Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities againstMycobacterium tuberculosis

Abstract

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 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.

Intracellular pH links energy metabolism to lymphocyte death and proliferation

“…Although our study focuses on lymphocytes, it is worth noting that glutaminolysis and the Warburg effect are found in various types of normal and malignant cells ( 34, 43 ). Moreover, the Warburg effect and the dependency on glutamines for cell proliferation are evolutionary conserved ( 44–47 ). Therefore, it is reasonable to speculate that the principles discovered in this study are applicable to other cell types across species, particularly cells that produce large amount of energy.…”

Glutaminolysis of CD4+ T Cells: A Potential Therapeutic Target in Viral Diseases

“…[1][2][3] Glutaminolysis is one of the most important hallmarks of metabolic reprogramming. 4,5 Several studies, including those on various tumours and Mycobacterium tuberculosis infections, [6][7][8][9] have reported that the immunomodulatory effects of glutaminolysis are driven by their impact on T cells, and glutaminolysis mediates viral latency or reactivation and alters viral susceptibility to host cells. 10,11 However, the mechanisms by which metabolic-mediated CD4 + T cells influence virulence development are still poorly understood.…”