Advisor(s)
Adrie Steyn
Committee Member(s)
Adrie Steyn
Anupam Agarwal
Eric Ubil
Hubert Tse
Lalita Shevde-Samant
Document Type
Dissertation
Date of Award
1-27-2026
Degree Name
Doctor of Philosophy (PhD)
School
Joint Health Sciences (Interdisciplinary)
Department
Microbiology
Abstract
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains the leading cause of morbidity and mortality worldwide from a single infectious agent. Individuals with active TB often display dysregulated immune responses that result in extensive tissue damage which, in severe cases, requires lung resection. Among the immune cell types implicated, neutrophils are being increasingly recognized as central mediators of TB-associated immunopathology, even though the underlying mechanisms remain poorly understood. Because cellular metabolism is a key regulator of immune function, we hypothesized that Mtb infection reprograms neutrophil immunometabolism to promote tissue injury. To test this hypothesis, we quantified the abundance and spatial distribution of proteins associated with neutrophil effector functions within the necrotic granulomas from human TB lung specimens. Using neutrophils from healthy donors, we investigated how Mtb infection alters neutrophil viability, energy metabolism, and immune responses. Necrotic TB granulomas exhibited elevated levels of proteins associated with neutrophil extracellular trap (NET) formation, which colocalized with the high affinity glucose transporter GLUT3. This spatial association suggests a novel link between glucose uptake, neutrophil activity, and TB immunopathology. In vitro, Mtb infection markedly enhances neutrophil effector responses which are strongly dependent on the concentration of glucose, but not on other inflammation-associated nutrients including fructose, lactate, pyruvate, and glutamine. Mtb infection also induces a rapid, glucose-dependent oxidative burst in neutrophils that requires direct contact with the pathogen and activation of pathogen recognition receptors Fcγ (CD16, CD32, and CD64) and Dectin-1. Notably, this oxidative response is specific to Mtb, as non-tuberculous mycobacteria and other bacterial pathogens, such as Staphylococcus aureus and Listeria monocytogenes did not elicit a comparable response. The neutrophil oxidative burst was accompanied by a metabolic shift from glycolysis to the pentose phosphate pathway (PPP) upon Mtb infection. Blocking the PPP by inhibiting glucose-6-phosphate dehydrogenase, or inhibition of NADPH oxidase or Peptidylarginine deiminase 4 (PAD4), significantly reduced the Mtb-induced oxidative burst in human neutrophils. Together, these findings demonstrate that Mtb reprograms neutrophil metabolism to drive oxidative burst and exacerbate tissue pathology in TB. Mitigating neutrophil-mediated TB immunopathology via targeted modulation of the PPP and/or NETosis represents a potential strategy for host-directed therapy.
Keywords
Glucose metabolism;Immunometabolism;Mycobacterium tuberculosis;Neutrophils;Oxidative burst;Pentose phosphate pathway
ProQuest Publication Number
32284184
ProQuest ID
ISBN
9798273381230
Recommended Citation
Chinta, Krishna, "Mycobacterium Tuberculosis Infection Reprograms Neutrophil Immunometabolism" (2026). ETDs from 2020-2029. 15.
https://digitalcommons.library.uab.edu/etd-2020s/15
