Research Teaching Specialist New Jersey Medical School Newark, New Jersey, United States
Disclosure(s):
Shamba Gupta, PhD: No financial relationships to disclose
Introduction/Rationale: Tuberculosis (TB) is a major public health burden. One microbial immune-regulatory mechanism is pathogen-driven modulation of host immunometabolism via the tryptophan catabolizing indoleamine 2,3-dioxygenases (IDO1 and IDO2). We used gene knockout (KO) mice and IDO inhibition to study how these enzymes impact anti-TB immunity and vaccine efficacy.
Methods: We used ido1-/-, ido2-/-, and ido1/ido2-/- mice, in conjunction with targeted pharmacological IDO inhibition to define the roles of IDO isoforms during Mtb infection and BCG immunization.
Results: Biochemical analysis revealed that the tryptophan catabolic pathway was active in Mtb infected tissue in mice. Flow cytometric analysis of lungs and lymph node (LN) cells from mice infected with Mtb Erdman showed that IDO1 expression is in general, higher than that of IDO2 in dendritic cells (DCs), plasmacytoid DCs, and macrophages. Results derived from IDO-deficient mice and inhibitor studies showed that i) the two isoforms differentially modulate Mtb susceptibility, as assessed by tissue bacterial loads and mortality rates, in a dose- and infection phase-dependent manner; impacting ii) the Th1, Th17, neutrophilic, Treg and the TNF+ CD4+ T cell response; iii) IDO1 inhibition during BCG vaccination resulted in higher levels of central memory CD4⁺ T cells (TCMs) in the lungs and LNs, compared to that observed in immunized mice without inhibitor treatment; iv) Mtb challenge in BCG vaccinated, IDO inhibitor-treated mice exhibited diminished tissue bacillary loads that was associated with reduced levels of granulomatous inflammation.
Conclusion: Our findings suggest that IDO1 and IDO2 serve as immunometabolic checkpoints in TB infection and vaccine response. We propose that targeting IDO1 during immunization could enhance vaccine-elicited immunity, possibly via the augmentation of lung and LN TCM response. This metabolic modulation may be applicable to other microbes to augment vaccine immunogenicity.
