Killy B, Bodendorfer B, Mages J, Ritter K, Schreiber J, Hölscher C, Pracht K, Ekici A, Jäck HM, Lang R. DGCR8 deficiency impairs macrophage growth and unleashes the interferon response to mycobacteria, Life Science Alliance 2021, 4 (6): e202000810.
MicroRNAs (miRNA) play an important role in regulation gene expression in innate immune cells and may be exploited by intracellular bacteria. In her PhD project, Barbara Killy addressed the question how a global abrogation of miRNA biosynthesis in DGCR8-deficient bone marrow cells affects the differentiation of macrophages and their interaction with the mycobacterial Mincle ligand TDM. Morphologically macrophages developed despite the lack of DGCR8, but were prone to overshooting type I interferon responses to TDM and to stimulation with whole bacteria of the Mycobacterium tuberculosis complex. Whether high IFNb expression in the absence of regulation by miRNA benefits the host or the mycobacteria will be interesting to explore in future studies.
Huber A et al. Mycobacterial cord factor reprograms the macrophage response to IFNg towards enhanced inflammation yet impaired antigen presentation and expression of GBP1. J Immunol August 12, 2020, ji2000337; DOI: doi.org/10.4049/jimmunol.2000337
Trehalose-6,6-dimycolate (aka the cord factor) is the major PAMP of the mycobacterial cell wall and activates inflammatory cytokine production through MINCLE-CARD9 signaling. Alexandra Huber, Barbara Killy, Nadine Grummer and Barbara Bodendorfer, together with groups from Erlangen and Dresden show in this manuscript that cord factor signaling has ambiguous effects on the macrophage response to IFNg: while inflammatory cytokine and mediator production are enhanced, IFNg-induced MHC-II expression and induction of several GBPs is suppressed by the cord factor. This antagonism of IFNg-induced antigen presentation and anti-mycobacterial proteins may contribute to establish the intracellular niche of M. tuberculosis in its macrophage host.
Schick J et al. TNF is essential for mycobacteria-induced MINCLE expression, macrophage activation and Th17 adjuvanticity.
J Immunol (Cutting Edge) July 15, 2020, 205 (2) 323-328; DOI: https://doi.org/10.4049/jimmunol.200042
Several C-type lectin receptors (CLR) involved in the recognition of mycobacteria are upregulated on macrophages by microbial stimuli. The work by Judith Schick and colleagues from Erlangen, Munich, Düsseldorf, Borstel and Copenhagen now demonstrates that upregulation of the cord factor-receptor MINCLE in macrophages depends on the cytokine TNF. In vivo, deletion or pharmacologic blockade of TNF prevented Th17 adjuvanticity of the synthetic MINCLE ligand TDB. The findings implicate regulation of MINCLE and related CLR as a potential new mechanism in inhibition of resistance to mycobacteria and in vaccination responses by TNF blockade. The later will be further investigated in a PhD project in the new GRK 2599 (see https://www.lymphozyten.med.fau.de/ for more information).
Stebner A et al., (2020) Molecular diagnosis of polymicrobial brain abscesses with 16S-rDNA-based next-generation sequencing, Clinical Microbiology and Infection, doi.org/10.1016/j.cmi.2020.03.028
Bacterial brain abscesses are severe infections requiring prolonged antibiotic treatment. Identification of bacteria present in brain abscesses is important for appropriate treatment but difficult with standard microbiological methods. In a collaboration with the Institute of Virology and the Department of Neurosurgery, Alexander Stebner tested the feasibility of Illumina MiSeq Next Generation Sequencing of 16S rDNA amplicons in a large set of samples from patients with brain abscess or bacterial meningitis. The majority of brain abscesses was indeed polymicrobial, with up to 16 different bacteria taxa detected per sample. The results published in Clinical Microbiology and Infection demonstrate that NGS expands the spectrum of bacteria detected in brain abscesses and is suitable for metagenomic diagnostics of this severe infection
Kohl L, Hayek I, Daniel C, Schulze-Lührmann J, Bodendorfer B, Lührmann A and Lang R (2019) MyD88 Is Required for Efficient Control of Coxiella burnetii Infection and Dissemination. Front. Immunol. 10:165. doi: 10.3389/fimmu.2019.00165
Infection with the zoonotic bacterium Coxiella burnetii is mostly self-limiting and resolves within several weeks, but becomes chronic and severe in some patients. To investigate the contribution of innate immune sensing mechanisms in the decision between resolution and chronicity, Lisa Kohl has used mice deficient in the central TLR adapter MyD88 in infection models with the attenuated Coxiella burnetii strain Nine Mile Phase II. Strongly increased bacterial burden, that persisted in the lungs for at least 4 months after infection, show that TLR signaling is essential for early control of C. burnetii replication and to prevent persistent chronic infection. The study was performed in collaboration with the lab of Anja Lührmann and with Dr. Christoph Daniel (Department of Nephropathology).
Hansen M, Peltier J, et al. (2019) Macrophage Phosphoproteome Analysis Reveals MINCLE-dependent and –independent Mycobacterial Cord Factor Signaling Molecular & Cellular Proteomics 18: 669–685, 2019. DOI: 10.1074/mcp. RA118.000929.
In a collaboration with Julien Peltier from the lab of Matthias Trost, Madlen Hansen performed the first quantitative phosphoproteome analysis of TDM-activated macrophages. Surprisingly, the bioinformatic results revealed Mincle-dependent and -independent phosphorylation, which appear to affect different biological processes. Whereas PI3K/AKT signaling, dependent on Mincle, is involved in TDM-induced cytokine regulation, Mincle-independent phosphorylation and transcriptomic changes were linked to cell cycle regulation. Collectively, the combined phosphoproteome and RNAseq datasets show substantial reprogramming of macrophages by TDM and reveal a dichotomy of MINCLE-dependent and -independent signaling linked to distinct biological responses.