Vascular allografts are resistant to methicillin-resistant Staphylococcus aureus through indoleamine 2,3-dioxygenase in a murine model.
OBJECTIVE
Surgical results have shown the superiority of human heart valve and vascular allografts over artificial prostheses when used for the treatment of infectious cardiovascular diseases. However, the mechanism of infection resistance in these allografts has not been determined. In this study the contribution of the inflammatory response after allogeneic transplantation to the antimicrobial mechanism was assessed, focusing on the induction of indoleamine 2,3-dioxygenase, a tryptophan-metabolizing enzyme.


METHODS
Aortic transplantation was performed with inbred rats, and aortic allografts, isografts, and control grafts were obtained for the following analyses. The extent of inflammatory-related and indoleamine 2,3-dioxygenase gene expression was measured by means of quantitative reverse transcriptase-polymerase chain reaction, and tryptophan metabolite production in the graft was measured by means of liquid chromatographic/tandem mass spectrometric analysis. The bacteriostatic effect of each graft and tryptophan metabolites was determined by using the methicillin-resistant Staphylococcus aureus proliferation assay.


RESULTS
The inflammatory response, including interferon gamma, tumor necrosis factor alpha, and indoleamine 2,3-dioxygenase gene expression, was significant in the allografts but minimal in the isografts and control grafts. Methicillin-resistant S. aureus proliferation was remarkably suppressed when cultured with the allografts but not with the control grafts. Among tryptophan metabolites, the bacteriostatic effect against methicillin-resistant S. aureus was remarkable with 3-hydroxykynurenine, with a minimum inhibitory concentration of 32 mg/L. The 3-hydroxykynurenine level in the allografts was 9-fold greater than that in the control grafts.


CONCLUSIONS
The bacteriostatic effect of the allografts was acquired by inducing indoleamine 2,3-dioxygenase, which resulted in local production of 3-hydroxykynurenine as an antimicrobial agent. This is the first report to document a mechanism of the allograft's infection-resistant property against methicillin-resistant S. aureus growth.
Saito
A
A
Department of Cardiothoracic Surgery, the University of Tokyo Graduate School of Medicine, Tokyo, Japan. ayasaitou-ths@umin.ac.jp
Motomura
N
N
Kakimi
K
K
Narui
K
K
Noguchi
N
N
Sasatsu
M
M
Kubo
K
K
Koezuka
Y
Y
Takai
D
D
Ueha
S
S
Takamoto
S
S
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001011:Aorta / Q000637:transplantation; D001807:Blood Vessel Prosthesis / Q000382:microbiology*; D016207:Cytokines / Q000378:metabolism; D004696:Endocarditis / Q000382:microbiology / Q000517:prevention & control; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000494:pharmacology*; D007737:Kynurenine / Q000031:analogs & derivatives / Q000096:biosynthesis; D016106:Methicillin Resistance / Q000187:drug effects*; D051381:Rats; D011917:Rats, Inbred Lew; D013203:Staphylococcal Infections / Q000382:microbiology / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification*; D014184:Transplantation, Homologous
D000900:Anti-Bacterial Agents; D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C005045:3-hydroxykynurenine; D007737:Kynurenine