IMS Highlighted Publications

We would like to congratulate the authors below for having their paper highlighted this month (March 2021) by their Research Programme Leads:

Infection & Immunity

The Rab32/BLOC-3–dependent pathway mediates host defense against different pathogens in human macrophages

Baldassarre, M., Solano Collado, M. V., Balci, A., Colamarino, R. A., Dambuza, I. M., Reid, D. M., Wilson, H., Brown, G. D., Mukhopadyay, S., Dougan, G. & Spano, S., 15 Jan 2021, In: Science Advances. 7, 3, 9 p., eabb1795

Summary
Macrophages provide a first line of defense against microorganisms, and while some mechanisms to kill pathogens such as the oxidative burst are well described, others are still undefined or unknown. We recently discovered a novel host-defence mechanism in mouse macrophages active against Salmonella Typhi. This pathway depends on an intracellular trafficking pathway regulated by the Rab GTPase Rab32 and its guanine nucleotide exchange factor (GEF) BLOC3 and we called it BRAM (BLOC-3 and Rab32 Anti-Microbial pathway). The antimicrobial mechanisms of this pathway are not completely elucidated yet, however in this new paper we demonstrated that that well-known antimicrobial mechanisms such as the production of reactive oxygen and nitrogen species are not required for the BRAM pathway-dependent bacterial killing. More importantly, we have shown that the antimicrobial activity of the pathway protects against a number of different pathogens such as Staphylococcus aureus and Candida albicans. Finally, we showed that the BRAM pathway is active in human macrophages and that human-adapted Salmonella Typhi has evolved to counteract this pathway to survive in human macrophages.


Our PhD/postdoc first author paper this month is by Dora Corzo Leon

Host responses in an ex-vivo human skin model challenged with Malassezia sympodialis

Corzo Leon, D. E., MacCallum, D. M. & Munro, C. A., 21 Jan 2021, In: Frontiers in cellular and infection microbiology. 10, 14 p., 561382

Summary
Malassezia species are part of the normal mycobiota and colonize several regions of the body, mainly sebum-rich skin areas such as the scalp and thorax. These species can also cause Malassezia related-diseases, such as seborrheic dermatitis and pityriasis versicolor. Atopic eczema/dermatitis is a chronic inflammatory disease affecting up to 20% of children and 3% of adults and, Malassezia species seem to play a role on its pathogenesis.

We have characterized the host-pathogen interactions of M. sympodialis with human skin at the molecular level using a human skin explant model. The model consisted of inoculating skin explants with M. sympodialis yeasts and incubating them for 6 days. Two different skin conditions were tested and compared. The presence of yeasts was confirmed by fluorescence microscopy and SEM in the inoculated samples. Then, host responses were evaluated by gene expression, proteomics and immunoassays. This study is important as we demonstrated that local host response to M. sympodialis can be characterized using this ex vivo human skin model. In the future, such model can be used to evaluate different Malassezia species, different local host factors and for potential therapeutic agents. Most of these conditions can potentially be mimicked in this ex vivo skin model.

Molecular Medicine

TORC1 determines Fab1 lipid kinase function at signaling endosomes and vacuoles

Chen, Z., Carpio Malia, P., Hatakeyama, R., Nicastro, R., Hu, Z., Péli-Gulli, M., Gao, J., Nishimura, T., Eskes, E., Stefan, C. J., Winderickx, J., Dengje, J., De Virgilio, C. & Ungermann, C., 25 Jan 2021, In: Current Biology. 31, 2, p. 297-309 12 p.  Research output: Contribution to journal › Article › peer-review

Summary

The membrane lipid phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) is crucial for membrane homeostasis and intracellular trafficking processes. PI(3,5)P2 is required for the proper functioning of diverse cell types and organs including neurons, macrophages, platelets, melanosomes, intestines, heart and lung. However, how its production is regulated has been unclear. In this paper, we demonstrate that the evolutionarily conserved PI(3,5)P2-generating enzyme, Fab1 lipid kinase, is directly phosphorylated by the conserved Target of Rapamycin Complex 1 (TORC1) kinase, a central cell growth regulator, in yeast. Fab1 phosphorylation redirected it from lysosomes to endosomes. Consequently, PI(3,5)P2 shifted its location from lysosomes to endosomes with no major change in its total abundance, causing abnormal lysosome morphology and feedback inhibition of TORC1 activity. Our results thus placed PI(3,5)P2 in a regulatory feedback loop essential for homeostatic control of cell growth. 

The significance of subcellular localization (rather than the abundance) of PI(3,5)P2 is a new angle in understanding the regulation and functions of this pleiotropic lipid. The unique tool to visualize PI(3,5)P2 (“biosensor”) I developed during this work will fuel future studies on this lipid in various organisms, organs and cell types.

Systems Physiology

Atorvastatin pleiotropically decreases intraplaque angiogenesis and intraplaque haemorrhage by inhibiting ANGPT2 release and VE‑Cadherin internalization

Fabiana Baganha*, Rob C. M. de Jong, Erna A. Peters , Wietske Voorham , J. Wouter Jukema,  Mirela Delibegovic, Margreet R. de Vries, Paul H. A. Quax.,  Angiogenesis (2021)

 

Summary: 

Objective
Statins pleiotropically provide additional benefits in reducing atherosclerosis, but their effects on intraplaque angiogenesis (IPA) and hemorrhage (IPH) remain unclear. Therefore, we discriminated statin’s lipid-lowering dependent and independent effects on IPA and IPH.

Approach and results
ApoE3*Leiden mice are statin-responsive due to ApoE and LDLR presence, but also allow to titrate plasma cholesterol levels by diet. Therefore, ApoE3*Leiden mice were fed a high-cholesterol-inducing-diet (HCD) with or without atorvastatin (A) or a moderate-cholesterol-inducing-diet (MCD). Mice underwent vein graft surgery to induce lesions with IPA and IPH. Cholesterol levels were significantly reduced in MCD (56%) and HCD + A (39%) compared to HCD with no significant differences between MCD and HCD + A. Both MCD and HCD + A have a similar reduction in vessel remodeling and inflammation comparing to HCD. IPA was significantly decreased by 30% in HCD + A compared to HCD or MCD. Atorvastatin treatment reduced the presence of immature vessels by 34% vs. HCD and by 25% vs. MCD, resulting in a significant reduction of IPH. Atorvastatin’s anti-angiogenic capacity was further illustrated by a dose-dependent reduction of ECs proliferation and migration. Cultured mouse aortic-segments lost sprouting capacity upon atorvastatin treatment and became 30% richer in VE-Cadherin expression and pericyte coverage. Moreover, Atorvastatin inhibited ANGPT2 release and decreased VE-Cadherin(Y685)-phosphorylation in ECs.

Conclusions
Atorvastatin has beneficial effects on vessel remodeling due to its lipid-lowering capacity. Atorvastatin has strong pleiotropic effects on IPA by decreasing the number of neovessels and on IPH by increasing vessel maturation. Atorvastatin improves vessel maturation by inhibiting ANGPT2 release and phospho(Y658)-mediated VE-Cadherin internalization.

*PhD student who was awarded a joint/dual degree PhD in May from UoA and University of Leiden (horizon 2020 studentship)

Translational Neuroscience

Cu, Fe and Zn isotope ratios in murine Alzheimer's disease models suggest specific signatures of amyloidogenesis and tauopathy

Solovyev, N., El-Khatib, A. H., Costas Rodríguez, M., Schwab, K., Griffin, E., Raab, A., Platt, B., Theuring, F., Vogl, J. & Vanhaecke, F., 13 Jan 2021, In: The Journal of Biological Chemistry. 100292.  Research output: Contribution to journal › Article › peer-review

Summary

Alzheimer’s disease (AD) is characterized by accumulation of tau and amyloid-beta in the brain, and recent evidence suggests a correlation between associated protein aggregates and trace elements, such as copper, iron, and zinc. Many of these metals play important functional roles, yet, if present at too high or low concentrations, cause damage and impair brain function. We used a highly sensitive novel method (inductively coupled plasma–mass spectrometry, (ICP-MS)) to determine the total Cu, Fe, and Zn contents in mouse brain and serum. Mice were genetically designed to over-expressed the AD-associated hallmarks, i.e. either tau or amyloid/presenilin; these were compared with the corresponding wild-type control mice (WT).

Our data show that Tau-expressing mouse brains have significantly higher Fe levels than those from the corresponding WT. Significantly less Cu, but more Zn was found the brains with high amyloid load. We also observed significantly lighter isotopes of Fe in the brain and serum of Tau mice compared with WT. For amyloid, Zn exhibited a trend toward a lighter isotopic composition in the brain and a heavier isotopic composition in serum compared with WT. Neither mouse model yielded differences in the isotopic composition of Cu.

Our findings indicate significant pathology-specific alterations of metal homeostasis and accumulation in mouse models of AD. The associated changes in metal and isotope composition may serve as a marker for pathologies underlying AD and other types of dementia.