Targeted pulmonary delivery of inducers of host macrophage autophagy as a potential host-directed chemotherapy of tuberculosis

Abstract

One of the promising host-directed chemotherapeutic interventions in tuberculosis (TB) is based on inducing autophagy as an immune effector. Here we consider the strengths and weaknesses of potential autophagy-based pharmacological intervention. Using the existing drugs that induce autophagy is an option, but it has limitations given the broad role of autophagy in most cells, tissues, and organs. Thus, it may be desirable that the agent being used to modulate autophagy is applied in a targeted manner, e.g. delivered to affected tissues, with infected macrophages being an obvious choice. This review addresses the advantages and disadvantages of delivering drugs to induce autophagy in M. tuberculosis-infected macrophages. One option, already being tested in models, is to design particles for inhalation delivery to lung macrophages. The choice of drugs, drug release kinetics and intracellular residence times, non-target cell exposure and feasibility of use by patients is discussed. We term here this (still experimental) approach, of compartment-targeting, autophagy-based, host-directed therapy as "Track-II antituberculosis chemotherapy."

Keywords: Aerosols; Apoptosis; Host-pathogen interaction; Inhalations; Microautophagy; Phagocytosis.

Fig. 1

A spectrum of macrophage responses to invasion by Mtb. (A) Sensing the presence of Mtb in a phagosome. (B) Mobilization of innate effector molecules such as free radicals and antimicrobial peptides. (C) Secretion of signaling molecules such as cytokines and chemokines. (D) Maturation of phagosomes into phagolysosomes and mobilization of innate immunity devices such as the inflammasome, both inhibited or manipulated by Mtb). (E) Autophagy. (F) Cell death.

Fig. 2

Stages of autophagy and proposed Mtb countermeasures. Autophagy initiates with the internalization of the microbe. Ingested material is surrounded by double-membrane bound autophagosomes. Autophagosome contents are degraded by lysosomal hydrolases. Mtb cell wall components like Lipoarabinomannan (LAM), mannosylated LAM (ManLAM), secretory proteins and virulence factors inhibit fusion of phagosome with lysosome via suppression of the release of TACO or recruitment of V0H+ ATPases and prevent phagosome maturation.

Fig. 3

(A): An upright, nose-only inhalation apparatus allows animals to inhale powders at ambient pressure. The animal is restrained with its nostrils inserted in a chamber which contains a powder aerosol. Powder properties and duration of exposure reproducibly control inhaled dose. The apparatus is suitable for use in an ABSL3 setting. (B): The DP-4M PennCentury™ insufflator is a positive-pressure apparatus inserted into the trachea of anesthetized animals using a bronchoscope. (C): Orientation of the test animal for receiving the DP-4M apparatus that delivers precise doses to deep lungs, without loss of material in the mouth and upper airway region. Photographs in Panels B and C: courtesy, Prof. Hiroshi Terada, Niigata University of Pharmacy and Applied Life Sciences.

Fig. 4

TEM of lung section from a mouse infected with Mtb and treated with inhaled particles. (A): an alveolar macrophage in which Mtb debris co-localizes with a particle (arrow). (B) a lysosome releasing its contents into a phagosome with an inhaled particle (arrow). (C) condensed mitochondria and (D) intense Golgi activity in the vicinity of the particle phagosome (arrows). Panels A and B reprinted from reference [149] with permission from Oxford University Press.