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
- mouse model
- single cell
- endothelial cells
- acute myeloid leukemia
- bone marrow
- body mass index
- dendritic cells
- signaling pathway
- induced apoptosis
- oxidative stress
- physical activity
- newly diagnosed
- hepatitis c virus
- birth weight
- intensive care unit
- mass spectrometry
- high throughput
- high fat diet induced
- hiv infected
- immune response
- cell death
- risk factors
- type diabetes
- cell therapy
- genome wide
- big data
- dna methylation
- acute respiratory distress syndrome
- emergency department
- essential oil
- multidrug resistant
- deep learning