One unmet challenge in lung cancer diagnosis is to accurately differentiate lung cancer from other lung diseases with similar clinical symptoms and radiological features, such as pulmonary tuberculosis (TB). To identify reliable biomarkers for lung cancer screening, we leverage the recently discovered non-canonical small non-coding RNAs (i.e., tRNA-derived small RNAs [tsRNAs], rRNA-derived small RNAs [rsRNAs], and YRNA-derived small RNAs [ysRNAs]) in human peripheral blood mononuclear cells and develop a molecular signature composed of distinct ts/rs/ysRNAs (TRY-RNA). Our TRY-RNA signature precisely discriminates between control, lung cancer, and pulmonary TB subjects in both the discovery and validation cohorts and outperforms microRNA-based biomarkers, which bears the diagnostic potential for lung cancer screening.

Mycobacterium tuberculosis (M. tuberculosis) is the pathogen which causes tuberculosis (TB), a significant human public health threat. Co-infection of M. tuberculosis and the human immunodeficiency virus (HIV), emergence of drug resistant M. tuberculosis, and failure to develop highly effective TB vaccines have limited control of the TB epidemic. Trained immunity is an enhanced innate immune response which functions independently of the adaptive/acquired immune system and responds non-specifically to reinfection with invading agents. Recently, several studies have found trained immunity has the capability to control and eliminate M. tuberculosis infection. Over the past decades, however, the consensus was adaptive immunity is the only protective mechanism by which hosts inhibit M. tuberculosis growth. Furthermore, autophagy plays an essential role in the development of trained immunity. Further investigation of trained immunity, M. tuberculosis infection, and the role of autophagy in this process provide new possibilities for vaccine development. In this review, we present the general characteristics of trained immunity and autophagy. We additionally summarize several examples where initiation of trained immunity contributes to the prevention of M. tuberculosis infection and propose future directions for research in this area.

Autophagy has been identified as an important immune regulatory mechanism. Recent studies have linked macrophage autophagy with innate immune responses against Mycobacterium tuberculosis (M. tuberculosis), which can survive within macrophages by blocking fusion of the phagosome with lysosomes. These findings suggest that autophagy is a regulatable cellular mechanism of M. tuberculosis defense in macrophages. Transcriptomic profiles in human blood in TB patients suggest that M. tuberculosis affects autophagy related pathways. In order to better understand the role of macrophage autophagy in enhancing protective immunity against M. tuberculosis, in this study, we investigate the effects of the autophagy activators rapamycin and LPS in macrophage autophagy and immunity against M. tuberculosis. We confirm that rapamycin and LPS induce autophagy in M. tuberculosis infected THP-1-derived macrophages or PMA primed THP-1 macrophages [THP-1(A)]. LPS restores M. tuberculosis-inhibited IL-12 synthesis and secretion in THP-1(A) cells via autophagy. Similarly, autophagy activators increase IL-12 synthesis and secretion in THP-1(A) cells. These studies demonstrate the importance of autophagy in M. tuberculosis elimination in macrophages and may lead to novel therapies for tuberculosis and other bacterial infections.

Mycobacterium tuberculosis (M. tb) is an intracellular pathogen adept at evading the human immune system through a variety of mechanisms. During infection, M. tb secretes numerous virulence factors, including the 6 kDa early secretory antigen target (ESAT-6), which is produced by the ESX-1 secretion system. ESAT-6 plays a crucial role in host–pathogen interactions, either independently or in association with culture filtrate protein 10 (CFP-10). While some research has investigated the role of ESAT-6 in M. tb pathogenicity and vaccine development, its precise contribution to immune evasion and the cellular mechanisms involved remain poorly understood. To address this, we used cultured THP-1(A) macrophages to characterize the effects of secreted ESAT-6 on cellular host defenses and apoptosis. We found that ESAT-6 (5 μg/ml) inhibited M. tb-induced apoptosis in THP-1(A) macrophages by suppressing Toll-like receptor 2 (TLR2) through the Caspase-9/Caspase-3 pathway. Additionally, ESAT-6 reduced phagocytosis of M. tb by THP-1(A) macrophages by downregulating the production of interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and interleukin-12 (IL-12). Furthermore, ESAT-6 diminished the bactericidal activity of macrophages by inducing reactive oxygen species (ROS) production. In parallel, our in silico analysis of differentially expressed genes in dendritic cells (DCs) infected with Bacille Calmette-Guérin (BCG) strains, with or without the region of difference-1 (RD1) gene, strongly suggests that ESAT-6, located within the RD1 region, modulates host defense functions and apoptosis in DCs during BCG infection. Collectively, these findings indicate that ESAT-6 plays a pivotal role in modulating the innate immune response of macrophages against M. tb by regulating macrophage recognition, phagocytosis, bactericidal activity, and apoptosis. Our study provides valuable insights into potential molecular targets for the development of innovative vaccines and therapeutic strategies against M. tb.