Intracellular Mycobacterium Tuberculosis – Martin Rottenberg group

Our research focus lies in the regulation of immune responses that control the infection with Mycobacterium tuberculosis. We study the role of major molecular controllers of T cell and macrophage functions in bacterial control after infection and vaccination.

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Department of Microbiology, Tumor and Cell Biology

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Immune responses determining the outcome of infection with Mycobacterium tuberculosis

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (Mtb), remains a leading public health problem. While most individuals infected with Mtb remain asymptomatic, in 2020, ten million individuals fell ill with this disease and 1.5 million died¹.

It is not completely understood why some individuals will develop a life-threatening disease while others harbour a lifelong asymptomatic infection, but the crosstalk of mycobacteria and cellular immune components plays a major role. HIV and Diabetes Mellitus (DM) are risk factors for development of diseases. DM has been associated with TB for centuries, however, in the complex relation between TB and DM and their respective treatments, many important topics have been poorly studied or not studied at all.

Infection with Mtb occurs when the inhaled bacilli are phagocytized by resident lung alveolar macrophages (1). Infected cells recruit mononuclear phagocytes to the infection site, forming a nascent granuloma. During the subclinical stage of infection, the granuloma provides the immune environment required for the containment of bacteria. Although innate immune responses are initialized, Mtb-specific T cells are crucial for the granuloma maturation, maintenance and control of the bacterial spread (2). However, if due to impaired immunity the integrity of the granuloma is lost, reactivation of Mtb leads to the destruction of the lung structure and to the transmission of Mtb to other humans. Thus, the TB granuloma is the niche in which bacilli either can grow and disseminate or in which host cells interact to prevent bacterial dissemination. In the granuloma, macrophage activation by antigen-specific T cells is crucial for a successful control of the bacterial spread.

AIMS

We explore immune mechanisms of bacterial control and to topologically define immune-bacterial interactions in the lung in experimental or clinical Tuberculosis. T-cell immunity is critical for control of the infection with M. tuberculosis (Mtb).

We propose to study the spatial coordination of T cells with other cell types and the balance of activating and inhibitory immune responses in situ in association to the morphology of the lesion.

Using spatially resolved transcriptomics technology we will simultaneously target 256 immune and mycobacterial transcripts in pulmonary sections from patients with Tuberculosis (TB), TB and Diabetes, and sarcoidosis, and thereby define the distinct topography of the granuloma in these conditions. We have successfully applied in situ sequencing to delineate an immunological landscapes of the granuloma in lungs from mice at different time points after infection; in lungs developing encapsulated necrotic or non-encapsulated cellular granulomas; in different granulomas of the same lung and in different areas within the lesions.

An example of transcript colocalization in TB granulomas.

Mapping of mRNA coding for diverse immune molecules in TB granulomas by in situ sequencing where different transcripts locate in the granuloma core, the rim and the lung parenchyma. (Carow et al. Nat Commun. 2019;10(1):1823) Photo: Martin Rottenberg group.

We aim to understand the role played by major molecular pathways regulate the outcome of infection Mycobacterium tuberculosis in experimental models by controlling the protective activity of T cells and macrophages.

The role of STAT3 and HIF-1α in T cells during Mtb infection of otherwise healthy or diabetic mice are investigated using genetically manipulated animals.

The hypoxia-inducible factors (HIF) are central regulators of the cellular responses to hypoxia. We show that HIF-1 stabilization in T cells impairs the activation, cell cycle progression, proliferation, and differentiation of CD4 T cells, and the control of infection with M. tuberculosis. Liu et al submitted.

Figure 2. VHL promotes the cell cycle progression, growth responses, proliferation, IL-2 secretion and expression of activation markers of TCR-stimulated CD4 T cells, the differentiation and the protective function of T cells against M. tuberculosis infection as well as the responses to immunization by impairing HIF-1 stabilization. (Liu et al submitted). Photo: Martin Rottenberg group.