Research program of the Department of Immunology
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1. Introduction
Research of our group focuses on the crosstalk between Mycobacterium tuberculosis (Mtb) and its host. Our research covers a chain of activities comprising: (i) basic investigations on both the host and the pathogen; (ii) targeted research on intervention measures; (iii) translation into the clinical setting. Our research on tuberculosis (TB) is complemented by basic immunological studies to facilitate better understanding of protection and pathology in TB. Thus, we preserve a strategy delineated in previous SAB reports of highly intertwined basic and translational research (see also Box). The following gives a short overview with emphasis on issues that led to the decision to unite basic and translational research to: (i) better understand the complex crosstalk between pathogen and host during a chronic infection that eventually, but not necessarily, causes disease; (ii) exploit knowledge gathered through basic research for translation into intervention measures; (iii) feed back into basic research those questions arising in the field. Our research in the near future will build on this knowledge and aim at expanding into the realm of Mtb systems biology. In the long-term, our future research will attempt to combine our knowledge in TB systems biology with immunological model systems to build up an integrative TB infection biology platform that aims at understanding the regulatory networks within and between host and pathogen. It is obvious that such a broad scope of research on such a complex disease requires a broad range of expertise. We are fortunate to not only have available the broad expertise provided by our department, but also the availability of other departments and core facilities of the MPIIB. We have also established tight links with expert collaborators from all over the world in structural biology, systems biology, modeling, as well as clinical field studies both in developing and industrialized countries.

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TB is a health threat of global dimension which in particular affects Sub-Saharan Africa. Moreover, TB is a highly interesting target for basic research since it reflects the outcome of a long-standing coevolutionary process between the pathogen, Mtb, and the human host. Worldwide an estimated 2 billion individuals are infected with Mtb, of whom ca. 90% will carry the pathogen lifelong. These individuals remain latently infected with dormant Mtb demonstrating low metabolic and replicative activity (in short, active Mtb). In 10% of infected individuals, TB disease develops, typically within the first two years but occasionally at later times of life. Reactivation TB develops after resuscitation of dormant Mtb, which then acquires high metabolic and replicative activity. Accordingly, protection and pathology in TB are the outcome of a complex crosstalk between Mtb and the immune system which renders this infection particularly attractive for us. On a cellular level, the crosstalk is focused on mononuclear phagocytes (MP), which serve both as effector cells and as habitat for Mtb. At the tissue level, interactions focus on granulomas, which as solid granulomas contain Mtb and as caseous granulomatous lesions provide the soil for rapid growth of Mtb. Accordingly, protection against TB is likely mediated differently in solid granulomas than in caseous granulomas, where disease is more manifest. T lymphocytes are common denominators of the underlying processes. They depend on MP and other antigen presenting cells (APC), notably dendritic cells (DC) for appropriate activation. The pathogen actively influences the infection process, disease outbreak and pathogenesis of TB by virtue of: (i) virulence factors, which manipulate MP; (ii) a complex cell wall that allows for combinatorial interactions with MP; (iii) the capacity to alternate between a dormant stage under stressful conditions and an active stage under more favorable conditions.

It is for these reasons that we consider TB a highly attractive target both for a better understanding of basic mechanisms of protective and pathologic processes of infectious disease and for developing novel intervention measures. The box delineates the different areas of current, recently started and future research.

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Roadmap of current and future activities of the Department of Immunology

Center:
Current activities in immunology focus on receptor–ligand interactions that assemble the signals emitted from infection, homeostatic processes and environment. Our main interest focuses on toll-like receptors (TLR) and NOD-like receptors (NLR) (infection), C-type lectin receptors and B7/CD28 family cognates (immune homeostasis and infection) and aryl hydrocarbon receptors (environment, infection). Signals from these receptors are received by adaptors of which members of the caspase recruitment domain (CARD) family are of particular interest to us. Induction of the acquired immune response is an important but insufficient step. We are particularly interested in how the immune response is sustained and how the crosstalk is maintained within granulomas. Understanding the signaling network between Mtb and different host cells within the granuloma has become a major focus. We are also interested in the fine-tuning of the immune response which we consider critical for maintenance of protection. Fine-tuning of the immune response will gain particular importance in the face of coinfection, notably if the pathogens stimulate different or even antagonistic immune mechanisms. We intend to include coinfections in our research agenda in the near future. Long-term protection may be paralleled by collateral damage and we are interested in mechanisms that sustain protection and reduce inflammatory sequelae. We want to define the effector molecules and cytokines critical for granuloma formation and sustenance, notably, the role of cathepsins and serpins. In addition to analysis of regulatory receptor–counter receptor interactions, we have put significant efforts into the newly emerging field of regulatory RNA in fine-tuning of the immune response.

Left:
We are aware that in-depth understanding of the infection process in TB has to take into account the pathogen, which stays in a continuous crosstalk with the host. At the site of the pathogen we are interested in defining how different lineages and genotypes of Mtb differ from each other with respect to virulence and persistence. Moreover, we study the metabolic and regulatory networks of Mtb during different stages, including metabolically active versus dormant stages and resuscitation. More recently, these investigations have included insights into DNA methylation and regulatory microRNA. To strengthen this area of research we have enrolled into two larger consortia which aim at elucidating metabolic and regulatory networks of Mtb through global profiling and structural analyses. This will lead to a systems biology view of Mtb as a major step forward towards future research directions (see below). At the interface between host cell and pathogen, we will continue to analyze interactions of microbial ligands with host receptors and future work will aim at understanding how Mtb senses signals from the host environment, and through which signals Mtb organisms communicate with each other. Once we have gained further insights in the role of regulatory RNA in the host and in the pathogen we will address the question of whether such RNA participates in the crosstalk between both partners.

Right:
In the translational research area, we remain interested in rational design of vaccines and definition of biomarkers. There is also some interest in the identification of potential drugs, mostly as a spin-off of the Mtb systems biology approaches. We will continue to improve the rBCG .ureC:Hly vaccine developed by our group with the aim in mind to render it both more efficacious and safer. We will combine forces with other vaccine groups to establish heterologous prime–boost vaccination schemes, both for pre- and post-exposure vaccination. By harnessing our knowledge about immune regulation we hope to further improve vaccine efficacy so that ultimately sterile eradication can be achieved. As a highly ambitious alternative without precedents, we will try to develop a vaccine that can prevent infection by stimulating antibody responses in the lung. Our translational research in the field of biomarkers will soon be ready for "proof-of-principle". Sufficient recruitments of study participants will allow us to determine whether we can define biomarkers that predict risk of TB outbreak and can be used for monitoring clinical trials. Currently, we are focusing on transcriptomic and metabolomic analyses complemented by measurements of antigen-specific T cell responses. We have also added serum microRNA to this list of easily available sources for biomarkers and hope to obtain proof-of-principle in the near future.

Lower Part:
We envisage completion of the Mtb systems biology approach within the next 3–4 years (as the result of two large collaborative networks). We expect a wealth of information from our translational research, notably from the results of clinical trials with our vaccine candidate as well as from field studies aimed at biomarker identification. This information will feed back into our basic research programs and will allow us to reevaluate and readjust data obtained in model systems and provide information for new hypothesis-driven research questions. This reverse-translational research will be a major aspect of the near-future perspective (2–4 years). The major long-term research goal (3–6 years) however will be an integrative infection biology view of TB, which will extend the Mtb systems biology studies to the host side and ultimately to the interface between host and pathogen.

Introductory remarks
Understanding the immune response in TB remains our core activity. We are interested in the different stages of immunity including initial recognition of Mtb by the innate immune system, induction of T cell responses, susceptibility/resistance to Mtb, sustenance and fine tuning of the immune response as underlying mechanisms of protection and pathology. In our view, the innate and the acquired immune system are highly intertwined and continue their crosstalk after the initiation of the immune response. Chronicity of infection needs continuous fine tuning and a certain plasticity of the immune response to integrate endogenous and exogenous signals such as inflammation and coinfection, respectively.

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We remain interested in receptors that sense infection (notably TLR, NLR, and DC-SIGN), immune homeostasis (notably DC-SIGN, receptor for advanced glycation end-products or RAGE, and members of the CD28 and B7 families) and the environment (aryl hydrocarbon receptor). As a next step in the cascade, we are interested in adaptors, notably of the CARD family and in the inflammasome in regulating host response to Mtb, and inflammation. Sustenance of the T cell response requires fine tuning to adapt to the changing internal and external conditions. An additional layer of complexity is added by coinfections which may perturb the immune response against TB. During chronic Mtb infection and active TB disease, the immune system has to find a balance between efficient control of Mtb and avoidance of collateral damage. A most recent addition to our investigations into fine tuning is the role of microRNA in immune regulation. The granuloma as the center of protection and pathology has gained increasing interest in the past. We aim to better understand the molecular mechanisms that are operative in the granuloma and control its fate (protection in solid granuloma vs. disease in caseous granuloma). Special interest focuses on cathepsins and serpins. We do not only attempt to understand the underlying mechanisms, but also harness our knowledge for rational design of better vaccines and of biomarkers. Finally, in years to come we expect a wealth of information from our field studies which will address open issues that await answers from basic immunology. We consider this reverse translational research a unique opportunity.

Introductory remarks
Our research into Mtb biology first aims at the identification of genes involved in virulence and persistence by comparing different lineages, genotypes and mutants of Mtb that directly influence the host immune response. Second, we are also interested in understanding the metabolic and regulatory networks that are operative in different stages of Mtb, notably during dormancy, resuscitation and high metabolic and replicative activity. Our collaborative efforts on structural characterization of several Mtb gene products have already provided insights into structure–function relationships. Future emphasis will be given to gene regulatory circuits, the role of DNA methylation and transcriptional regulation in Mtb. We have entered into multidisciplinary consortia, which aim at understanding Mtb from a systems biology view, and are confident that these collaborations will accelerate the elucidation of Mtb biology through a combination of biomics profiling, high throughput promoter mapping and computational modeling. As an added value, we expect that this research will reveal several potential targets for novel drug candidates. Finally, we hope that our increasing experience with systems biology of Mtb in combination with our immunology expertise will provide a basis for an integrative infection biology platform of TB.

4. Translational research (and reverse translational research) [full pdf-Version]

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