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( ), the causative agent of tuberculosis (TB), is a uniquely successful pathogen due in large part to its complex lipid-rich cell envelope. Comprising nearly 40% of its dry weight, lipids-such as mycolic acids, phthiocerol dimycocerosates (PDIM), trehalose dimycolate (TDM), and sulfolipids (SLs)-play crucial roles in infection, immune evasion, intracellular persistence, granuloma formation, transmission, and drug resistance. These lipids modulate host-pathogen interactions by altering host membrane biophysics, hijacking phagosome maturation, and interfering with host immune pathways, including autophagy and inflammatory signaling. Upon inhalation, surface lipids inhibit pulmonary surfactant function and mask pathogen-associated molecular patterns, facilitating uptake by permissive macrophage subsets. Intracellularly, lipoglycans like mannose-capped lipoarabinomannan block phagolysosome fusion, while PDIM and TDM promote phagosomal escape and subversion of vesicular trafficking. Lipid-mediated modulation of autophagy pathways further enhances bacterial survival within host cells. In addition to shaping host immune responses, lipids orchestrate granuloma development and promote pathological features such as foam cell formation and caseation, which are central to transmission. Specifically, phenolic glycolipids and SLs stimulate neuronal pathways, triggering cough, thereby facilitating aerosol spread. Finally, the lipid-rich envelope acts as a formidable barrier to antibiotics, with resistance partly driven by the altered lipid composition and architecture in multidrug-resistant strains. Targeting lipid biosynthesis and transport pathways offers promising avenues for novel anti-TB therapies. This review highlights the multifaceted roles of lipids at the host-pathogen interface, recent technical advances enabling these insights, and emerging challenges in translating lipid biology into improved TB control.

Bacille Calmette Guerin (BCG) vaccination in genetically diverse outbred (DO) mice provides significant protection against Mycobacterium tuberculosis ( Mtb) challenge. This protection induced pathways associated with transforming growth factor B (TGF-β) receptor complex, genes associated with lung repair, and Toll-like receptor (TLR)-10 pathway. The enhanced protection observed in BCG-vaccinated mice correlated with improved formation of B-cell follicles and IL-17-producing CD4 + T-cell responses. CD4 + T-cell responses mediated the enhanced protection in the lungs of DO mice vaccinated with BCG + adjuvant, as depletion of CD4 + T-cell responses reversed the enhanced protection. The DO mouse model of tuberculosis vaccination is a highly relevant model to probe mechanisms of vaccine-induced protection and provide novel insights into lung pathways that mediate protection. The study also found that genes associated with lung repair, including TGF-β receptor complex pathways, were induced in BCG-vaccinated Mtb -infected DO mouse lungs. The study suggests that the activation of lung innate pathways in BCG vaccination through the use of mucosal Amph CpG delivery, CD40L activation, and IL-10 neutralization could significantly enhance protection upon Mtb challenge.

Tuberculosis (TB) is one of the world’s leading causes of death from a single infectious agent, with Mycobacterium tuberculosis (Mtb) primarily infecting the lungs via the respiratory tract. Following infection, immune cells such as macrophages and neutrophils phagocytose Mtb and initiate complex inflammatory and immune responses, driving the formation of granulomas and cavities within the lungs, ultimately leading to structural damage. In this intricate cascade, the MAPK signaling emerges as a critical regulator, orchestrating various cellular processes including inflammatory signaling, autophagy, apoptosis, and immune cell differentiation. Emerging evidence indicates that MAPK signaling critically shapes anti-TB immunity predominantly within macrophages, neutrophils, T cells and dendritic cells. Through extensive crosstalk among immune cells, MAPK signaling influences both host defense and disease progression. This review systematically summarizes current advances in understanding MAPK-mediated immune regulation during TB infection, with particular emphasis on the distinct roles of p38, ERK, and JNK signaling pathways. Furthermore, we discuss emerging therapeutic strategies to enhance anti-mycobacterial immunity by targeting MAPK signaling, thereby providing a valuable theoretical framework for the development of novel TB treatments.

The success of any invading bacteria to survive within the host is dictated by their ability to acquire nutrients and overcome the host immune response. Bacterial cell surface proteins play critical roles in these processes at the host-pathogen interface. Here, we show that the PPE64 mycomembrane channel protein is required for heme iron acquisition and biofilm formation, which are fundamental processes that are of great significance to Mycobacterium tuberculosis ( Mtb ) survival within the host. These discrete functions of PPE64 are dictated by the culturing environment and are important for Mtb growth within human macrophages. These observations support an emerging theme in the Mtb field that the PPE protein family functions in trafficking molecules across the outer mycomembrane and has far-reaching implications for understanding of Mtb physiology.

Mycobacterium tuberculosis (Mtb) remains a leading cause of infectious disease mortality worldwide, largely due to its ability to survive within host macrophages. Despite advances in understanding the environmental pressures Mtb encounters in vivo , the genetic requirements for adaptation and survival within the intracellular niche remain incompletely defined. Here, we employed a genome-wide CRISPR interference (CRISPRi) screen in an ex vivo model exploiting single-cell suspensions from Mtb-infected mouse lung homogenates to identify genes critical for intracellular survival at different time points in the infection continuum. This novel approach enabled us to identify how different bacterial metabolic pathways were of greater importance to the bacterium at different time points post-infection. The results provide insights into how the evolving immune response to infection shapes the metabolic and replicative status of the bacterium. This information has significance in the design of therapeutic strategies toward cure.

Maintaining immune homeostasis is paramount for efficient Mycobacterium tuberculosis (Mtb) clearance and tissue repair. Current therapeutic strategies, however, predominantly focus on achieving maximal bacterial suppression within compressed timelines while overlooking the immunomodulatory consequences of anti-tuberculosis agents. This critical knowledge gap underscores the urgent need for mechanistic investigations to establish evidence-based frameworks for optimizing drug combinations and integrating therapies with host-directed approaches.

The impermeable outer membrane of pathogenic mycobacteria presents a major obstacle to nutrient acquisition and antibiotic penetration. PPE51, a substrate of the ESX-5 secretion system, has previously been linked to glucose and glycerol uptake. Our study in Mycobacterium marinum reveals an unexpected additional role for PPE51 in maintaining membrane integrity. Loss of PPE51 not only impairs nutrient uptake but also causes increased membrane permeability, altered antibiotic susceptibility, and reduced virulence. These findings redefine PPE51 as more than a nutrient transporter, highlighting its broader role in cell envelope stability. This dual function has important implications for understanding how mycobacteria balance impermeability with metabolic needs and suggests new strategies to enhance antibiotic efficacy by targeting membrane-associated proteins like PPE51.

Mycobacterial infections, including bovine tuberculosis (TB), have a profound impact on global health. This is exemplified by zoonotic TB in humans and animal TB, which is a life-threatening disease in livestock and wildlife. Mycobacteria cause the formation of granulomas, which significantly impact disease progression. Therefore, decoding granulomas is essential for an in-depth understanding of immune responses to mycobacteria. Conventional mouse models frequently fail to develop organized granulomas, and the procurement of samples from granulomatous lesions in cattle and humans is challenging, offering limited insights into the course of infection. Most in vitro TB research is confined to two-dimensional cell cultures, which neglect the spatial characteristics and cellular architecture of granulomas in vivo . To address this gap in knowledge, we have developed a novel multicellular in vitro model for TB. Our spheroid granuloma model, derived from bovine leukocytes using nanotechnologies, offers an adaptable platform for deciphering immune events within granulomas.

Tuberculosis remains a significant global health challenge, partly due to Mycobacterium tuberculosis (Mtb)’s remarkable evolutionary adaptation to antibiotics and human immune responses. Around 10% of its genome comprises PE/PPE genes, whose functions and evolutionary dynamics are poorly understood due to their repetitive sequences and high GC content. In this study, we analyzed 51,229 global Mtb genomes using an advanced genome-masking method, revealing numerous PE/PPE genes under positive selection, potentially facilitating antibiotic resistance and immune evasion. Notably, PPE51 often loses its function in strains resistant to multiple antibiotics, suggesting a role in bacterial survival during drug treatment. Additionally, we identified mutation-prone regions within six PE/PPE genes, highlighting potential targets for future vaccine development. Collectively, our findings underscore the crucial role of PE/PPE genes in Mtb evolution and drug resistance, providing valuable insights to inform novel therapeutic and vaccine strategies.

Pulmonary tuberculosis (PTB) remains a leading cause of global mortality, yet the ecological principles shaping its respiratory microbiome are poorly understood. By integrating 16S rRNA datasets from upper and lower airway specimens, this study provides the first comprehensive meta-analysis of respiratory microbial diversity and function in PTB. We reveal distinct community structures and functional potentials among upper airways, sputum, and bronchoalveolar lavage fluid, driven by niche-specific ecological processes rather than stochastic assembly. These findings establish a baseline framework for interpreting microbial biogeography across the respiratory tract and highlight potential microbial biomarkers for site-specific monitoring and therapeutic targeting in PTB.