Biology subjects

Mueller, A. J.

Publications and source records attributed to Mueller, A. J..

6 recordsLinked to original sources

bioRxiv2026

Mast cells initiate lymphocyte egress from distant lymph nodes upon skin inflammation via a RANKL-sphingosine-1-phosphate axis

Receptor activator of NF{kappa}B ligand (RANKL) is important for bone metabolism, but also modulates immune processes. We showed that mast cells (MCs) are involved in RANKL regulation, but the importance of MC-derived RANKL in skin inflammation has not yet been investigated. In contact hypersensitivity (CHS), the absence of MC-derived RANKL led to reduced skin inflammation due to impaired leukocyte infiltration and blood lymphopenia. Surprisingly, we observed a massive hyperplasia of the distant inguinal lymph nodes in the absence of MC-RANKL. Using adoptive transfers, flow cytometry and whole-mount 3D imaging, we demonstrated that this was not caused by structural maladaptation, but rather by the inability of lymphocytes to exit in a timely manner. Importantly, RANKL deletion in skin MCs only replicated the effect of LN hyperplasia and blood lymphopenia. Moreover, MCs were involved in serum sphingosine-1-phosphate (S1P) regulation during sensitization and challenge. Intravascular administration of S1P restored timely lymphocyte egress, demonstrating a MC-induced organ-spanning RANKL-S1P axis. Consequently, peripheral skin MC-derived RANKL is essential for the timely lymphocyte egress from distant LNs, which may have important implications for the targeted treatment of inflammatory skin diseases.

immunology↗

bioRxiv2025

CD36 is a metabolic checkpoint for Th2 cell tissue residency during allergic airway inflammation

The prevalence of allergic diseases, including asthma, continues to rise in industrialized societies, yet the mechanisms sustaining pathogenic T helper 2 (Th2) responses remain incompletely understood. Here, we show that patients with allergic asthma exhibit elevated lipophilic volatile organic compounds in exhaled air and altered fatty acid-metabolism gene expression in sputum-derived Th2 cells. Using a mouse model of house dust mite-induced allergic airway inflammation, we find that the lipid transporter CD36 is dispensable for T follicular helper and germinal center B cell responses but is critical for maintaining lung-resident memory Th2 cells. CD36 regulates GATA3 and PPAR{gamma} expression in lung-resident memory Th2 cells and their interaction with type-2 conventional dendritic cells during airway inflammation. In human T cells, pharmacological inhibition of CD36 does not impair initial activation but blocks terminal Th2 differentiation. These findings identify CD36 as a metabolic checkpoint that sustains Th2 effector function and tissue residency, and establish lipid metabolism as a yet unrecognized therapeutic target in allergic asthma. SummaryAllergic asthma is marked by rising prevalence yet the drivers of persistent T helper 2 (Th2) immunity remain unclear. We show that asthma patients exhibit altered fatty acid-metabolism signatures in sputum Th2 cells and elevated lipophilic volatile organic compounds in exhaled air. In a mouse model of house dust mite-induced airway inflammation, the lipid transporter CD36 was dispensable for germinal center responses but essential for lung-resident memory Th2 cells, controlling GATA3 and PPAR{gamma} expression and promoting cDC2 interactions. Pharmacological inhibition of CD36 in human T cells preserved activation but blocked terminal Th2 differentiation. These findings identify CD36 as a metabolic checkpoint that sustains Th2 effector function and tissue residency, and nominate it as a therapeutic target in allergic asthma. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/676489v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@117da6eorg.highwire.dtl.DTLVardef@105934corg.highwire.dtl.DTLVardef@109903corg.highwire.dtl.DTLVardef@dc9345_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Novel nitrifying symbiont lineages are vertically inherited and widespread in marine sponges

Ammonia-oxidising archaea and nitrite-oxidising bacteria are common members of marine sponge microbiomes. They derive energy for carbon fixation and growth from nitrification - the oxidation of ammonia to nitrite and further to nitrate - and are proposed to play essential roles in the carbon and nitrogen cycling of sponge holobionts. In this study, we characterise two novel nitrifying symbiont lineages, Ca. Nitrosokoinonia and Ca. Nitrosymbion in the marine sponge Coscinoderma matthewsi using a combination of molecular tools, single-cell imaging techniques, and physiological rate measurements. Both represent a new genus in the ammonia-oxidising archaeal class Nitrososphaeria and the nitrite-oxidising bacterial order Nitrospirales, respectively. Furthermore, we show that larvae of this viviparous sponge are densely colonised by representatives of Ca. Nitrosokoinonia and Ca. Nitrosymbion indicating vertical transmission. In adults, the representatives of both symbiont genera are located extracellularly in the mesohyl. Comparative metagenome analyses and physiological data suggest that ammonia-oxidising archaeal symbionts of the genus Ca. Nitrosokoinonia strongly rely on endogenously produced nitrogenous compounds (i.e., ammonium, urea, nitriles/cyanides, and creatinine) rather than on exogenous ammonium sources taken up by the sponge. Additionally, the nitrite-oxidising bacterial symbionts Ca. Nitrosymbion may reciprocally support the ammonia-oxidisers with ammonia via the utilisation of sponge-derived urea and cyanate. Interestingly, comparative analyses of published environmental 16S rRNA amplicon data revealed that Ca. Nitrosokoinonia and Ca. Nitrosymbion are widely distributed and predominantly associated with marine sponges and corals, suggesting a broad relevance of our findings.

microbiology↗

bioRxiv2021

Ammonia-oxidizing archaea possess a wide range of cellular ammonia affinities

Nitrification, the oxidation of ammonia to nitrate, is an essential process in the biogeochemical nitrogen cycle. The first step of nitrification, ammonia oxidation, is performed by three, often co- occurring guilds of chemolithoautotrophs: ammonia-oxidizing bacteria (AOB), archaea (AOA), and complete ammonia oxidizers (comammox). Substrate kinetics are considered to be a major niche-differentiating factor between these guilds, but few AOA strains have been kinetically characterized. Here, the ammonia oxidation kinetic properties of 12 AOA representing all major phylogenetic lineages were determined using microrespirometry. Members of the genus Nitrosocosmicus have the lowest substrate affinity of any characterized AOA, which are similar to previously determined affinities of AOB. This contrasts previous assumptions that all AOA possess much higher substrate affinities than their comammox or AOB counterparts. The substrate affinity of ammonia oxidizers correlated with their cell surface area to volume ratios. In addition, kinetic measurements across a range of pH values strongly supports the hypothesis that - like for AOB - ammonia and not ammonium is the substrate for the ammonia monooxygenase enzyme of AOA and comammox. Together, these data will facilitate predictions and interpretation of ammonia oxidizer community structures and provide a robust basis for establishing testable hypotheses on competition between AOB, AOA, and comammox.

microbiology↗

bioRxiv2020

Genomic and kinetic analysis of novel Nitrospinae enriched by cell sorting

Chemolithoautotrophic nitrite-oxidizing bacteria (NOB) are key players in global nitrogen and carbon cycling. Members of the phylum Nitrospinae are the most abundant, known NOB in the oceans. To date, only two closely affiliated Nitrospinae species have been isolated, which are only distantly related to the environmentally abundant uncultured Nitrospinae clades. Here, we applied live cell sorting, activity screening, and subcultivation on marine nitrite-oxidizing enrichments to obtain novel marine Nitrospinae. Two binary cultures were obtained, each containing one Nitrospinae strain and one alphaproteobacterial heterotroph. The Nitrospinae strains represent two new genera, and one strain is more closely related to environmentally abundant Nitrospinae than previously cultured NOB. With an apparent half-saturation constant of 8.7{+/-}2.5 {micro}M, this strain has the highest affinity for nitrite among characterized marine NOB, while the other strain (16.2{+/-}1.6 {micro}M) and Nitrospina gracilis (20.1{+/-}2.1 {micro}M) displayed slightly lower nitrite affinities. The new strains and N. gracilis share core metabolic pathways for nitrite oxidation and CO2 fixation but differ remarkably in their genomic repertoires of terminal oxidases, use of organic N sources, alternative energy metabolisms, osmotic stress and phage defense. The new strains, tentatively named "Candidatus Nitrohelix vancouverensis" and "Candidatus Nitronauta litoralis", shed light on the niche differentiation and potential ecological roles of Nitrospinae.

microbiology↗

bioRxiv2019

A prospective role for the rumen in generating antibiotic resistance

Antibiotics were a revolutionary discovery of the 20th century, but the ability of bacteria to spread the genetic determinants of resistance via horizontal gene transfer (HGT) has quickly endangered their use1. Indeed, there is a global network of microbial gene exchange, the analysis of which has revealed particularly frequent transfer of resistance determinants between farm animals and human-associated bacteria2. Here, we leverage the recent release of a rumen microbial genome reference set and show that the wide-spread resistance gene cluster aadE-sat4-aphA-3 is harboured in ruminal Bacteroidetes. While this cluster appears to have been recently transferred between commensal bacteria in the rumen and many diverse animal and human pathogens, comparative analysis suggests that the cluster stabilized in the pathogens. Then, focusing on streptomycin resistance, it was found that homologues from the rumen span much of the known diversity of aminoglycoside O-nucleotidyltransferases (AadEs) and that distinct variants of the enzyme are present in a single rumen bacterial genome. Notably, a second variant of AadE has also been recently transferred, albeit more often as a single gene, throughout a different set of animal and human associated bacteria. By examining the synteny of AadE orthologues in various bacterial genomes and analyzing corresponding gene trees in an environmental context, we speculate that the ruminant associated microbiome has a salient role in the emergence of specific resistance variants and clusters. In light of the recent literature on the evolutionary origin of antibiotic resistance, we further suggest that the rumen provides a possible route of dissemination of resistance genes from soil resistomes, throughout the farm, and to human pathogens3.

microbiology↗