Biology subjects

Moya-Nilges, M.

Publications and source records attributed to Moya-Nilges, M..

5 recordsLinked to original sources

bioRxiv2026

A cilia-dependent inflammatory programme links bacterial detection to kidney disease

The primary cilium is a microtubule-based sensory organelle projecting from the plasma membrane of most mammalian cells. Genetic defects in ciliary components cause chronic kidney disease (CKD) characterized by heightened production of inflammatory and fibrogenic mediators by tubular epithelial cells. Yet, whether this reflects a physiological role of the primary cilium remains unknown. Here, we show that primary cilia on kidney tubular cells bind uropathogenic Escherichia coli and, in response to bacterial components, initiate a fibro-inflammatory program reminiscent of CKD. Integrating single-cell transcriptomics with conditional mouse models, we observed that epithelial cilia orchestrate a similar fibro-inflammatory response in the absence of infection during CKD. This convergence reveals a shared cilia-dependent signalling axis governing both host-pathogen responses and CKD progression. Mechanistically, cilia ablation selectively impairs tubular responses to ADP-heptose, a pathogen-associated molecular pattern that activates NF-{kappa}B via the cytosolic innate immune receptor ALPK1. In human kidney organoids, ADP-heptose induces robust fibro-inflammation, and genetic or pharmacological inhibition of ALPK1 attenuates this response in a rodent CKD model. Together, these findings identify primary cilia as central orchestrators of a fibro-inflammatory program linking pathogen detection to kidney disease progression.

physiology↗

bioRxiv2024

HIV-1 budding requires cortical actin disassembly by the oxidoreductase MICAL1

Many enveloped viruses bud from the plasma membrane that is tightly associated with a dense and thick actin cortex. This actin network represents a significant challenge for membrane deformation and scission, and how it is remodeled during the late steps of the viral cycle is largely unknown. Using super-resolution microscopy, we show that HIV-1 buds in areas of the plasma membrane with low cortical F-actin levels. We find that the cellular oxidoreductase MICAL1 locally depolymerizes actin at budding sites to promote HIV-1 budding and release. In the absence of MICAL1, F-actin abnormally remains at viral budding sites, incompletely budded viruses accumulate at the plasma membrane and viral release is impaired. Remarkably, normal viral release can be restored in MICAL1-depleted cells by inhibiting Arp2/3-dependent branched actin networks. Mechanistically, we find that MICAL1 directly disassembles branched-actin networks and controls the timely recruitment of the ESCRT scission machinery during viral budding. In addition, the MICAL1 activator Rab35 is recruited at budding sites, functions in the same pathway as MICAL1 and is also required for viral release. This work reveals a role for oxidoreduction in triggering local actin depolymerization to control HIV-1 budding, a mechanism that may be widely used by other viruses. The debranching activity of MICAL1 could be involved beyond viral budding in various other cellular functions requiring local plasma membrane deformation.

cell biology↗

bioRxiv2023

The unique Legionella longbeachae capsule favors intracellular replication and immune evasion

Legionella longbeachae and Legionella pneumophila cause Legionnaires disease despite species-specific differences in environmental niches, disease epidemiology, and genomic content. Here, we characterized a new L. longbeachae virulence factor, a capsule that is expressed in post-exponential growth phase as shown by electron microscopy. Analysis of the capsule composition via HLPC revealed the presence of a highly anionic polysaccharide absent in a capsule mutant. The capsule is crucial for replication and virulence in vivo in a mouse model of infection and in the natural host Acanthamoeba castellanii. It has anti-phagocytic function when encountering innate immune cells, it is involved in a low cytokine responses in mice and in human monocyte derived macrophages and helps to dampen the innate immune response. The L. longbeachae capsule is a novel virulence factor, unique among known Legionella species, that aids L. longbeachae to survive in specific niches and partly confers L. longbeachae its unique infection characteristics.

microbiology↗

bioRxiv2021

Mitochondrial fission process 1 (MTFP1) controls bioenergetic efficiency and prevents inflammatory cardiomyopathy and heart failure in mice

Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in adult-onset dilated cardiomyopathy (DCM) characterized by sterile inflammation and cardiac fibrosis that progressed to heart failure and middle-aged death. Failing hearts from cardiomyocyte-restricted knockout mice displayed a general decline in mitochondrial gene expression and oxidative phosphorylation (OXPHOS) activity. Pre-DCM, we observed no defects in mitochondrial morphology, content, gene expression, OXPHOS assembly nor phosphorylation dependent respiration. However, knockout cardiac mitochondria displayed reduced membrane potential and increased non-phosphorylation dependent respiration, which could be rescued by pharmacological inhibition of the adenine nucleotide translocase ANT. Primary cardiomyocytes from pre-symptomatic knockout mice exhibited normal excitation-contraction coupling but increased sensitivity to programmed cell death (PCD), which was accompanied by an opening of the mitochondrial permeability transition pore (mPTP). Intriguingly, mouse embryonic fibroblasts deleted for Mtfp1 recapitulated PCD sensitivity and mPTP opening, both of which could be rescued by pharmacological or genetic inhibition of the mPTP regulator Cyclophilin D. Collectively, our data demonstrate that contrary to previous in vitro studies, the loss of the MTFP1 promotes mitochondrial uncoupling and increases cell death sensitivity, causally mediating pathogenic cardiac remodeling.

physiology↗

bioRxiv2020

Dynamic High-Content Imaging Reveals Surface Exposure Of Virulent Leishmania Amastigotes In Infected Macrophages Undergoing Pyroptosis

Leishmania spp are obligate intracellular parasites that infect vertebrate phagocytes, notably macrophages. We previously reported that Leishmania amazonensis (L. am) subvert the host cell pro-inflammatory response by dampening the macrophage NLRP3 inflammasome. No information is available on how Leishmania infection affects inflammatory cell death termed pyroptosis, known to limit microbial infection. Here, we provide first evidence that L. amazonensis-infected macrophages can undergo pyroptosis when subjected to pro-inflammatory stimuli. We analyzed the dynamics of the pyroptotic process and the fate of intracellular amastigotes at the single cell level using spinning disk confocal microscopy and high-content, real-time imaging. Bone marrow-derived macrophages (BMDMs) were infected with L. am amastigotes isolated from footpad lesions and sequentially treated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP) for canonical NLRP3 inflammasome priming and activation. Real-time monitoring was performed for 240 min post ATP addition. Longitudinal analyses revealed distinct phases of the pyroptotic process, including rapid decay of the parasitophorous vacuole (PV) as monitored by the pH-sensitive lysotracker fluid phase marker, progressive decrease in macrophage viability as monitored by accumulation of the nuclear dye YO-PRO-1, followed by translocation of the luminal PV membrane to the cell surface observed for 40% of macrophages, resulting in the extracellular exposure of amastigotes that remained anchored to the PV membrane. Scanning and transmission electron microscopy analyses revealed a highly polarized orientation of parasites with exclusive exposure of the anterior pole toward the extracellular milieu, and an attachment site forming a potential biological junction between the parasite posterior pole and the PV membrane. We showed that the exposed parasites are resistant to the cytolytic host cell activities linked to pyroptosis and retain their full infectious potential in reinfection experiments using naive macrophages. Together these data uncover a novel Leishmania immune subversion strategy that may allow stealthy parasite dissemination via the uptake of pyroptotic host debris by uninfected phagocytes.

immunology↗