SIV and Mycobacterium tuberculosis synergy within the granuloma accelerates the reactivation pattern of latent tuberculosis

Abstract

Human immunodeficiency virus infection is the most common risk factor for severe forms of tuberculosis (TB), regardless of CD4 T cell count. Using a well-characterized cynomolgus macaque model of human TB, we compared radiographic, immunologic and microbiologic characteristics of early (subclinical) reactivation of latent M. tuberculosis (Mtb) infection among animals subsequently infected with simian immunodeficiency virus (SIV) or who underwent anti-CD4 depletion by a depletion antibody. CD4 depleted animals had significantly fewer CD4 T cells within granulomas compared to Mtb/SIV co-infected and Mtb-only control animals. After 2 months of treatment, subclinical reactivation occurred at similar rates among CD4 depleted (5 of 7 animals) and SIV infected animals (4 of 8 animals). However, SIV-induced reactivation was associated with more dissemination of lung granulomas that were permissive to Mtb growth resulting in greater bacterial burden within granulomas compared to CD4 depleted reactivators. Granulomas from Mtb/SIV animals displayed a more robust T cell activation profile (IFN-α, IFN-γ, TNF, IL-17, IL-2, IL-10, IL-4 and granzyme B) compared to CD4 depleted animals and controls though these effectors did not protect against reactivation or dissemination, but instead may be related to increased viral and/ or Mtb antigens. SIV replication within the granuloma was associated with reactivation, greater overall Mtb growth and reduced Mtb killing resulting in greater overall Mtb burden. These data support that SIV disrupts protective immune responses against latent Mtb infection beyond the loss of CD4 T cells, and that synergy between SIV and Mtb occurs within granulomas.

Multimodal profiling of lung granulomas reveals cellular correlates of tuberculosis control

“…Strikingly, however, individual granulomas within a single host follow independent trajectories with respect to inflammation, cellular composition, reactivation risk, and ability to kill Mtb (Coleman et al, 2014b;Gideon et al, 2015;Lenaerts et al, 2015;Lin et al, 2013;Lin et al, 2014b;Malherbe et al, 2016;Martin et al, 2017). We and others have profiled immune responses among individual cell types in macaque lung granulomas, including those of T cells (Diedrich et al, 2020;Foreman et al, 2016;Gideon et al, 2015;Lin et al, 2012;Mattila et al, 2011;, macrophages (Mattila et al, 2013), B cells (Phuah et al, 2016Phuah et al, 2012), and neutrophils (Gideon et al, 2019;Mattila et al, 2015), and also examined the instructive roles of cytokines, including IFN-g, IL-2, TNF, IL-17 and IL-10 (Gideon et al, 2015;Lin et al, 2010;Wong et al, 2020). While these analyses have enabled key insights into how specific canonical cell types and effector molecules relate to bacterial burden, they have been relatively narrow and directed in focus, and have not revealed how the integrated actions of diverse cell types within individual granulomas influence control.…”

Visualizing the dynamics of tuberculosis pathology using molecular imaging

“…Immune cells increase the use of glucose as an energy source during metabolic bursts associated with inflammatory responses due to infection, and this change in glucose utilization can be visualized with 18 F-FDG PET with high sensitivity ( 36 ). 18 F-FDG PET/CT has been successfully used to assess TB pathogenesis, bacterial dissemination, and disease progression in animal models that mimic different stages of pulmonary TB disease ( 37 , 38 ). However, as an analog of glucose, 18 F-FDG is unable to differentiate among oncological, inflammatory, and infectious processes.…”

Advancing our understanding of HIV co-infections and neurological disease using the humanized mouse

“…A surprising observation in the HIS mouse model of HIV-mediated TB relapse was that regrowth did not appear to coincide with breakdown of contained granulomas as is generally assumed to occur [ 56 ]. Instead, lung lesions were observed to mostly resolve following 2 months of TB chemotherapy.…”