Advances in Host-Directed Therapies Against Tuberculosis

This book discusses specific immune cell regulatory pathway(s), immune cell types, or other mechanisms involved in host responses to tuberculosis that can be potentially targeted for host-directed therapy (HDT). The pathways/mechanisms investigated are either protective thus calling for pathway/factor enhancing drugs or maladaptive thus calling for pathway/factor inhibitory drugs. Discovery and development (pre-clinical and clinical) of candidate HDT agents will also be elucidated, as well as approaches for HDT of other diseases. The benefit to the reader will derive from learning about the biology of multiple host pathways involved in health and disease, how these pathways are disrupted or dysregulated during tuberculosis, and which druggable targets exist in these pathways. This book provides the reader with a roadmap of current and future directions of HDT against tuberculosis. Since the host pathways/factors involved in protective or maladaptive responses to tuberculosis are not disease-specific, information learned from the context of tuberculosis likely will be relevant to other infectious and non-infectious diseases.

Host-directed therapy is a unique, innovative, and burgeoning new approach for the treatment of infectious diseases, and specifically for tuberculosis, the leading cause of death by a single infectious agent. As a new field, no similar comprehensive survey of completed and ongoing research exists Each section of the text contains several chapters written by a top expert in that specific area. The information provided represents a thorough and state-of-the-art analysis of the field The implications for host responses and pathways are of broad interest in physiology and in various diseases of non-infectious origin (e.g, autoimmunity, cancer, metabolic disorders), or those that can be exploited for treating infectious diseases other than tuberculosis

Autorentext
Petros C. Karakousis, M.D., is an infectious diseases-trained physician scientist and Professor of Medicine at the Johns Hopkins University School of Medicine. His research focus is on host-pathogen interactions contributing to Mycobacterium tuberculosis persistence and antibiotic tolerance. His laboratory is actively investigating the repurposing of clinically available agents with immune-modulatory properties as adjunctive host-directed therapy, in order to shorten the duration of TB treatment and improve lung pathology.

Maria Laura Gennaro, M.D., is Professor of Medicine at Rutgers New Jersey School of Medicine. Her laboratory studies mechanisms of adaptation expressed by Mycobacterium tuberculosis and by the host macrophage during infection, with the goal of finding targets for therapeutic intervention. She has a specific interest in macrophage lipid metabolism, which is altered following M. tuberculosis infection, thereby promoting bacterial survival.

Richard Hafner, M.D., is an infectious diseases-trained physician and Chief of the TB Clinical Research Branch in the Division of AIDS at NIAID/NIH. Throughout his career, he has had a long-standing interest in advancing innovative host-directed therapies for infections. He has been involved in several clinical trials, authored various articles, and hosted multiple scientific meetings related to research to develop targeted HDTs for TB.

Klappentext

This book discusses specific immune cell regulatory pathway(s), immune cell types, or other mechanisms involved in host responses to tuberculosis that can be potentially targeted for host-directed therapy (HDT). The pathways/mechanisms investigated are either protective thus calling for pathway/factor enhancing drugs or maladaptive thus calling for pathway/factor inhibitory drugs. Discovery and development (pre-clinical and clinical) of candidate HDT agents will also be elucidated, as well as approaches for HDT of other diseases. The benefit to the reader will derive from learning about the biology of multiple host pathways involved in health and disease, how these pathways are disrupted or dysregulated during tuberculosis, and which druggable targets exist in these pathways. This book provides the reader with a roadmap of current and future directions of HDT against tuberculosis. Since the host pathways/factors involved in protective or maladaptive responses to tuberculosis are not disease-specific, information learned from the context of tuberculosis likely will be relevant to other infectious and non-infectious diseases.

Inhalt

Section 1: Introduction.- Chapter 1: Introduction: An overview of host-directed therapies for tuberculosis.- Section 2: Targeting immunometabolism.- Chapter 2: Sirtuin deacetylases: Linking Mycobacterial infection and host metabolism.- Chapter 3:The mammalian target of rapamycin complex 1 (mTORC1): an ally of M. tuberculosis in host cells.- Chapter 4: HIF-1 as a potential therapeutic target for tuberculosis treatment.- Chapter 5: Nuclear receptors in host-directed therapies against tuberculosis.- Section 3: Enhancing anti-mycobacterial mechanisms.- Chapter 6: Autophagy as a target for host-directed therapy against tuberculosis.- Chapter 7: Metformin: a leading HDT candidate for TB.- Chapter 8: Statins as host-directed therapy for tuberculosis.- Chapter 9: Antimycobacterial attributes of mitochondria: An insight into host defense mechanisms.- Section 4: Targeting immune cells.- Chapter 10: Conventional and unconventional lymphocytes in immunity against Mycobacterium tuberculosis.- Chapter 11: Targeting inhibitory cells such as Tregs and MDSCs in the tuberculous granuloma.- Chapter 12: Targeting suppressor T cells.- Chapter 13: Neutrophil-mediated mechanisms as targets for host-directed therapies against tuberculosis.- Chapter 14: Type I interferon and interleukin-1 driven inflammatory pathways as targets for HDT in tuberculosis.- Chapter 15: Mucosal-associated invariant and V9V2 T cells.- Chapter 16: Airway epithelial cells.-Section 5: Preclinical models for assessing HDTs.- Chapter 17: In vitro models of human granuloma formation to analyze host-directed therapies.- Chapter 18: C3HeB/FeJ as a key mouse strain for testing host-directed therapies against tuberculosis.- Chapter 19: The Rabbit Model for Assessing Host-Directed Therapies for Tuberculosis.- Section 6: Clinical trials of HDTs and special considerations for study endpoints.- Chapter 20:Clinical trials of TB-HDT candidates.- Chapter 21:Outcomes for clinical trials of host-directed therapies for tuberculosis.- Chapter 22: Pharmacological considerations for clinical trials of host-directed therapies for tuberculosis.