Relationship between Kynurenine Pathway and TB-specific Th17 responses in People with HIV and Latent Tuberculosis Infection
Abstract
Tuberculosis (TB) remains the leading cause of death among people with HIV (PWH) globally and even among those with high CD4 counts during ART-mediated viral suppression. Evidence from animal studies indicate that interleukin (IL)-17 producing T cells (TH17) are likely beneficial in host immune response to Mycobacterium tuberculosis infection. TH17 cells are also important in HIV infection as loss of TH17 cells likely contributes to progression to AIDS through breakdown in mucosal immunity. Products of tryptophan catabolism, kynurenines, modulate T cell differentiation and function by inhibiting TH17 generation while promoting Treg development. Indoleamine 2,3-dioxygenase-1 (IDO-1) enzyme is crucial in kynurenine pathway, and IDO-1 activity is reflected by Kynurenine/Tryptophan (K/T) ratio. Since IDO-1 activity and generation of kynurenines influence T cell differentiation and function, and since T cell differentiation and function is perturbed in both HIV and TB (including latent tuberculosis infection (LTBI)), we hypothesize that IDO-1 activity and generation of kynurenines influences Th17 development and that K/T ratio and TH17 cells correlate in-vivo in M. tuberculosis infected people with HIV. We will extend our previous observations that IDO-1 activity limits expression of IL-17 in TB and inhibits TH17 development while favouring Treg expansion in HIV. We will address these by longitudinally assessing TB-specific TH17 and Treg cells by spectral flow cytometry and plasma K/T ratio (by LC/MS) in ART-treated participants with HIV whose PPD-skin test converts, are diagnosed with LTBI, and initiated on isoniazid treatment. We will also cross-sectionally compare these parameters to HIV-uninfected participants with LTBI in SCOPE. This study will demonstrate whether a higher K/T ratio is associated with decreased TB-specific TH17/Treg ratio in treated HIV and whether isoniazid-mediated decline in K/T ratio is associated with an increase in this ratio. This study will also provide me excellent training and cross-mentorship in HIV, accelerating my progress towards independence.