Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is one of the world's leading infectious causes of morbidity and mortality. As a mucosal-transmitted pathogen, Mtb infects humans and animals mainly through the mucosal tissue of the respiratory tract. Apart from providing a physical barrier against the invasion of pathogen, the major function of the respiratory mucosa may be to serve as the inductive sites to initiate mucosal immune responses and sequentially provide the first line of defense for the host to defend against this pathogen. A large body of studies in the animals and humans have demonstrated that the mucosal immune system, rather than the systemic immune system, plays fundamental roles in the host’s defense against Mtb infection. Therefore, the development of new vaccines and novel delivery routes capable of directly inducing respiratory mucosal immunity is emphasized for achieving enhanced protection from Mtb infection. In this paper, we outline the current state of knowledge regarding the mucosal immunity against Mtb infection, including the development of TB vaccines, and respiratory delivery routes to enhance mucosal immunity are discussed. 1. Introduction Tuberculosis (TB) is one of the world’s leading infectious disease with approximately two million deaths and eight million new cases annually. It is also a severe pulmonary disease and a public health burden caused by the infection of Mycobacterium tuberculosis (Mtb) [1]. Mtb is a facultative intracellular bacterium capable of surviving and persisting in host mononuclear cells where it is able to escape the elimination through numerous mechanisms [2]. The capacity of Mtb to survive within a host cell for decades without replicating may be partially due to the fact that it is a metabolically, fastidious, acid-fast bacillus that grows very slowly, as well as its ability to inhibit phagosomal maturation by preventing phagosome-lysosome fusion and acidification of the phagosome [3]. Transcriptomic analysis has revealed that Mtb was able to gain its abilities to evade the host immune surveillance, adopted its specialized intracellular niche, and resisted various agents and antibiotic drugs, by expressing various genes against the host immune responses [4]. The ability of Mtb to evade the host immune surveillance and establish a latent metabolic state in the host causes the difficulty to eradicate tuberculosis, even though most of patients infected with Mtb could be cured with appropriate therapy. In addition, the reactivation of Mtb at a latent state in
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