Type I interferons (IFNs) have diverse effects on innate and adaptive immune cells during infection with viruses, bacteria, parasites and fungi, directly and/or indirectly through the induction of other mediators. Type I IFNs are important for host defence against viruses. However, recently, they have been shown to cause immunopathology in some acute viral infections, such as influenza virus infection. Conversely, they can lead to immunosuppression during chronic viral infections, such as lymphocytic choriomeningitis virus infection. During bacterial infections, low levels of type I IFNs may be required at an early stage, to initiate cell-mediated immune responses. High concentrations of type I IFNs may block B cell responses or lead to the production of immunosuppressive molecules, and such concentrations also reduce the responsiveness of macrophages to activation by IFNγ, as has been shown for infections with Listeria monocytogenes and Mycobacterium tuberculosis. Recent studies in experimental models of tuberculosis have demonstrated that prostaglandin E2 and interleukin-1 inhibit type I IFN expression and its downstream effects, demonstrating that a cross-regulatory network of cytokines operates during infectious diseases to provide protection with minimum damage to the host.

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Type I interferons in infectious disease.

There are 9 million cases of active tuberculosis reported annually; however, an estimated one-third of the world's population is infected with Mycobacterium tuberculosis and remains asymptomatic. Of these latent individuals, only 5–10% will develop active tuberculosis disease in their lifetime. CD4+ T cells, as well as the cytokines IL-12, IFN-γ, and TNF, are critical in the control of Mycobacterium tuberculosis infection, but the host factors that determine why some individuals are protected from infection while others go on to develop disease are unclear. Genetic factors of the host and of the pathogen itself may be associated with an increased risk of patients developing active tuberculosis. This review aims to summarize what we know about the immune response in tuberculosis, in human disease, and in a range of experimental models, all of which are essential to advancing our mechanistic knowledge base of the host-pathogen interactions that influence disease outcome.

The Immune Response in Tuberculosis

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736%2815%2901316-1.pdf

A blood RNA signature for tuberculosis disease risk: a prospective cohort study.

Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), results in a range of clinical presentations in humans. Most infections manifest as a clinically asymptomatic, contained state that is termed latent TB infection (LTBI); a smaller subset of infected individuals present with symptomatic, active TB. Within these two seemingly binary states, there is a spectrum of host outcomes that have varying symptoms, microbiologies, immune responses and pathologies. Recently, it has become apparent that there is diversity of infection even within a single individual. A good understanding of the heterogeneity that is intrinsic to TB - at both the population level and the individual level - is crucial to inform the development of intervention strategies that account for and target the unique, complex and independent nature of the local host-pathogen interactions that occur in this infection. In this Review, we draw on model systems and human data to discuss multiple facets of TB biology and their relationship to the overall heterogeneity observed in the human disease.

Heterogeneity in tuberculosis

https://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(16)00048-5.pdf

Genome-wide expression for diagnosis of pulmonary tuberculosis: a multicohort analysis

Background. Accurate assessment of treatment efficacy would facilitate clinical trials of new antituberculosis drugs. We hypothesized that early alterations in peripheral immunity could be measured by gene expression profiling in tuberculosis patients undergoing successful conventional combination treatment. Methods. Ex vivo blood samples from 27 pulmonary tuberculosis patients were assayed at diagnosis and during treatment. RNA was processed and hybridized to Affymetrix GeneChips, to determine expression of over 47 000 transcripts. Results. There were significant ≥2-fold changes in expression of >4000 genes during treatment. Rapid, largescale changes were detected, with down-regulated expression of 1261 genes within the first week, including inflammatory markers such as complement components C1q and C2. This was followed by slower changes in expression of different networks of genes, including a later increase in expression of B-cell markers, transcription factors, and signaling molecules. Conclusions. The fast initial down-regulation of expression of inflammatory mediators coincided with rapid killing of actively dividing bacilli, whereas slower delayed changes occurred as drugs acted on dormant bacilli and coincided with lung pathology resolution. Measurement of biosignatures during clinical trials of new drugs could be useful predictors of rapid bactericidal or sterilizing drug activity, and would expedite the licensing of new treatment regimens.

Distinct phases of blood gene expression pattern through tuberculosis treatment reflect modulation of the humoral immune response.

Background Identification of patients at risk of tuberculosis relapse following treatment would revolutionize clinical trials of new drugs and regimens and facilitate clinical management. The study aim was to determine whether tuberculosis patients who subsequently suffer relapse have different immune responses to mycobacteria in vitro compared to patients who remain cured for two years post-treatment. Methods First episode pulmonary tuberculosis patients were recruited into a surrogate marker study in Cape Town, South Africa. Peripheral blood samples were collected at diagnosis and after two and four weeks of tuberculosis treatment. Diluted blood was cultured with live Mycobacterium tuberculosis for six days and cellular RNA was frozen. Gene expression in samples from ten patients who subsequently relapsed, confirmed by stain genotyping, was compared to those who remained cured using Affymetrix microarrays. Results At diagnosis, the expression of 668 genes was significantly different in samples from patients who subsequently relapsed compared to successfully cured patients, and these differences persisted for at least four weeks. Gene Ontology and biological pathways analyses revealed the most significant difference was up-regulation of genes involved in cytotoxic cell-mediated killing, such as perforin, granulysin and fas ligand. Results were confirmed by qRT-PCR in a wider patient cohort. Conclusions These data show that patients who will subsequently relapse exhibit altered immune responses at diagnosis, including excessively robust cytolytic responses to M. tuberculosis in vitro, compared to patients who will achieve durable cure. Together with microbiological and clinical indices, these differences could be exploited for patient stratification in drugs trials, or for host-directed therapy development. Venous blood samples were diluted in culture medium and stimulated with live M. tuberculosis for 6 days. Samples from 10 TB patients who subsequently relapsed and 10 patients whore remained disease-free for 2 years. Samples collected at TB diagnosis and after 2 weeks or 4 weeks of treatment of first TB episode.

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Excessive Cytolytic Responses Predict Tuberculosis Relapse After Apparently Successful Treatment

BACKGROUND Biomarkers predicting tuberculosis treatment response and cure would facilitate drug development. This study investigated expression patterns of the co-stimulation molecule NKG2D in human tuberculosis and treatment to determine its potential usefulness as a host biomarker of tuberculosis drug efficacy. 

METHODS Tuberculosis patients (n = 26) were recruited in Lahore, Pakistan, at diagnosis and followed up during treatment. Household contacts (n = 24) were also recruited. NKG2D expression was measured by qRT-PCR in RNA samples both ex vivo and following overnight mycobacterial stimulation in vitro. Protein expression of NKG2D and granzyme B was measured by flow cytometry. 

RESULTS NKG2D expression in newly diagnosed tuberculosis patients was similar to household contacts in ex vivo RNA, but was higher following in vitro stimulation. The NKG2D expression was dramatically reduced by intensive phase chemotherapy, in both ex vivo blood RNA and CD8(+) T cell protein expression, but then reverted to higher levels after the continuation phase in successfully treated patients. 

CONCLUSION The changes in NKG2D expression through successful treatment reflect modulation of the peripheral cytotoxic T cell response. This likely reflects firstly in vivo stimulation by live Mycobacterium tuberculosis, followed by the response to dead bacilli, antigen-release and finally immunopathology resolution. Such changes in host peripheral gene expression, alongside clinical and microbiological indices, could be developed into a biosignature of tuberculosis drug-induced cure to be used in future clinical trials.

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Modulation of NKG2D expression in human CD8(+) T cells corresponding with tuberculosis drug cure

Accurate assessment of treatment efficacy would facilitate clinical trials of new anti-tuberculosis drugs. TB patients exhibit altered peripheral immunity which reverts during successful treatment. We hypothesised that these changes could be observed in whole blood transcriptome profiles. Methods Ex vivo blood samples from 27 pulmonary TB patients were assayed at diagnosis and during conventional treatment. RNA was processed and hybridised to Affymetrix GeneChips, to determine expression of over 47,000 transcripts. Findings There were significant changes in expression of over 4,000 genes during treatment. Rapid, large scale changes were detected, with down-regulated expression of ~1,000 genes within the first week, including inflammatory markers such as the complement components C1q and C2. This was followed by slower changes in expression of different networks of genes, including a later increase in expression of B cell markers, transcription factors and signalling molecules. Interpretation The expression of many genes is drastically altered during TB disease, with components of the humoral immune response being markedly affected. The treatment-induced restoration reflects the simultaneous suppression and activation of different immune responses in TB. The rapid initial down-regulation of expression of inflammatory mediators coincides with rapid killing of actively dividing bacilli, whereas slower delayed changes occur as drugs act on dormant bacilli and as lung pathology resolves. Measurement of biosignatures during clinical trials of new drugs could be useful predictors of rapid bactericidal or sterilizing drug activity. Ex vivo blood samples analysed for 27 first episode pulmonary TB patients, at diagnosis and after 1, 2, 4 and 26 weeks of treatment.

Jang-Eun Cho

Papers

Distinct phases of blood gene expression pattern through tuberculosis treatment reflect modulation of the humoral immune response.

Excessive Cytolytic Responses Predict Tuberculosis Relapse After Apparently Successful Treatment

Modulation of NKG2D expression in human CD8(+) T cells corresponding with tuberculosis drug cure

Tuberculosis Patients Blood Gene Expression Through Treatment