Dr Edmee Eyraud - The lung-brain axis as a key player in Tuberculosis-associated cachexia
Dr Edmee Eyraud - The lung-brain axis as a key player in Tuberculosis-associated cachexia
Tuesday 8 December, 11:00
Edmee Eyraud
Inflammation and Innate Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
The lung-brain axis as a key player in Tuberculosis-associated cachexia
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a highly infectious bacterium leading to over a million deaths annually. The exact reasons for disease exacerbation are still not well understood. However, individuals with active TB disease exhibit conserved disease-defining features, such as body mass wasting, also known as cachexia. Despite the evidence of a link between nutrition, cachexia and TB, the role of TB-associated cachexia (TBAC) in host resistance to Mtb remains largely unexplored. Particularly, the immune, neuroimmune and metabolic -mediated mechanisms driving TBAC are poorly understood, emphasizing a critical gap in our understanding of the disease. We hypothesize that cachexia directly contributes to TB pathogenesis and represents a critical tipping point for disease progression.
Here we describe the weight change following Mtb infection in 3 different in vivo animal models: the mouse, marmoset and rhesus macaque. We show that mice and marmosets display cachexia more readily than rhesus macaques. Body weight loss and lung bacterial burdens positively correlated in cachectic mice and marmosets and was associated with loss of adipose and muscle tissues in mice. Importantly, Mtb disseminated to skeletal muscle and adipose tissue of mice, marmosets and rhesus-macaques. In both cachectic Il1r1-/- deficient mice and marmosets, increased pulmonary bacterial burdens were associated with increased bacilli in muscle and adipose tissue. Moreover, infected Il1r1-/- deficient mice displayed a reduction in food intake starting prior to the onset of cachexia resulting in adipose tissue wasting but not skeletal muscle, suggesting anorexic and sickness behaviors may underly progression to TBAC. In addition, the brain-acting mediator GDF15 was increased in lungs of susceptible Il1r1-/- mice following Mtb infection and associated with muscle wasting. To further investigate the lung-brain axis crosstalk as a key modulator of TBAC, we employed surgical approaches in WT and Il1r1-/- mice. Performing subdiaphragmatic and cervical vagotomies, we identified the lung-brain vagal axis as a crucial neuro-immune brake buffering TB and TBAC progression under severe disease exacerbation.
Understanding the role and mechanisms of TBAC could reveal new intervention points and pave the way for new host-directed therapeutic targets for tuberculosis, but also cancer-associated cachexia.
Selected references
- Eyraud E et al. Elife. 2023 Jul 26;12:RP85875. doi: 10.7554/eLife.85875.
- Dupin I et al. Am J Respir Cell Mol Biol. 2025 Oct;73(4):530-544. doi: 10.1165/rcmb.2024-0303OC
Dr Edmee Eyraud - The lung-brain axis as a key player in Tuberculosis-associated cachexia
Dr Edmee Eyraud - The lung-brain axis as a key player in Tuberculosis-associated cachexia
Tuesday 8 December, 11:00
Edmee Eyraud
Inflammation and Innate Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
The lung-brain axis as a key player in Tuberculosis-associated cachexia
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a highly infectious bacterium leading to over a million deaths annually. The exact reasons for disease exacerbation are still not well understood. However, individuals with active TB disease exhibit conserved disease-defining features, such as body mass wasting, also known as cachexia. Despite the evidence of a link between nutrition, cachexia and TB, the role of TB-associated cachexia (TBAC) in host resistance to Mtb remains largely unexplored. Particularly, the immune, neuroimmune and metabolic -mediated mechanisms driving TBAC are poorly understood, emphasizing a critical gap in our understanding of the disease. We hypothesize that cachexia directly contributes to TB pathogenesis and represents a critical tipping point for disease progression.
Here we describe the weight change following Mtb infection in 3 different in vivo animal models: the mouse, marmoset and rhesus macaque. We show that mice and marmosets display cachexia more readily than rhesus macaques. Body weight loss and lung bacterial burdens positively correlated in cachectic mice and marmosets and was associated with loss of adipose and muscle tissues in mice. Importantly, Mtb disseminated to skeletal muscle and adipose tissue of mice, marmosets and rhesus-macaques. In both cachectic Il1r1-/- deficient mice and marmosets, increased pulmonary bacterial burdens were associated with increased bacilli in muscle and adipose tissue. Moreover, infected Il1r1-/- deficient mice displayed a reduction in food intake starting prior to the onset of cachexia resulting in adipose tissue wasting but not skeletal muscle, suggesting anorexic and sickness behaviors may underly progression to TBAC. In addition, the brain-acting mediator GDF15 was increased in lungs of susceptible Il1r1-/- mice following Mtb infection and associated with muscle wasting. To further investigate the lung-brain axis crosstalk as a key modulator of TBAC, we employed surgical approaches in WT and Il1r1-/- mice. Performing subdiaphragmatic and cervical vagotomies, we identified the lung-brain vagal axis as a crucial neuro-immune brake buffering TB and TBAC progression under severe disease exacerbation.
Understanding the role and mechanisms of TBAC could reveal new intervention points and pave the way for new host-directed therapeutic targets for tuberculosis, but also cancer-associated cachexia.
Selected references
- Eyraud E et al. Elife. 2023 Jul 26;12:RP85875. doi: 10.7554/eLife.85875.
- Dupin I et al. Am J Respir Cell Mol Biol. 2025 Oct;73(4):530-544. doi: 10.1165/rcmb.2024-0303OC
