Abstract
Background Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), has the ability to persist in its human host for exceptionally long periods of time. However, little is known about the location of the bacilli in latently infected individuals. Long-term mycobacterial persistence in the lungs has been reported, but this may not sufficiently account for strictly extra-pulmonary TB, which represents 10–15% of the reactivation cases.Methodology/Principal FindingsWe applied in situ and conventional PCR to sections of adipose tissue samples of various anatomical origins from 19 individuals from Mexico and 20 from France who had died from causes other than TB. M. tuberculosis DNA could be detected by either or both techniques in fat tissue surrounding the kidneys, the stomach, the lymph nodes, the heart and the skin in 9/57 Mexican samples (6/19 individuals), and in 8/26 French samples (6/20 individuals). In addition, mycobacteria could be immuno-detected in perinodal adipose tissue of 1 out of 3 biopsy samples from individuals with active TB. In vitro, using a combination of adipose cell models, including the widely used murine adipose cell line 3T3-L1, as well as primary human adipocytes, we show that after binding to scavenger receptors, M. tuberculosis can enter within adipocytes, where it accumulates intracytoplasmic lipid inclusions and survives in a non-replicating state that is insensitive to the major anti-mycobacterial drug isoniazid.Conclusions/SignificanceGiven the abundance and the wide distribution of the adipose tissue throughout the body, our results suggest that this tissue, among others, might constitute a vast reservoir where the tubercle bacillus could persist for long periods of time, and avoid both killing by antimicrobials and recognition by the host immune system. In addition, M. tuberculosis-infected adipocytes might provide a new model to investigate dormancy and to evaluate new drugs for the treatment of persistent infection.
Highlights
Up to one third of the world’s population is estimated to carry latent M. tuberculosis infections, and hundreds of millions of tuberculosis (TB) reactivation cases are anticipated in the coming decades if control is not strengthened [1,2]
As mycobacteria are exceptionally rich in glyco-conjugates, especially in mannosylated compounds that can interact with a variety of host cell surface lectins [16], we considered yeast mannan and M. tuberculosis lipoarabinomannan (LAM), a major mannose-rich lipoglycan of the mycobacterial envelope, as possible inhibitors in the assay
scavenger receptors (SRs) ligands, such as polyinosinic acid (polyI), fucoidan and palmitoyl-2-azelaoyl phosphocholine (PAz-PC) could inhibit mycobacterial attachment to adipocytes of up to 80%, while polyadenosinic acid (polyA) had no effect on the binding process (Figure 1A)
Summary
Up to one third of the world’s population is estimated to carry latent M. tuberculosis infections, and hundreds of millions of tuberculosis (TB) reactivation cases are anticipated in the coming decades if control is not strengthened [1,2]. One important and historical question regarding TB latency deals with the location of the bacilli during that period of the disease [5] Numerous authors addressed this issue in the early part of the past century using lung and lymph node necropsy samples from individuals who had died of causes other than TB [6]. Of particular interest is a study by Opie and Aronson (1927) who reported that in addition to old lesions, unaffected portions of the lungs may host persistent bacilli [7] These results have been recently confirmed and expanded by Hernandez-Pando et al (2000), who reported in situ PCR-detection of M. tuberculosis DNA in normal-appearing lung tissues from about 35% of the necropsy specimen included in the study [8]. M. tuberculosis-infected adipocytes might provide a new model to investigate dormancy and to evaluate new drugs for the treatment of persistent infection
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