Latent Tuberculosis

Abstract

Treatment of latent tuberculosis infection (LTBI) requires a long period of chemotherapy (9 months), which makes treatment-compliance extremely difficult. Current knowledge of latent bacilli and of the lesions with which they are associated suggests that these bacilli survive in granulomas with a central necrotic core and an outermost layer of foamy macrophages (FM) that represent an important immunosuppressive barrier. The presence of FM, which is especially strong in mice, explains not only the kinetics of the drainage of dead bacilli, debris and surfactant, but also how latent bacilli can escape from the granuloma and re-grow in the periphery, particularly in the alveolar spaces where they can disseminate easily. (Ferebee 1970)

RUTI, a therapeutic vaccine made of detoxified, fragmented Mycobacterium tuberculosis cells, delivered in liposomes, was used to assess its effectiveness in a short period of chemotherapy (1 month). The rationale of this therapy was first to take advantage of the bactericidal properties of chemotherapy to kill active growing bacilli, eliminate the outermost layer of FM and reduce local inflammatory responses so as to avoid the predictable Koch phenomenon caused by M. tuberculosis antigens when given therapeutically. After chemotherapy, RUTI can be inoculated to reduce the probability of regrowth of the remaining latent bacilli.

RUTI has already demonstrated its efficacy in controlling LTBI in experimental models of mice and guinea-pigs after a short period of chemotherapy; these experiments in animals showed the induction of a mixed Th1/Th2/Th3, polyantigenic response with no local or systemic toxicity. Local accumulation of specific CD8 T cells and a strong humoral response are characteristic features of RUTI that explain its protective properties; these are particular improvements when compared with BCG, although the regulatory response to RUTI may also be an important advantage. Further experiments using bigger animals (goats and mini-pigs) will provide more data on the efficacy of RUTI before starting phase I clinical trials. (Middlebrook 1961)

Latent Tuberculosis

Chapter I: Introduction

Latent Bacillus

Despite this being a simple question, finding an appropriate answer is crucial to demonstrate the validity of any new treatment against latent Mycobacterium tuberculosis bacilli; latent bacilli are responsible for the long period of treatment currently required for sterilizing lesions infected with M. tuberculosis. (Guirado et al. 2005)

The nature of latent bacilli and their ability to survive “in vitro” in low pO2 conditions, and even in anaerobiosis, has been widely studied. To survive in low pO2, bacilli appear to acquire a state of nonreplicant persistence (NRP). Huge lesions with intragranulomatous necrosis (IN) that are induced in tuberculosis (TB) may develop such an extreme anaerobic environment,2 supporting the idea that latency induced by low pO2 occurs in lesions. However, direct measurements have never demonstrated the presence of anaerobiosis in TB lesions and factual support for the hypothesis is lacking. Furthermore, IN is a “living” tissue, full of collagen fibers, that also needs a physiological environment for survival. Anaerobiosis, therefore, appears unlikely in such a setting. Even if such atmosphere with low pO2 be induced in calcified lesions, experimental models demonstrate that the period in which the bacilli may survive ...