Biology subjects

Matt, U.

Publications and source records attributed to Matt, U..

3 recordsLinked to original sources

bioRxiv2024

TNF Superfamily Member 14 Drives Post-Influenza Depletion of Alveolar Macrophages Enabling Secondary Pneumococcal Pneumonia

Secondary bacterial infection, often caused by Streptococcus pneumoniae (Spn), is one of the most frequent and severe complications of influenza A virus (IAV)-induced pneumonia. Phenotyping of the pulmonary innate immune landscape after IAV infection revealed a significant depletion of the tissue-resident alveolar macrophage (TR-AM) population at day 7, which was associated with increased susceptibility to Spn outgrowth. To elucidate the molecular mechanisms underlying TR-AM depletion, and to define putative targets for treatment, we combined single-cell transcriptomics and cell-specific PCR profiling in an unbiased manner, using in vivo models of IAV infection and IAV/Spn co-infection. The TNF superfamily 14 (TNFSF14) ligand-receptor axis was revealed as the driving force behind post-influenza TR-AM death during the early infection phase, enabling the transition to pneumococcal pneumonia, while intrapulmonary transfer of genetically modified TR-AMs and antibody-mediated neutralization of specific pathway components alleviated disease severity. With a mainly neutrophilic expression and a high abundance in the bronchoalveolar fluid (BALF) of patients with severe virus-induced ARDS, TNFSF14 emerged as a novel determinant of virus-driven lung injury. Targeting the TNFSF14-mediated intercellular communication network in the virus-infected lung can, therefore, improve host defense, minimizing the risk of subsequent bacterial pneumonia, and ameliorating disease outcome.

molecular biology↗

bioRxiv2024

Nanoliter-scale selection of optimized bioengineered peptide antibiotics that rescue mice with bacterial lung infection

Increasing numbers of multi-drug resistant pathogens call for new chemical scaffolds, addressing novel targets, that can serve as lead structures for the development of life-saving drugs. For antibiotics, natural product-inspired molecules represent a most promising resource. Natural products evolved to high chemical complexity and occupy a chemical space different than synthetic libraries. However, clinical translation of promising natural products is often impeded by their relative inaccessibility to medicinal chemistry optimization, e.g. iterative synthesis of large series of derivatives. Here, this limitation is addressed with a randomized library of bicyclic heptapeptides based on the natural product darobactin that hits the clinically not addressed target BamA. Variants of the ribosomally synthesized and post-translationally modified peptides were generated using heterologous mutasynthesis. A parallelized screening assay is adapted in nanoliter-scale beads to test the darobactin derivatives against our sensor strain. Loss of fluorescence sorting prioritized 563 events out of the analyzed [~]500k beads. Re-testing confirmed 48 hit events, of which 40 proved to produce distinct darobactin-type molecules. Most promising structures were isolated and the growth inhibitory effects against Gram-negative pathogens validated. One of our current frontrunner compounds (i.e., darobactin B) was reinforced by the randomized screen. While microbiological investigations of the new derivatives is ongoing, darobactin B was profiled in later tier assays and compared to another promising, rationally-designed analog (i.e., darobactin B9, "D22"). Early ADMET profiling and efficacy tests in a mouse pneumonia model were performed. Darobactin B reduced bacterial load of Pseudomonas aeruginosa and Klebsiella pneumoniae by intraperitoneal, as well as intratracheal administration. Our study showcases the potential of mutasynthetic libraries for high-throughput screening and identification of functional peptides for drug lead discovery.

microbiology↗

bioRxiv2023

Neutrophil efferocytosis reprograms mitochondrial metabolism to switch alveolar macrophages to a pro-resolution phenotype at the cost of bacterial control

Resolution of lung injuries is vital to maintain gas exchange. Concurrently, there is an increased risk of secondary bacterial infections. Alveolar macrophages (AMs) are crucial to clear bacteria and control initiation and resolution of inflammation, but environmental cues that switch functional phenotypes of AMs remain elusive. Here, we discovered an incapacity of AMs to mount an effective immune response to bacteria during resolution of inflammation. AM efferocytosis of neutrophils (PMNs), a hallmark of resolution of inflammation, switched mitochondrial metabolism to shift AM functions. Mechanistically, PMN-derived myeloperoxidase (MPO) fueled canonical glutaminolysis via uncoupling protein 2 (UCP2) resulting in decreased mtROS-dependent killing of bacteria and secretion of pro-inflammatory cytokines. Instead, MPO-enhanced UCP2 expression inhibited mitochondrial hyperpolarization and boosted efferocytosis irrespective of the presence of bacterial pathogens. In contrast, efferocytosis of epithelial cells resulted in a distinct anti-inflammatory phenotype of AMs maintaining phenotypic plasticity towards bacteria. Overall, uptake of apoptotic PMNs switches AMs to prioritize resolution of inflammation over antibacterial responses and similarly affects murine macrophages at extra-pulmonary sites, and human AMs. One sentence summaryNeutrophil efferocytosis reprograms mitochondrial metabolism to switch alveolar macrophages to a pro-resolution phenotype at the cost of bacterial control.

immunology↗