Khayelitsha, South Africa: a peri-urban township of around 400000 people 30 km from the centre of Cape Town.

Robert J Wilkinson : Areas of interest

Introduction

The programme derives its research questions from the clinical care of tuberculosis (TB) and HIV-TB co-infected persons in South Africa and London. Through clinically-based studies we aim to improve knowledge of pathogenesis and thereby improve prevention and treatment.

Achievements have been in understanding the human immune response to tuberculosis, especially in the context of HIV-1 co-infection; and on translation of knowledge into novel intervention strategies. Notable is the work on the anti-inflammatory and antimicrobial functions of vitamin D in tuberculosis which led to multiple clinical trials. Of great impact is work on the description, understanding, prevention and management of the HIV-tuberculosis immune reconstitution inflammatory syndrome.

A model of innate receptor signaling in mediating TB-IRIS pathogenesis.

A model of innate receptor signaling in mediating TB-IRIS pathogenesis.

From no more than case-reports in 2004, we have made definitive contributions on the frequency (18% of persons receiving combined TB and HIV treatment), severity (neurological disease can have a death rate of 25%), clinical features, underlying immune mechanisms via inflammasome activation (Figure 1), and treatment and prevention with adjunctive corticosteroids such that management and a clear translational path to future interventions are now in place.

A second domain of major work is in understanding and treating latent tuberculosis. This work has used high-resolution PET/CT imaging to establish for the first time in humans the existence of a high-risk asymptomatic transition state between latent infection and active disease (Figure 2). The technique is thus a phenotypic benchmark for further experimental medicine studies of interventions to prevent progression of asymptomatic subclinical tuberculosis. Further work has identified that such high-risk individuals have elevation of transcripts representing the classical complement pathway and Fcγ receptor 1. Levels of circulating immune (antibody/antigen) complexes also increased in subclinical disease and were highly correlated with C1q transcript abundance. Our results indicate that levels of antibody/antigen complexes increase early in disease, associated with increased gene expression of C1q and Fcγ receptors that bind them. Understanding the role this plays in disease progression may facilitate development of interventions that prevent this, leading to a more favorable outcome and may also be important to diagnostic development.

Microarray profiling revealed that TLR signaling and inflammasome activation are critical in mediating TB-IRIS pathogenesis. Our proposed model begins with M. tuberculosis antigen recognition by surface-expressing TLRs, which triggers the downstream signaling cascade with adaptor molecules such as MyD88 and IRAK4 to activate IRF7, thereby triggering the production of type I IFN. Paracrine signaling of Type I IFN to IFNAR recruits and phosphorylates STAT1/2 dimers, leading to further recruitment of IRF9 and the formation of ISGF3, thereby inducing pro-caspase-11 (caspase-4/5 in human) and AIM-2 inflammasome (caspase-1). Caspase-11 cleaves IL-1α into its mature form and can lead to pyroptosis. The noncanonical inflammasome (caspase-11) can also activate the canonical inflammasome (caspase-1), which cleaves IL-1β and IL-18 into their mature form. Alternatively, TLR signaling via MyD88 can also activate NF-κb via the TAK1/IKK complex. Activation of NF-κb triggers the production of an array of cytokines, including TNF-α, IL-6 and IL-12. In addition, NF-κB can also activates NLRP1/3 inflammasomes and subsequently leads to the production of IL-1β and IL-18.

Images

Radiological and clinical findings in participants with evidence of subclinical tuberculosis.

Figure 2: Radiological and clinical findings in participants with evidence of subclinical tuberculosis (infiltrates, scars or active nodules). e– Lesions from six participants with infiltrates shown on fused FDG-PET/CT images in coronal plane. Participants uniquely numbered 1 – 6 in top left of image.

Baseline scans denoted by “B” in top right corner with baseline lesions circled in green. Follow-up scans denoted by “Tx” in top right corner of image with lesions post-treatment circled in blue. For participants “4”, “5” and “6” the treatment received between scans was IPT, 2HRZE and 2HRZE/4HR respectively. f – Lesions from six participants with scars (at least one example from each participant). Three participants numbered “3”, “4” and “6” also have infiltrates corresponding to Figure 1e. Lesions in baseline PET/CT scan circled in green. Mediastinal lymph nodes pre and post IPT circled green and blue respectively for participants “7” and “8”.