Protective immunity against tuberculosis: what does it look like and how do we find it?

Huang, Lu; Russell, David G.

doi:10.1016/j.coi.2017.08.001

Cited by 30 publications

(31 citation statements)

References 57 publications

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“…While we are making previously unimaginable progress in defining the cells, molecules and pathways of TB, we are making little discernable progress in putting the pieces together to understand how the organisms accomplish the two functions of systemic immunity to protect the host and local susceptibility to produce and maintain a cavity. Our lack of understanding of these functions is still a major impediment to development of vaccines and new therapies ( 3 – 6 ). Dr. Anthony Fauci, Director of NIAID, expressed a nearly universal opinion with the statement: “We need to better understand the delicate balance between the host and pathogen in the context of the entire biological system and this requires a ‘radical and transformational approach.’ “Our goal should be to transform the entire field.” ( 7 , 8 ).…”

Section: Introductionmentioning

confidence: 99%

The Pathogenesis of Tuberculosis: The Early Infiltrate of Post-primary (Adult Pulmonary) Tuberculosis: A Distinct Disease Entity

Hunter

2018

Front. Immunol.

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It has long been recognized that tuberculosis (TB) induces both protective and tissue damaging immune responses. This paper reviews nearly two centuries of evidence that protection and tissue damage are mediated by separate disease entities in humans. Primary TB mediates protective immunity to disseminated infection while post-primary TB causes tissue damage that results in formation of cavities. Both are necessary for continued survival of Mycobacterium tuberculosis (MTB). Primary TB has been extensively studied in humans and animals. Post-primary TB, in contrast, is seldom recognized or studied. It begins as an asymptomatic early infiltrate that may resolve or progress by bronchogenic spread to caseous pneumonia that either fragments to produce cavities or is retained to produce post-primary granulomas and fibrocaseous disease. Primary and post-primary TB differ in typical age of onset, histopathology, organ distribution, x-ray appearance, genetic predisposition, immune status of the host, clinical course and susceptibility to protection by BCG. MTB is a highly successful human parasite because it produces both primary and post-primary TB as distinct disease entities in humans. No animal reproduces this sequence of lesions. Recognition of these facts immediately suggests plausible solutions, animal models and testable hypotheses to otherwise inaccessible questions of the immunity and pathogenesis of TB.

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Section: Introductionmentioning

confidence: 99%

The Pathogenesis of Tuberculosis: The Early Infiltrate of Post-primary (Adult Pulmonary) Tuberculosis: A Distinct Disease Entity

Hunter

2018

Front. Immunol.

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“…For example, Mycobacterium tuberculosis (Mtb) targets lungs of immune-competent hosts to ensure its survival in granulomas and later transmission via aerosols [2]. The acquisition of permissiveness to infection by certain host cells in TB granulomas does not equate to loss of control mechanisms at the whole organism level [3,4]. Thus, induced susceptibility may be effectively exploited by specialized pathogens, and, play an important role in their transmission and coevolution with hosts.…”

Section: Introductionmentioning

confidence: 99%

Increased susceptibility to intracellular bacteria and necrotic inflammation driven by a dysregulated macrophage response to TNF

Bhattacharya

Chatterjee

Berland

et al. 2017

Preprint

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The development of protective immunity vs immunopathology in tuberculosis is controlled by a mouse genetic locus, sst1, which mediates formation of human-like necrotic granulomas, but its molecular mechanisms have been unclear.We demonstrate that sst1 deficient macrophages develop aberrant, biphasic responses to TNF, characterized by super-induction of IFNb and ISR pathways after prolonged TNF stimulation. This late stage was initiated by oxidative stress and driven by Myc via a JNK -IFNb -PKR feed forward circuit. By locking the susceptible macrophages in a state of escalating stress, prolonged TNF stimulation reduces resilience to subsequent infection with intracellular bacteria.We propose a generalizable paradigm in host -pathogen interactions, where susceptibility emerges gradually within inflammatory tissue due to imbalanced macrophage responses to growth, differentiation and stress stimuli prior to encountering pathogens. This explains how successful pathogens may locally bypass mechanisms of resistance in otherwise immunocompetent hosts and suggests novel therapeutic strategies.peer-reviewed)

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“…It has also underpinned the use of alternative screens to identify compounds active against bacilli in this intracellular environment (81)(82)(83)(84), as well as approaches to understand the impact of the intracellular environment on drug partitioning and how this knowledge might be exploited for rationale drug and drug regimen design (60). The perceived centrality of the host macrophage in infection outcomes (85)(86)(87) has also been key to the use of standard mouse models as distinct from the "Kramnik" or C3HeB/FeJ model (29,88) in pre-clinical efficacy assessments (89). Therefore, while cultured cells in vitro do not fully recapitulate the specialist functional properties of differentiated macrophages in vivo (3,90) -with their diverse ontogenies and differential trajectories of activation and development (91) -the utility of the macrophage model in inferring disease-relevant mycobacterial physiological and metabolic adaptations, as well as innate host defence strategies, seems convincing (3,75,92).…”

Section: Probing the Unit Of Infection: The Mtb-infected Macrophagementioning

confidence: 99%

Drug permeation and metabolism in Mycobacterium tuberculosis: Prioritising local exposure as essential criterion in new TB drug development

et al. 2018

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Anti-tuberculosis (TB) drugs possess diverse abilities to penetrate the different host tissues and cell types in which infecting Mycobacterium tuberculosis bacilli are located during active disease. This is important since there is increasing evidence that the respective "lesion-penetrating" properties of the front-line TB drugs appear to correlate well with their specific activity in standard combination therapy. In turn, these observations suggest that rational efforts to discover novel treatment-shortening drugs and drug combinations should incorporate knowledge about the comparative abilities of both existing and experimental anti-TB agents to access bacilli in defined physiological states at different sites of infection, as well as avoid elimination by efflux or inactivation by host or bacterial metabolism. However, while there is a fundamental requirement to understand the mode of action and pharmacological properties of any current or experimental anti-TB agent within the context of the obligate human host, this is complex and, until recently, has been severely limited by the available methodologies and models. Here, we discuss advances in analytical models and technologies which have enabled investigations of drug metabolism and pharmacokinetics (DMPK) for new TB drug development. In particular, we consider the potential to shift the focus of traditional pharmacokinetic-pharmacodynamic analyses away from plasma to a more specific "site of action" drug exposure as an essential criterion for drug development and the design of dosing strategies. Moreover, in summarising approaches to determine DMPK data for the "unit of infection" comprising host macrophage and intracellular bacillus, we evaluate the potential benefits of including these analyses at an early stage in the preclinical drug development algorithm. © 2018 IUBMB Life, 70(9):926-937, 2018.

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Protective immunity against tuberculosis: what does it look like and how do we find it?

Cited by 30 publications

References 57 publications

The Pathogenesis of Tuberculosis: The Early Infiltrate of Post-primary (Adult Pulmonary) Tuberculosis: A Distinct Disease Entity

The Pathogenesis of Tuberculosis: The Early Infiltrate of Post-primary (Adult Pulmonary) Tuberculosis: A Distinct Disease Entity

Increased susceptibility to intracellular bacteria and necrotic inflammation driven by a dysregulated macrophage response to TNF

Drug permeation and metabolism in Mycobacterium tuberculosis: Prioritising local exposure as essential criterion in new TB drug development

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