Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis .
Sadiya ParveenJessica ShenShichun LunLiang ZhaoBenjamin KoleskeRobert D LeoneRana RaisJonathan D PowellJohn R MurphyBarbara S SlusherWilliam R BishaiPublished in: bioRxiv : the preprint server for biology (2023)
As one of the most successful human pathogens, Mycobacterium tuberculosis ( Mtb ) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a novel glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomics analysis of lungs from JHU083-treated Mtb -infected mice revealed reduced glutamine levels, citrulline accumulation suggesting elevated NOS activity, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. When tested in an immunocompromised mouse model of Mtb infection, JHU083 lost its therapeutic efficacy suggesting the drug’s host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.
Keyphrases
- mycobacterium tuberculosis
- pulmonary tuberculosis
- weight gain
- single cell
- mouse model
- bone marrow
- endothelial cells
- acute myeloid leukemia
- high fat diet induced
- metabolic syndrome
- high throughput
- high resolution
- genome wide
- newly diagnosed
- big data
- type diabetes
- insulin resistance
- machine learning
- mesenchymal stem cells
- hiv infected
- cell death
- hiv aids
- risk factors
- deep learning
- multidrug resistant
- high density