Bridgette M. Cumming ¹ Kelvin W. Addicott ¹ Fernanda Maruri ^2,3 Vanessa Pillay ¹ Rukaya Asmal ¹ Sashen Moodley ¹ Beatriz Barreto-Durate ^4,5 Mariana Araújo-Pereira ^4,5 Matilda Mazibuko ¹ Zoey Mhlane ¹ Nikiwe Mbatha ¹ Khadija Khan ¹ Senamile Makhari ¹ Farina Karim ¹ Lauren Peetluk ² Alexander S. Pym ¹ Mahomed Yunus S. Moosa ⁶ Yuri F. Van Der Heijden ^2,3,7 Timothy S. Sterling ^2,3 Bruno B. Andrade ^4,5 Alasdair Leslie ¹ Adrie J. Steyn ^1,8*

• ¹ Africa Health Research Institute (AHRI), Durban, South Africa
• ² Vanderbilt Tuberculosis Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States
• ³ Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
• ⁴ Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER), Salvador, Bahia, Brazil
• ⁵ Laboratório de Pesquisa Clínica e Translacional, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz,, Salvador, Bahia, Brazil
• ⁶ Department of Infectious Diseases, University of KwaZulu-Natal, Durban, South Africa
• ⁷ Global Division, The Aurum Institute, Johannesburg, South Africa
• ⁸ University of Alabama at Birmingham, Birmingham, United States

The impact of human pulmonary tuberculosis (TB) on the bioenergetic metabolism of circulating immune cells remains elusive, as does the resolution of these effects with TB treatment. In this study, the rates of oxidative phosphorylation (OXPHOS) and glycolysis in circulating lymphocytes and monocytes of patients with drug-susceptible TB at diagnosis, 2 months, and 6 months during treatment, and at 12 months following diagnosis were investigated using extracellular flux analysis. At diagnosis, the bioenergetic parameters of both blood lymphocytes and monocytes of TB patients were severely impaired in comparison to non-TB, non-HIV infected controls. However, most bioenergetic parameters were not affected by HIV status nor glycaemic index. Treatment of TB patients restored the % spare respiratory capacity (%SRC) of the circulating lymphocytes to that observed in non-TB and non-HIV infected controls by 12 months. Treatment also improved the maximal respiration of the circulating lymphocytes and the %SRC of the circulating monocytes of the TB patients. Notably, differential correlation of the clinical and bioenergetic parameters of the monocytes and lymphocytes from the controls and TB patients at baseline and month 12 were consistent with improved metabolic health and resolution of inflammation following successful TB treatment. Network analysis of the bioenergetic parameters of the circulating immune cells with the serum cytokine levels indicated a highly co-ordinated immune response at month 6. These findings underscore the importance of metabolic health in combating TB, supporting the need for further investigation of the bioenergetic immunometabolism associated with TB infection for novel therapeutic approaches aimed at bolstering cellular energetics to enhance immune responses and expedite recovery in TB patients.