Biology subjects

Melcher, L.

Publications and source records attributed to Melcher, L..

3 recordsLinked to original sources

bioRxiv2025

Emergent Morphologies, Slow Dynamics, and Phase Behavior in Dps:DNA assemblies

The DNA-binding protein from starved cells (Dps) compacts bacterial DNA into stress-protective condensates, but the physical ingredients that are sufficient to produce the observed morphological and dynamical phenomenology remain unclear. Here we use Dps:DNA as the motivation for a broader soft-matter question: which properties govern the co-condensation of a semiflexible polymer with a binding co-solute, and how is the resulting condensate morphology selected? We combine coarse-grained Brownian dynamics (BD) simulations, in which DNA is a semiflexible bead-spring chain and Dps a spherical particle interacting through heterotypic attraction and homotypic repulsion, with a ternary Flory-Huggins free energy evolved under conserved Cahn-Hilliard-Cook dynamics. Both frameworks show that the condensate morphology is governed jointly by the heterotypic Dps:DNA attraction and by composition: attraction drives co-condensation, while at fixed attraction the relative abundance of the two species selects between extended, network-like structures and compact, droplet-like condensates. That two independent models, sampling different concentration regimes, both show composition-controlled morphology selection indicates it is a robust feature of the co-condensation thermodynamics. The simulations further reveal slow, heterogeneous dynamics: sub-diffusive Dps motion and a stretched-exponential collapse of chain dimensions, signatures of the dynamical arrest that accompanies compaction. The framework provides general, transferable principles for protein-nucleic-acid phase separation in soft and living matter.

biophysics↗

bioRxiv2023

Epigenetic changes and serotype-specific interferon-responses of lung epithelial cells in late post-influenza pneumococcal pneumonia

Pneumococcal infection following influenza A virus (IAV) pneumonia is a synergistic complication with high mortality. IAV modulates host antibacterial responses and invasiveness of pneumococcal serotypes and is an important pathogenic factor 2. Yet, serotype-specifc immediate-early responses of the IAV-perturbed alveolar epithelium have not been adressed. We analyzed gene transcription in alveolar type II epithelial cells (AECII) from mice infected with IAV and/or one of three S. pneumoniae (S.pn.) serotypes of varying invasiveness (4 > 7F > 19F). IAV, 14 days post infection, rendered the lung susceptible to invasive S.pn. infection with serotype 4 and the mildly invasive 7F but not 19F. Only 7F secondary infection induced exacerbated cytokine/chemokine responses. IAV/7F infection induced superior protein expression of type I and II interferons, exceeding that in IAV/serotype 4 infection. Inference of a scale-free-like ARACNE gene co-expression network revealed interferon-response network modules. Network-mapping unfolded S.pn. serotype-specific transcriptional network responses/usage. Secondary S.pn. infection abrogated the IAV-induced pneumocyte proliferative configuration and IAV infection rendered the transcriptional response to 7F comparable to that of serotype 4. This related to network genes correlating with the expression of two master regulators of interferon responses: Irf7 and Stat1. Epigenetic ATAC-seq analysis of AECII in resolved IAV infection identified enhanced expression of ARACNE network genes Hist1h2bf, Igtp, Mki67, Rasl10b, H2-Q6 and H2-Q7 to be associated with increased chromatin accessability at promoter regions. We show that AECII retain a sustained IAV-associated transcriptional configuration with epigenetic involvement that serotype-specifically affects proliferation and intensifies the AECII transcriptional response, mainly to interferons, in S.pn. infection.

immunology↗

bioRxiv2022

TMPRSS2 is essential for SARS-CoV-2 Beta and Omicron infection

The COVID-19 pandemic remains a global health threat and novel antiviral strategies are urgently needed. SARS-CoV-2 employs the cellular serine protease TMPRSS2 for entry into lung cells and TMPRSS2 inhibitors are being developed for COVID-19 therapy. However, the SARS-CoV-2 Omicron variant, which currently dominates the pandemic, prefers the endo/lysosomal cysteine protease cathepsin L over TMPRSS2 for cell entry, raising doubts whether TMPRSS2 inhibitors would be suitable for treatment of patients infected with the Omicron variant. Nevertheless, the contribution of TMPRSS2 to spread of SARS-CoV-2 in the infected host is largely unclear. Here, we show that loss of TMPRSS2 strongly reduced the replication of the Beta variant in nose, trachea and lung of C57BL mice and protected the animals from weight loss and disease. Infection of mice with the Omicron variant did not cause disease, as expected, but again TMPRSS2 was essential for efficient viral spread in the upper and lower respiratory tract. These results identify a key role of TMPRSS2 in SARS-CoV-2 Beta and Omicron infection and highlight TMPRSS2 as an attractive target for antiviral intervention.

immunology↗