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Levo-1-methyl tryptophan aggravates the effects of mouse hepatitis virus (MHV-A59) infection
Maite Duhalde Vega1, José L Aparício1, Lilia A Retegui1
1Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
Abstract:
Mice infected with mouse hepatitis virus A59 (MHV-A59) develop autoantibodies (autoAb) to liver and kidney fumarylacetoacetate hydrolase (FAH) with a concomitant enhancement of transaminases and release of alarmins such as uric acid and high-mobility group box protein 1 (HMGB1). Tryptophan catabolism is an endogenous mechanism that restricts excessive immune responses, thereby preventing immunopathology. Since indoleamine-2,3-dioxygenase (IDO) is the key and rate-limiting enzyme of tryptophan catabolism, the aim of this work was to explore whether specific inhibition of IDO by Levo-1-methyl tryptophan (MT) could affect MHV actions. Results showed that MT strongly enhanced the hypergammaglobulinemia induced by the virus, as well as anti-MHV Ab and uric acid release. Moreover, infected mice treated with MT did express anti-FAH autoAb and high levels of serum HMGB1. Survival of MHV-infected animals treated with MT was severely reduced compared with that of MHV-infected mice or controls only treated with MT. Furthermore, histological liver examination indicated that MT induced fibrosis in MHV-infected animals, whereas MT itself increased uric acid levels without shortening the animal life Thus, under our experimental conditions, results indicated an exacerbated response to MHV infection when IDO was blocked by MT.
Insights
Blocking indoleamine-2,3-dioxygenase (IDO) with Levo-1-methyl tryptophan (MT) in mice infected with mouse hepatitis virus (MHV) exacerbated the immune response, leading to reduced survival and increased liver fibrosis.
Area of Science:
- Immunology
- Virology
- Biochemistry
Background:
- Mouse hepatitis virus A59 (MHV-A59) infection in mice triggers autoantibodies to fumarylacetoacetate hydrolase (FAH), elevated transaminases, and alarmins like uric acid and high-mobility group box protein 1 (HMGB1).
- Tryptophan catabolism, regulated by indoleamine-2,3-dioxygenase (IDO), is a crucial mechanism for limiting excessive immune responses and preventing immunopathology.
Purpose of the Study:
- To investigate the effects of specifically inhibiting IDO using Levo-1-methyl tryptophan (MT) on the host response to MHV-A59 infection in mice.
Main Methods:
- Mice were infected with MHV-A59 and treated with MT or a control.
- Key immunological markers, autoantibody production, alarmin levels, survival rates, and liver histology were assessed.
Main Results:
- MT treatment significantly enhanced virus-induced hypergammaglobulinemia, anti-MHV antibodies, and uric acid release.
- Infected mice treated with MT exhibited anti-FAH autoantibodies and elevated serum HMGB1.
- MT administration led to a severe reduction in survival and induced liver fibrosis in MHV-infected mice, while MT alone increased uric acid without affecting survival.
Conclusions:
- Specific inhibition of IDO by MT exacerbates the host response to MHV-A59 infection.
- IDO plays a critical role in regulating immune responses during viral infections and preventing immunopathology.
