7th joint conference "Joint Microbiology & Infection Conference 2024" of the DGHM and VAAM

Prof. Dr.

Chair

Professor

Activin A levels are raised during tuberculosis and blockade of the activin signaling axis influences experimental M. tuberculosis infection

Infection Immunology

Introduction: The TGF-beta superfamily member activin A is an important immunomodulatory cytokine, but few studies have examined its roles in infectious diseases. Activin A has been implicated in lung pathophysiology, driving us to examine whether it is increased in tuberculosis (TB) and pneumonia, as well as sarcoidosis, a granulomatous inflammatory disease of unknown aetiology that mainly affects the lungs.Goals: We aimed to determine whether serum activin A levels are increased during pulmonary TB, pneumonia and sarcoidosis. Furthermore, we aimed to investigate whether the activin signaling axis plays a role in experimental TB.Materials &amp; Methods: Serum activin A levels were measured in patients with TB, pneumonia (including bacterial and viral pneumonia), and sarcoidosis. A soluble activin type IIB receptor fused to human IgG1 Fc (sActRIIB-Fc) was used to inhibit the activin signaling axis in a murine TB model.Results: In two independent cohorts of TB patients from Gambia and Germany, serum activin A levels were increased during active TB, and levels were associated with increased X-ray scores. In the Gambian cohort, Activin A levels were strongly increased in patients with active TB compared to healthy household contacts, and were reduced in most patients by six months of therapy. Many pneumonia patients also had elevated activin A levels, but activin A levels remained low in sarcoidosis patients. Administration of a soluble ActRIIB-Fc complex to M. tuberculosis-infected mice decreased lung bacterial loads, altered cytokine profiles and increased numbers of CD103+ T cells. The decreased frequencies of CD103+ T cells corresponded with downregulated T-bet expression in both CD4 and CD8 T cells, without changes to TGF-beta expression.Summary: Activin A shows potential as a useful cytokine biomarker for diagnosis of active TB. The activin signalling axis appears to play a functional role during murine TB.

Oral Presentation

Elucidating the role of IL4/IL13 signaling in tuberculous granuloma formation

Tuberculous granulomas are highly organized structures that form upon infection with a member of the Mycobacterium tuberculosis complex (MTBC) or close relatives like M. marinum. Granulomas act as a double-edged sword: they contain infection but can also enable bacterial expansion and limit antibiotic penetration. The central scaffold of the granuloma is a layer of epithelioid macrophages that shields the necrotic core, harboring the bulk of the bacterial burden away from immune cells and antibiotics that struggle to penetrate this structure. The transcription factor STAT6 has been shown to be vital for the epithelioid transformation of macrophages and necrotic granuloma formation through upstream IL4R signaling (Cronan et al. Cell 2021). Here, we investigate the cellular reservoirs of IL4 and IL13 within the granuloma and the contribution of each of these cytokines to granuloma formation and mycobacterial pathogenesis.Goal: To delineate the role of IL4 and IL13 signaling in to the development and architecture of tuberculous granulomas, and assess these pathways as novel adjunct host-directed therapies.We employed a zebrafish (Danio rerio)-M. marinum infection model, which closely mimics human tuberculosis pathology. Genetically modified zebrafish were used to disrupt IL4, IL13 or IL4/IL13 signaling. Histological and immunofluorescence staining were used to monitor granuloma organization and the induction and spatial distribution of IL4/IL13 throughout chronic mycobacterial infection. The functional outcomes of altered IL4/IL13 signaling were assessed by bacterial number within these hosts.We expect to identify the significance of IL4/IL13 signaling within the granuloma and the role of the signals in the overall trajectory of mycobacterial infection. These findings will be critical to understanding the immunological mechanisms governing granuloma formation. As granulomas act as a substantial barrier to the effective treatment of mycobacterial infection, these insights could offer novel treatment approaches through modulation of granuloma formation and function.

Prof. Dr. med.

PD. Dr.

Type 2 conventional dendritic cells play a critical role in the disease outcome of Leishmania mexicana infection, but not in Leishmania major infection

Depending on the parasite species, cutaneous leishmaniasis (CL) in C57BL/6 mice differs in the disease outcome. Leishmania (L). major infection usually shows a strong Th1-driven interferon (IFN)γ response and subsequent production of leishmanicidal nitric oxide, limiting parasite growth and skin pathology, whereas L. mexicana infection ends up in chronic skin lesions due to a mixed IFNγ and interleukin (IL)-10 Th response. As Th responses are triggered by myeloid antigen-presenting cells, we hypothesized that differences in the infection and/or functionality of myeloid subpopulations at the site of infection control disease progression in self-healing versus chronic CL.Using fluorescently labeled Leishmania and flow cytometry, we identified dendritic cells (DCs), monocytes, macrophages and granulocytes as Leishmania host cells in the skin early after infection. Dermal cDC2 showed higher infection rates than cDC1 in both infections. Single-cell RNA sequencing during early L. major and L. mexicana infection revealed that there is a distinct Cxcl9-positive macrophage population present in the draining lymph nodes of L. mexicana-infected mice, but not of L. major-infected animals after 24 hrs of infection. Other myeloid cell subclusters in skin and lymph nodes after 24 and 120 hrs of infection were similar for both parasites. To study the role of cDC2s in vivo, we analyzed Irf4ΔItgax mice that have reduced levels of cDC2 in their lymphoid organs. L. major-infected cDC2-deficient mice and wild-type (WT) littermates showed a comparable, self-healing course of disease. In contrast, L. mexicana infection caused the expected chronic skin lesions in WT controls, whereas L. mexicana-infected Irf4ΔItgax mice developed only mild pathology and resolved the disease. Quantitative PCR analysis of the infected tissue of these animals revealed a shift towards a stronger Th1 response and a subsequent dampening of Th2 related gene expression. Thus, cDC2 exert a hitherto unknown detrimental effect in chronic CL. Ongoing studies aim to unravel the disease-promoting mechanism of cDC2.

Raum 12

Infection Immunology 1

Oral Session

Oral Sessions

Oral Session
Infection Immunology

Appointment

Chair

Topic

Programme

Oral SessionInfection Immunology

Appointment

Chair

Topic

Programme

Oral Session
Infection Immunology