PetrosC.Karakousis

RichardHafner

MariaLauraGennaroEditors

Advances in

Host-Directed

Therapies

Against

Tuberculosis

Advances in Host-Directed Therapies Against

Tuberculosis

Petros C. Karakousis • Richard Hafner

Maria Laura Gennaro

Editors

Advances in Host-Directed

Therapies Against

Tuberculosis

ISBN 978-3-030-56904-4 ISBN 978-3-030-56905-1 (eBook)

https://doi.org/10.1007/978-3-030-56905-1

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Editors

Petros C. Karakousis

Department of Medicine

Johns Hopkins University

School of Medicine

Baltimore, MD, USA

Maria Laura Gennaro

Public Health Research Institute

New Jersey Medical School

Rutgers Biomedical and Health Sciences

Rutgers-The State University of New Jersey

Newark, NJ, USA

Richard Hafner

Division of AIDS (DAIDS)

National Institute of Allergy

and Infectious Diseases

Rockville, MD, USA

Preface

Tuberculosis (TB) has caused at least 1 billion deaths over the past two centuries,

more than the combined number of deaths from malaria, smallpox, HIV/AIDS,

cholera, plague, and inuenza. The WHO estimates that there are more than 2 bil-

lion people latently infected with Mycobacterium tuberculosis (Mtb). TB is the

leading cause of death among infectious diseases and one of the top 10 causes of

death worldwide. In 2016, TB caused an estimated 1.7 million deaths including over

400,000in persons living with HIV/AIDS.An estimated 10.4 million new TB cases

occurred in 2016, 10% of which were among individuals living with HIV infection.

About 4.1% of the new cases were multidrug-resistant (MDR) TB, with 6.2% of

those cases identied as extensively drug-resistant (XDR) TB.Current treatment

has major limitations, including long duration with poor adherence, high rates of

intolerability and toxicity, and frequent drug interactions. One result of these draw-

backs is the steady emergence of MDR/XDR TB, which is notoriously difcult and

expensive to treat. Because of limited protability, development of new agents by

pharmaceutical companies has been slow and sporadic. With increasing resistance

to current antibiotics and reduced investment in the development of new antimicro-

bial drug classes, the World Health Organization has warned that we are at risk of

entering a “post-antibiotic era.”

To meet the challenges of increasing antimicrobial resistance, the infectious dis-

ease community needs innovative therapeutics. The eld of oncology has addressed

complex treatment challenges by developing approaches to reverse disruptions in

cell regulatory mechanism that cause malignancies and often lead to suppression of

immune processes. Effective and far less toxic new therapeutic approaches are

based on discoveries of basic pathogenic mechanisms of malignancies. These strat-

egies include “precision medicine” (targeted reversal of cell pathway disruptions

caused by mutations as pathogenic drivers) and novel “immuno-oncology” inter-

ventions, for example, immune checkpoint reversal, now transforming cancer thera-

peutics. Pathogens target many of the same regulatory pathways as they modulate

host cell regulatory and metabolic functions to promote their own survival by

impeding host immunity. The same knowledge, tools, and interventions now revo-

lutionizing oncology can be adapted for improved therapy of many infections.

Host-directed therapy (HDT) is intended to enhance microbial killing and

lessen detrimental inammation/tissue damage by targeting host regulatory mole-

cules and pathways modulated by pathogenesis. Preclinical studies have identied

drugs with promising HDT benets for adjunctive TB treatment. Choosing candi-

date agents for evaluation needs to be based on knowledge of the host regulatory

signaling pathways disrupted by pathogens and identifying specic pathway mol-

ecules that can be therapeutically targeted. Promising host-based interventions

already in clinical use and in evaluation for TB therapy include tyrosine kinase and

phosphodiesterase inhibitors; agents to restore disruptions in immunometabolism,

regulatory pathways, and effector mechanisms; modulation of immune suppres-

sive cells (especially MDSCs); immune co-receptor-based checkpoint interven-

tions; epigenetic agents; and combinations of these agents. New HDT strategies

are urgently needed for TB meningitis to reduce the associated high mortality and

morbidity.

HDT goals include reversing TB-induced immune defects to achieve increased

bacillary killing to shorten treatment duration and improve MDR treatment out-

comes, both by directly improving immune function and also by decreasing exces-

sive tissue inammation and death (and reversing inhibition of autophagy and

apoptotic pathways) to improve drug and immune cell penetration and function.

Another important goal is prevention of inammatory lung tissue damage with

loss of pulmonary function. Impaired pulmonary function (both obstructive and

restrictive) often persists after TB treatment. Even mild decreases in FEV1 have

been associated with signicantly increased mortality in very large cohort studies

of broadly inclusive populations. One key aspect of HDT target discovery research

is distinguishing between detrimental immune cell regulation changes and tissue

damage caused by pathogen molecular drivers and adaptive changes that are nec-

essary for enhancing antimicrobial control and killing. Thus, some HDTs could

lead to an over-reactive immune response, causing excessive tissue damage. Both

preclinical and clinical HDT studies must carefully address and monitor for this

risk. Successful adoption of HDT for infectious diseases also requires careful

research into how to identify which patient subpopulations, types of agents, timing

of initiation, and dosing regimens/duration will result in the most benet and

least harm.

Re-purposing of HDT drugs for many non-infectious diseases provides a prac-

tical approach to address the lack of incentive in developing novel antimicrobial

agents due to the high cost and lengthy development time needed for approval of

new drug classes relative to the limited nancial return on investment. In order to

develop innovative new HDT strategies for infectious diseases based on precision

medicine/immunotherapy principles, multi-disciplinary teams of researchers will

be needed with expertise in microbiology/clinical infectious diseases, classical

immunology, and the still-emerging eld of molecular biology of cell regulation.

One initial step in this process is to facilitate collaboration among researchers

studying key regulatory signaling pathways and targeted interventions for non-

communicable diseases and those in the infectious diseases community. These

Preface

vii

approaches will create a transformative new paradigm for the treatment and pre-

vention of TB and a wide variety of other infectious diseases, and will have a high

global health impact, particularly in the face of progressive emergence of antimi-

crobial resistance.

Baltimore, MD, USA PetrosC.Karakousis

Rockville, MD, USA RichardHafner

Newark, NJ, USA MariaLauraGennaro

Preface

Contents

Part I Introduction

1 Introduction: An Overview of Host- Directed Therapies

for Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Daniel J. Frank and Robert N. Mahon

Part II Targeting Immunometabolism

2 Sirtuin Deacetylases: Linking Mycobacterial Infection

and Host Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Lorissa Smulan, Hardy Kornfeld, and Amit Singhal

3 The Mammalian Target of Rapamycin Complex 1 (mTORC1):

An Ally of M. tuberculosis in Host Cells . . . . . . . . . . . . . . . . . . . . . . . . 27

Natalie Bruiners, Valentina Guerrini, and Maria Laura Gennaro

4 HIF-1α as a Potential Therapeutic Target for Tuberculosis

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Qingkui Jiang, Maria Laura Gennaro, and Lanbo Shi

5 Nuclear Receptors in Host-Directed Therapies

against Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Eun-Kyeong Jo

Part III Enhancing Anti-mycobacterial Mechanisms

6 Autophagy as a Target for Host-Directed Therapy

Against Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Surbhi Verma, Raman Deep Sharma, and Dhiraj Kumar

7 Metformin: A Leading HDT Candidate for TB . . . . . . . . . . . . . . . . . . 97

Amit Singhal and Hardy Kornfeld

8 Statins as Host-Directed Therapy for Tuberculosis . . . . . . . . . . . . . . . 109

Noton K. Dutta and Petros C. Karakousis

9 Antimycobacterial Attributes of Mitochondria:

An Insight into Host Defense Mechanisms . . . . . . . . . . . . . . . . . . . . . . 121

Rikesh K. Dubey and Apoorva Narain

Part IV Targeting Immune Cells

10 Conventional and Unconventional Lymphocytes

in Immunity Against Mycobacterium tuberculosis . . . . . . . . . . . . . . . . 133

Paula Ruibal, Tom H. M. Ottenhoff, and Simone A. Joosten

11 Targeting Inhibitory Cells Such as Tregs and MDSCs

in the Tuberculous Granuloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

Sadiya Parveen, John R. Murphy, and William R. Bishai

12 Targeting Suppressor T Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

Léanie Kleynhans and Gerhard Walzl

13 Neutrophil-Mediated Mechanisms as Targets

for Host-Directed Therapies Against Tuberculosis . . . . . . . . . . . . . . . 211

Tobias K. Dallenga and Ulrich E. Schaible

14 Type I Interferon and Interleukin-1 Driven Inflammatory

Pathways as Targets for HDT in Tuberculosis . . . . . . . . . . . . . . . . . . . 219

Katrin D. Mayer-Barber and Christopher M. Sassetti

15 H. Mucosal-Associated Invariant and Vγ9Vδ2 T Cells . . . . . . . . . . . . 233

Charles Kyriakos Vorkas and Michael Stephen Glickman

16 Alveolar Epithelial Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

Angélica M. Olmo-Fontánez and Jordi B. Torrelles

Part V Preclinical Models for Assessing HDTs

17 In Vitro Models of Human Granuloma Formation

to Analyze Host-Directed Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . 259

Liku B. Tezera, Michaela T. Reichmann, Basim Al Shammari,

and Paul T. Elkington

18 C3HeB/FeJ as a Key Mouse Strain for Testing

Host-Directed Therapies Against Tuberculosis . . . . . . . . . . . . . . . . . . 267

Pere-Joan Cardona and Cristina Vilaplana

19 The Rabbit Model for Assessing Host- Directed

Therapies for Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275

Selvakumar Subbian and Gilla Kaplan

Part VI Clinical Trials of HDTs and Special Considerations

for Study Endpoints

20 Clinical Trials of TB-HDT Candidates . . . . . . . . . . . . . . . . . . . . . . . . . 285

Robert S. Wallis

Contents

21 Outcomes for Clinical Trials of Host- Directed

Therapies for Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

Akshay N. Gupte, Sara C. Auld, William N. Checkley,

and Gregory P. Bisson

22 Pharmacological Considerations for Clinical Trials

of Host-Directed Therapies for Tuberculosis . . . . . . . . . . . . . . . . . . . . 311

Elisa H. Ignatius and Kelly E. Dooley

Contents