan; Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Sciences, Aichi 470-1192, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Saito
mesh_terms: D000208:Acute Disease; D000818:Animals; D015415:Biomarkers; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D050601:Kynurenine 3-Monooxygenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008297:Male; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D009205:Myocarditis / Q000235:genetics* / Q000401:mortality / Q000821:virology*; D011379:Prognosis
chemical_list: D015415:Biomarkers; D016207:Cytokines; D050601:Kynurenine 3-Monooxygenase
keywords: Chemokines; Encephalomyocarditis virus; KMO knockout mice; Kynurenine 3-monooxygenase; Kynurenine pathway metabolites; Tryptophan catabolism