Article
Cell Biology
Tomasz K. Prajsnar, Justyna J. Serba, Bernice M. Dekker, Josie F. Gibson, Samrah Masud, Angeleen Fleming, Simon A. Johnston, Stephen A. Renshaw, Annemarie H. Meijer
Summary: The study reveals that intracellular autophagy in neutrophils may have both beneficial and detrimental effects on hosts infected with Staphylococcus aureus, with different pathways leading to conflicting outcomes.
Article
Cell Biology
Enrica Pellegrino, Beren Aylan, Claudio Bussi, Antony Fearns, Elliott M. Bernard, Natalia Athanasiadi, Pierre Santucci, Laure Botella, Maximiliano G. Gutierrez
Summary: Peroxisomes play a role in restricting cytosolic Mycobacterium tuberculosis (Mtb) infection in human macrophages by increasing ROS levels.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Immunology
Wenhui Chen, Zhen Liu, Ying Zheng, Bo Wei, Jingdong Shi, Baowei Shao, Di Wang
Summary: The study found that selenium is associated with pulmonary tuberculosis infection and may function through proinflammatory and autophagy pathways; In in vivo experiments, selenium was shown to combat MTB by enhancing macrophage autophagy related pathways.
MICROBIAL PATHOGENESIS
(2021)
Editorial Material
Biochemistry & Molecular Biology
Christophe Viret, Mathias Faure
Summary: ATG8 proteins are core components of autophagy, decorating autophagosomes and organelles. Recent studies show that the membrane anchoring of single-membrane associated ATG8 proteins may involve phosphatidylserine conjugation, and their stability depends on ATG4 protease inhibition.
TRENDS IN BIOCHEMICAL SCIENCES
(2021)
Article
Medicine, Research & Experimental
Patrick F. Asare, Plinio R. Hurtado, Hai B. Tran, Griffith B. Perkins, Eugene Roscioli, Sandra Hodge
Summary: A common feature of COPD is defective lung macrophage phagocytic capacity. This study investigated the molecular basis by which cigarette smoke extract (CSE) reduces Rubicon expression in macrophages and its relationship with impaired phagocytosis. The results showed that CSE decreases Rubicon through lysosomal degradation, which may lead to dysregulated phagocytosis.
CLINICAL AND EXPERIMENTAL MEDICINE
(2023)
Review
Multidisciplinary Sciences
Joanne Durgan, Oliver Florey
Summary: Autophagy is a fundamental catabolic process coordinated by a network of autophagy-related proteins. The noncanonical autophagy pathway, which utilizes the same proteins, plays a crucial role in immunity, inflammation, cancer, and neurodegeneration. This review discusses the various stimuli and processes involved in noncanonical autophagy, as well as the molecular features of the associated pathways. The authors propose an updated and unified mechanism for noncanonical autophagy.
Review
Biochemistry & Molecular Biology
Julia Juelg, Laura Strohm, Christian Behrends
Summary: Autophagy is a major degradation pathway within cells, contributing to the maintenance of organelle, protein, and metabolite homeostasis as well as innate immunity. In addition to canonical autophagy, there exists a noncanonical form. Studies have shown that dysfunction in autophagy is associated with several human pathologies, including cancer, immune diseases, and neurodegenerative disorders.
MOLECULAR AND CELLULAR BIOLOGY
(2021)
Article
Medicine, General & Internal
Anam Farhan, Ghulam Hassan, Sheikha Hina Liaqat Ali, Zainab Yousaf, Kandeel Shafique, Amir Faisal, Bilal Bin Younis, Shaper Mirza
Summary: Type 2-diabetes, especially poorly controlled diabetes, increases the risk of infections such as respiratory tract and skin infections. Poorly controlled diabetes leads to hyperglycemia, which impairs the function of immune cells, particularly neutrophils. This study demonstrates that hyperglycemia enhances the production of reactive oxygen species (ROS) in neutrophils from individuals with diabetes, resulting in increased autophagy and neutrophil extracellular trap (NET) formation. Diabetes is also associated with decreased phagocytosis and killing of bacteria. Blocking ROS production or autophagy pathways reduces NETosis. This study provides novel insights into the role of ROS and autophagy in diabetes-related immune dysregulation.
FRONTIERS IN MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Femmy C. Stempels, Maaike H. Janssens, Martin ter Beest, Rob J. Mesman, Natalia H. Revelo, Melina Ioannidis, Geert van den Bogaart
Summary: This study elucidated the effects of autophagy inhibitors on LC3-associated phagocytosis (LAP). The inhibitor of VPS34 reduced levels of LC3-II and inhibited LAP, while the inhibitors of endosomal acidification increased levels of LC3-II. However, only the inhibitor of VPS34 could inhibit LAP.
Article
Chemistry, Multidisciplinary
Xiaodi Liu, Wenyue Zhang, Yanni Xu, Xiaolin Xu, Qiongchao Jiang, Jingliang Ruan, Ye Wu, Yingshi Zhou, Phei Er Saw, Baoming Luo
Summary: Residual tumors after insufficient radiofrequency ablation (IRFA) exhibit accelerated progression and anti-PD-1 resistance, with reports indicating that macrophages infiltrating into these tumors may be a contributing factor. The involvement of autophagic elements, particularly LC3, in residual tumors is being investigated to understand the mechanisms between LC3 and macrophages, aiming to enhance immunotherapy for these tumors.
Review
Multidisciplinary Sciences
Yingxue Wang, Maria Ramos, Matthew Jefferson, Weijiao Zhang, Naiara Beraza, Simon Carding, Penny P. Powell, James P. Stewart, Ulrike Mayer, Thomas Wileman
Summary: The delivery of pathogens to lysosomes for degradation is an important defense mechanism against infection. The activation of the V-ATPase-ATG16L1 axis and the stabilization of NADPH oxidase play crucial roles in facilitating the conjugation of LC3 to pathogens and promoting their degradation. However, many microbes have developed strategies to inhibit LC3 recruitment and avoid lysosomal degradation by blocking ROS production and the V-ATPase-ATG16L1 axis.
Review
Immunology
Retsepile E. Maphasa, Mervin Meyer, Admire Dube
Summary: This review focuses on macrophage responses to Mtb infection, particularly the mechanistic aspects of autophagy and how intracellular Mtb evades autophagy. The relationship between autophagy and apoptosis is also discussed, along with known autophagy inducing compounds for Mtb infection. The use of nanoparticles to induce autophagy is explored as a potential avenue for further research into nanomedicine HDTs for TB therapy.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Review
Pharmacology & Pharmacy
Zhiqiang Deng, Yu Dong, Xiaoting Zhou, Jia-Hong Lu, Zhenyu Yue
Summary: Alzheimer's disease is a prevalent and harmful neurodegenerative disorder with no effective interventions currently available. Dysfunctional autophagy may be a cellular mechanism underlying the progression of the disease, and autophagy modulators could provide new approaches for Alzheimer's disease treatment.
ACTA PHARMACEUTICA SINICA B
(2022)
Review
Neurosciences
Gaigai Li, Prativa Sherchan, Zhouping Tang, Jiping Tang
Summary: Autophagy and phagocytosis are two important endogenous lysosomal dependent clearing systems that play crucial roles in neurological disorders, with recent studies revealing underlying interactions between them. However, the contribution of autophagy to the phagocytic process in diverse phagocytes remains inconsistent, especially in the brain. Understanding the roles of autophagy in phagocytosis is critical for promoting the clearance of detrimental materials, and balancing these processes may be a promising therapeutic strategy for the treatment of neurological diseases in the future.
CURRENT NEUROPHARMACOLOGY
(2021)
Review
Immunology
Jun-Hao Wen, Dong-Yi Li, Shan Liang, Chen Yang, Ji-Xin Tang, Hua-Feng Liu
Summary: This article summarizes the role of macrophages in organ fibrosis and the importance of autophagy in maintaining macrophage homeostasis. It discusses the heterogeneity of macrophages in different organs and highlights the potential of macrophage autophagy in fibrosis treatment. The article also briefly discusses important unresolved issues in this field.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Chemistry, Medicinal
Pankaj Bhattarai, Pooja Hegde, Wei Li, Pavan Kumar Prathipati, Casey M. Stevens, Lixinhao Yang, Hinman Zhou, Amit Pandya, Katie Cunningham, Jenny Grissom, Mariaelena Roman Sotelo, Melanie Sowards, Lilian Calisto, Christopher J. Destache, Sonia Rocha-Sanchez, James C. Gumbart, Helen I. Zgurskaya, Mary Jackson, E. Jeffrey North
Summary: Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is a leading cause of death in developing countries. Non-tuberculous mycobacteria (NTM) infections are increasing and affecting patients with structural lung diseases. New antimycobacterial compounds are urgently needed, and this project focused on developing compounds with improved solubility and inhibitory activity against MmpL3.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Immunology
Urs A. Ochsner, Mary A. De Groote, Thale C. Jarvis, Hang Liu, Tessa Youmans, Teresa Hoang, Wendy Ribble, Joshua Day, Wei Li, Camron Pearce, Amanda Walz, Chandra M. Panthi, Binayak Rimal, Casey M. Stevens, Helen I. Zgurskaya, Mary Jackson, Diane Ordway, Mercedes Gonzalez-Juarrero, Xicheng Sun, Gyanu Lamichhane, Clifford Mason
Summary: The benzothiazole amide CRS0393 showed excellent in vitro activity against nontuberculous mycobacteria (NTM), including M. abscessus isolates from cystic fibrosis (CF) patients, with MICs of <= 0.03-0.5 mu g/mL. The essential transport protein MmpL3 was confirmed as the target via analysis of resistant mutants and further profiling. In mouse pharmacokinetic studies, CRS0393 achieved high concentrations in epithelial lining fluid (ELF) and lung tissue, remaining above the M. abscessus MIC for at least 9 hours post-dose.
Article
Biochemistry & Molecular Biology
Heather Hodges, Kwaku Obeng, Charlotte Avanzi, Alex P. Ausmus, Shiva Kumar Angala, Karishma Kalera, Zuzana Palcekova, Benjamin M. Swarts, Mary Jackson
Summary: This article discusses the composition and organization of the mycobacterial cell envelope, particularly the glycans, and their importance in mycobacterial physiology and pathogenesis. The development of synthetic azido inositol analogues as probes for labeling and studying these glycans is reported, along with the discovery of an inositol importer and catabolic pathway.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Cheryl F. Frankfater, Mariana G. Sartorio, Ezequiel Valguarnera, Mario F. Feldman, Fong-Fu Hsu
Summary: This study used mass spectrometry-based approaches to reveal the lipidome of the membrane and outer membrane vesicles of Bacteroides bacteria cells, and even discovered several lipid classes that have not been reported previously. The study found lipid diversity among different strains and demonstrated the utility of multiple-stage mass spectrometry with high-resolution mass spectrometry in the structural elucidation of complex lipids.
Article
Biophysics
Yupeng Li, Atanu Acharya, Lixinhao Yang, Jinchan Liu, Emad Tajkhorshid, Helen I. Zgurskaya, Mary Jackson, James C. Gumbart
Summary: Mycobacteria, including Mycobacterium tuberculosis, have a unique cell envelope consisting of two membranes and various mycolates. MmpL3 protein is responsible for transporting trehalose monomycolate (TMM) from the inner membrane to the periplasmic space. This study investigates the possible pathways for TMM and proton transport using molecular dynamics simulations.
BIOPHYSICAL JOURNAL
(2023)
Review
Pharmacology & Pharmacy
E. Jeffrey North, Chris P. Schwartz, Helen I. Zgurskaya, Mary Jackson
Summary: This paper summarizes the mechanism, therapeutic potential, and different classes of MmpL3 inhibitors currently under development, as well as the available assays to study the inhibition of MmpL3 by these compounds. MmpL3 has emerged as a target with high therapeutic value, and several classes of MmpL3 inhibitors are currently being developed, with one drug candidate (SQ109) undergoing a Phase 2b clinical study. However, the hydrophobic character of most MmpL3 series identified to date poses a significant obstacle to their development due to poor bioavailability. Moreover, there is a need for more high-throughput and informative assays to further understand the mechanism of action of MmpL3 inhibitors and optimize analogues.
EXPERT OPINION ON DRUG DISCOVERY
(2023)
Article
Immunology
Daniel Mott, Jason Yang, Christina Baer, Kadamba Papavinasasundaram, Christopher M. Sassetti, Samuel M. Behar
Summary: We used a mouse model to investigate how Mycobacterium tuberculosis survives in macrophages despite immune pressure. CD4 T cells can recognize infected macrophages, while CD8 T cells show limited recognition and cannot inhibit M. tuberculosis growth. High numbers of M. tuberculosis inside macrophages lead to cell death and presentation of TB10.4 antigen to CD8 T cells by other macrophages. This mode of antigen presentation may have both beneficial and harmful effects on the host.
JOURNAL OF IMMUNOLOGY
(2023)
Editorial Material
Immunology
Anil K. Ojha, Mary Jackson
Article
Biology
Ekansh Mittal, Andrew T. Roth, Anushree Seth, Srikanth Singamaneni, Wandy Beatty, Jennifer A. Philips, Bavesh D. Kana
Summary: For decades, researchers have studied the interaction between Mycobacterium tuberculosis (Mtb) and macrophages, a major cellular environment for the bacterium. Different methods used to disaggregate Mtb have been found to impact the bacterial cell envelope integrity, macrophage inflammatory responses, and intracellular Mtb survival. Sonication and filtering, two commonly used preparation methods, were found to damage the mycobacterial cell envelope and affect the outcome of infections in mouse macrophages. These findings highlight the potential for experimental artifacts in Mtb-host interaction studies and the interpretation of bacterial mutants due to the widely used disaggregation methods.
Review
Biochemistry & Molecular Biology
Fong-Fu Hsu
Summary: Advances in mass spectrometry techniques have greatly contributed to the field of lipidomics, particularly in the study of bacterial lipids. These techniques help to characterize the complex structures and diverse functionalities of both common and unique lipids in bacteria.
Article
Multidisciplinary Sciences
Shiva Kumar Angala, Ana Carreras-Gonzalez, Emilie Huc-Claustre, Itxaso Anso, Devinder Kaur, Victoria Jones, Zuzana Palcekova, Juan M. Belardinelli, Celia de Sousa-d'Auria, Libin Shi, Nawel Slama, Christine Houssin, Annaik Quemard, Michael McNeil, Marcelo E. Guerin, Mary Jackson
Summary: This study reports on the existence of two phosphatidic acid biosynthetic pathways in mycobacteria. Two unique acyltransferases, PlsM and PlsB2, participate in both pathways and play a key role in the distribution of acyl chains in mycobacterial glycerolipids. The findings provide insights into the unusual positional distribution of acyl chains in these compounds.
NATURE COMMUNICATIONS
(2023)
Article
Microbiology
Michal Bar-Oz, Maria Carla Martini, Maria Natalia Alonso, Michal Meir, Nicola Ivan Lore, Paolo Miotto, Camilla Riva, Shiva K. Angala, Junpei Xiao, Catherine S. Masiello, Maria-Anna Misiakou, Huaming Sun, Justin K. Moy, Mary Jackson, Helle Krogh Johansen, Daniela Maria Cirillo, Scarlet S. Shell, Daniel Barkan
Summary: This study reveals that the sRNA B11 controls gene expression and virulence-associated phenotypes in Mycobacterium abscessus. Deletion of B11 increased pro-inflammatory signaling, virulence, and antibiotic resistance. Clinical isolates with B11 mutations or reduced expression were also identified. This is the first report on the role of sRNA in M. abscessus.
Article
Microbiology
Zuzana Palcekova, Andres Obregon-Henao, Kavita De, Amanda Walz, Ha Lam, Jamie Philp, Shiva Kumar Angala, Johnathan Patterson, Camron Pearce, Sophie Zuberogoitia, Charlotte Avanzi, Jerome Nigou, Michael Mcneil, Juan F. Munoz Gutierrez, Martine Gilleron, William H. Wheat, Mercedes Gonzalez-Juarrero, Mary Jackson
Summary: This study demonstrates that strategically positioned succinyl substituents on Mycobacterium tuberculosis (Mtb) lipoarabinomannan control the mannose-capping of this lipoglycan, and thus, the biological activity of the molecule. Furthermore, the absence of succinyl substituents on the two main cell envelope glycans of Mtb leads to an increase in pro-inflammatory cytokines and chemokines in infected macrophages. These results validate polysaccharide succinylation as a critical mechanism by which Mtb controls inflammation.
Article
Chemistry, Medicinal
Tomayo Berida, Samuel R. Mckee, Shamba Chatterjee, Destinee L. Manning, Wei Li, Pankaj Pandey, Siddharth Kaushal Tripathi, Yassin Mreyoud, Asya Smirnov, Robert J. Doerksen, Mary Jackson, Christian Ducho, Christina L. Stallings, Sudeshna Roy
Summary: The increase in multidrug-resistant cases of tuberculosis highlights the urgency of developing new treatment strategies. In this study, a series of compounds containing a 3-thio-1,2,4-triazole moiety were discovered and synthesized. These compounds exhibited inhibitory activity against Mycobacterium tuberculosis (Mtb) growth and survival. Structure-activity relationship studies identified several potent analogs with low micromolar to nanomolar inhibitory activity against Mtb. These potent analogs showed no cytotoxicity in mammalian cells and were bactericidal against Mtb during infection of macrophages. Further investigations into the mechanism of action revealed potential metabolic liabilities for optimization. The findings suggest the potential of these compounds as a new class of 1,2,4-triazole compounds for tuberculosis treatment.
ACS INFECTIOUS DISEASES
(2023)
Article
Biochemistry & Molecular Biology
Yahani P. Jayasinghe, Michael T. Banco, Jared J. Lindenberger, Lorenza Favrot, Zuzana Palcekova, Mary Jackson, Shino Manabe, Donald R. Ronning
Summary: This study further characterized the functionality of Mycothiol S-transferase (MST) in Mycobacterium tuberculosis and examined its role in xenobiotic stress. The results showed that MST is stabilized by the binding of Mycothiol (MSH) and the presence of metal ions. However, cell-based experiments failed to provide evidence for the involvement of MST in the processing of rifampicin or isoniazid, suggesting the need for further research to identify the acceptors of the enzyme and better define its biological role.
RSC MEDICINAL CHEMISTRY
(2023)
