Can Mycobacterium tuberculosis infection lead to cancer? Call for a paradigm shift in understanding TB and cancer.

ABSTRACT Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, an infectious disease with one of the highest morbidity and mortality rates worldwide. Leveraging its highly evolved repertoire of non-protein and protein virulence factors, Mtb invades through the airway, subverts host immunity, establishes its survival niche, and ultimately escapes in the setting of active disease to initiate another round of infection in a naive host. In this review, we will provide a concise synopsis of the infectious life cycle of Mtb and its clinical and epidemiologic significance. We will also take stock of its virulence factors and pathogenic mechanisms that modulate host immunity and facilitate its spread. Developing a greater understanding of the interface between Mtb virulence factors and host defences will enable progress toward improved vaccines and therapeutics to prevent and treat tuberculosis.

https://doi.org/10.1080/21505594.2022.2150449

Pathogenicity and virulence of Mycobacterium tuberculosis

Tuberculosis, caused by Mycobacterium tuberculosis, engenders an onerous burden on public hygiene. Congenital and adaptive immunity in the human body act as robust defenses against the pathogens. However, in coevolution with humans, this microbe has gained multiple lines of mechanisms to circumvent the immune response to sustain its intracellular persistence and long-term survival inside a host. Moreover, emerging evidence has revealed that this stealthy bacterium can alter the expression of demic noncoding RNAs (ncRNAs), leading to dysregulated biological processes subsequently, which may be the rationale behind the pathogenesis of tuberculosis. Meanwhile, the differential accumulation in clinical samples endows them with the capacity to be indicators in the time of tuberculosis suffering. In this article, we reviewed the nearest insights into the impact of ncRNAs during Mycobacterium tuberculosis infection as realized via immune response modulation and their potential as biomarkers for the diagnosis, drug resistance identification, treatment evaluation, and adverse drug reaction prediction of tuberculosis, aiming to inspire novel and precise therapy development to combat this pathogen in the future.

Immune regulation and emerging roles of noncoding RNAs in Mycobacterium tuberculosis infection

Bag it, tag it: ubiquitin ligases and host resistance to Mycobacterium tuberculosis.

Abstract Background Cancer stem cells (CSCs) are regarded as the "seed cells" for tumorigenesis, metastasis, recurrence and drug resistance. However, specific surface markers of CSCs of different origins have not been documented. Methods Single-cell sequencing was used to analyze the highly expressed genes in cancer stem cells of gastric cancer patients, and it was verified that AQP5 was specifically highly expressed in gastric cancer stem cells (GC-CSCs) in vivo and in vitro. The effect of AQP5-promoting LGR5 on the malignant biological function of GC-CSCs was investigated. The mechanism by which AQP5 affects GC-CSCs was explored through transcriptome sequencing, proteomic detection, mass spectrometry, etc. Results We report the identification and validation of AQP5 as a potentially specific surface marker of GC-CSCs. AQP5 was significantly upregulated in CSCs isolated from gastric cancer patients and in spheroid cells, and AQP5 was coexpressed with the canonical stem marker LGR5. Biologically, AQP5 promoted the sphere formation, proliferation, migration and invasion of GC cells in vitro and enhanced tumorigenesis in vivo. Furthermore, AQP5 coordinated with LGR5 and synergistically promoted the tumorigenesis of GC-CSCs. At the mechanistic level, AQP5 activated autophagy by inducing the LC3I/LC3II transformation in GC-CSCs, which was crucial for the biological functions of AQP5. Finally, we demonstrated that AQP5 recruited the E3 ligase TRIM21 to the key autophagy protein ULK1 and induced the K63-mediated ubiquitination of ULK1. Conclusions We elucidate a novel surface marker, AQP5, which is specifically expressed by GC-CSCs. Furthermore, our study creates a link between AQP5 and LGR5 and highlights the necessity of targeting both surface markers simultaneously as a promising approach for the treatment of gastric cancer patients. 

/pdf/aqp5-complements-lgr5-to-determine-the-fates-of-gastric-2kebocea.pdf

AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination

ABSTRACT Intracellular pathogens have evolved various efficient molecular armaments to subvert innate defenses. Cellular ubiquitination, a normal physiological process to maintain homeostasis, is emerging one such exploited mechanism. Ubiquitin (Ub), a small protein modifier, is conjugated to diverse protein substrates to regulate many functions. Structurally diverse linkages of poly-Ub to target proteins allow enormous functional diversity with specificity being governed by evolutionarily conserved enzymes (E3-Ub ligases). The Ub-binding domain (UBD) and LC3-interacting region (LIR) are critical features of macroautophagy/autophagy receptors that recognize Ub-conjugated on protein substrates. Emerging evidence suggests that E3-Ub ligases unexpectedly protect against intracellular pathogens by tagging poly-Ub on their surfaces and targeting them to phagophores. Two E3-Ub ligases, PRKN and SMURF1, provide immunity against Mycobacterium tuberculosis (M. tb). Both enzymes conjugate K63 and K48-linked poly-Ub to M. tb for successful delivery to phagophores. Intriguingly, M. tb exploits virulence factors to effectively dampen host-directed autophagy utilizing diverse mechanisms. Autophagy receptors contain LIR-motifs that interact with conserved Atg8-family proteins to modulate phagophore biogenesis and fusion to the lysosome. Intracellular pathogens have evolved a vast repertoire of virulence effectors to subdue host-immunity via hijacking the host ubiquitination process. This review highlights the xenophagy-mediated clearance of M. tb involving host E3-Ub ligases and counter-strategy of autophagy inhibition by M. tb using virulence factors. The role of Ub-binding receptors and their mode of autophagy regulation is also explained. We also discuss the co-opting and utilization of the host Ub system by M. tb for its survival and virulence. Abbreviations: APC: anaphase promoting complex/cyclosome; ATG5: autophagy related 5; BCG: bacille Calmette-Guerin; C2: Ca2+-binding motif; CALCOCO2: calcium binding and coiled-coil domain 2; CUE: coupling of ubiquitin conjugation to ER degradation domains; DUB: deubiquitinating enzyme; GABARAP: GABA type A receptor-associated protein; HECT: homologous to the E6-AP carboxyl terminus; IBR: in-between-ring fingers; IFN: interferon; IL1B: interleukin 1 beta; KEAP1: kelch like ECH associated protein 1; LAMP1: lysosomal associated membrane protein 1; LGALS: galectin; LIR: LC3-interacting region; MAPK11/p38: mitogen-activated protein kinase 11; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MAPK8/JNK: mitogen-activated protein kinase 8; MHC-II: major histocompatibility complex-II; MTOR: mechanistic target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; NFKB1/p50: nuclear factor kappa B subunit 1; OPTN: optineurin; PB1: phox and bem 1; PE/PPE: proline-glutamic acid/proline-proline-glutamic acid; PknG: serine/threonine-protein kinase PknG; PRKN: parkin RBR E3 ubiquitin protein ligase; RBR: RING-in between RING; RING: really interesting new gene; RNF166: RING finger protein 166; ROS: reactive oxygen species; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TNF: tumor necrosis factor; TRAF6: TNF receptor associated factor 6; Ub: ubiquitin; UBA: ubiquitin-associated; UBAN: ubiquitin-binding domain in ABIN proteins and NEMO; UBD: ubiquitin-binding domain; UBL: ubiquitin-like; ULK1: unc-51 like autophagy activating kinase 1.

The exploitation of host autophagy and ubiquitin machinery by Mycobacterium tuberculosis in shaping immune responses and host defense during infection

Mycobacterium tuberculosis (M. tb), the causative pathogen of tuberculosis (TB) remains the leading cause of death from single infectious agent. Further, its evolution to multi-drug resistant (MDR) and extremely drug-resistant (XDR) strains necessitate de-novo identification of drug- targets/candidates or to repurpose existing drugs against known targets through drug repurposing. Repurposing of drugs has gained traction recently where orphan drugs are exploited for new indications. In the current study, we have combined drug repurposing with polypharmacological targeting approach to modulate structure-function of multiple proteins in M. tb. Based on previously established essentiality of genes in M. tb, four proteins implicated in acceleration of protein folding (PpiB), chaperone assisted protein folding (MoxR1), microbial replication (RipA) and host immune modulation (S-adenosyl dependent methyltransferase, sMTase) were selected. Genetic diversity analyses in target proteins showed accumulation of mutations outside respective substrate/drug binding sites. Using a composite receptor-template based screening method followed by molecular dynamics simulations, we have identified potential candidates from FDA approved drugs database; Anidulafungin (anti-fungal), Azilsartan (anti-hypertensive) and Degarelix (anti-cancer). Isothermal titration calorimetric analyses showed that the drugs can bind with high affinity to target proteins and interfere with known protein-protein interaction of MoxR1 and RipA. Cell based inhibitory assays of these drugs against M. tb (H37Ra) culture indicates their potential to interfere with pathogen growth and replication. Topographic assessment of drug-treated bacteria showed induction of morphological aberrations in M. tb. The approved candidates may also serve as scaffolds for optimization to future anti-mycobacterial agents which can target MDR strains of M. tb.

Uzair Ahmad

Papers

The exploitation of host autophagy and ubiquitin machinery by Mycobacterium tuberculosis in shaping immune responses and host defense during infection

Polypharmacological repurposing approach identifies approved drugs as potential inhibitors of Mycobacterium tuberculosis.