News Release 

Hodor 'holds the door' open for a potential new way to curb mosquito populations

MRC London Institute of Medical Sciences

The identification of an insect-specific metal-sensing receptor in the gut lining highlights a possible new way to curb populations of disease-transmitting insects such as mosquitoes.

In this new study led by the MRC London Institute of Medical Sciences, researchers discovered that removal of this nutrient-sensing receptor called Hodor was fatal in Anopheles mosquitoes as the insects did not make it past their larval stage.

The findings, published in the journal Nature, identify an attractive drug target that is easily accessible in the gut lining which can act to curb mosquito populations. It again emphasises the value of investigating insect specific biology, and not just human research, to lead to healthcare treatments and interventions.

The ability for cells in the gut to sense nutrients is essential to maintain homeostasis and their ability to adapt to a changing environment. Micronutrients, such as metal ions, are known to have important roles in growth and development, but our understanding of how metals are sensed is limited. These nutrient sensors are most commonly found in the gut lining, specifically in the enteroendocrine cells. However, Professor Irene Miguel-Aliaga, the principal investigator on this study, and colleagues were curious about enterocytes - which play more of a role in digestion and absorption of nutrients - and whether they have any ability to sense nutrients themselves.

They performed a genetic screen of over 100 candidate proteins thought to be involved in nutrient sensing. This screen uncovered a receptor that seems to regulate the development of larvae, particularly in nutrient-poor conditions that was expressed in the gut lining. Inhibiting the expression of this protein resulted in developmental delay, as referenced in the name 'Hodor' (an abbreviation for 'hold on, don't rush').

Hodor is a zinc-sensing protein that uses the metal to transport chloride within and out of cells, facilitating pathways that regulate nutrient-sensing and growth. Increasing the levels of zinc in the flies' diet led to increased feeding, which was reversed when Hodor was blocked. The authors suggest that the receptor helps to direct the animals to nutrient-rich food sources (metals such as zinc are produced by yeasts, which are found on fruit and other foods). Finally, they demonstrate that deleting the gene in mosquitoes is fatal, suggesting that such disease vectors could be targeted and controlled by using ingestible drugs and also could be harmless to humans due to its insect specificity.

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Notes to Editors

For more information or interview requests, please contact: Sophie Arthur, LMS Science Communications Officer. Tel: +44 (0)7725 159772, Email: sophie.arthur@lms.mrc.ac.uk

Siamak Redhai, Clare Pilgrim, Pedro Gaspar, Lena van Giesen, Tatiana Lopes, Olena Riabinina, Théodore Grenier, Alexandra MIlona, Bhavna Chanana, Jacob B. Swadling, Yi-Fang Wang, Farah Dahalan, Michaela Yuan, Michaela Wilsch-Brauninger, Wei-hsiang Lin, Nathan Dennison, Paolo Capriotti, Mara K. N. Lawniczak, Richard A. Baines, Tobias Warnecke, Nikolai Windbichler, Francois Leulier, Nicholas Bellono and Irene Miguel-Aliaga. 'The intestinal zinc sensor regulates food and developmental growth' will be published online in Nature on Wednesday 18th March 16:00 UK time / 12:00 US ET, and is under strict embargo until then.

The DOI for this paper will be: https://doi.org/10.1038/s41586-020-2111-5

About the MRC London Institute of Medical Sciences (LMS)

The MRC London Institute of Medical Sciences (LMS) is a research institute which aims to advance the understanding of biology and its application to medicine. Our research is focused on some of the UK's major health challenges that arise from changes in diet (obesity, diabetes and heart disease) and increased lifespan (dementia and cancer). Through tackling fundamental questions about the links between our genes, environmental stresses such as diet, and the way our bodies age researchers aim to translate this knowledge to improve the understanding, diagnosis and treatment of diverse medical conditions. Research at the institute falls into three sections: epigenetics, genes and metabolism and quantitative biology. The LMS is core funded by the Medical Research Council (MRC), which is part of UK Research and Innovation (UKRI).

http://www.lms.mrc.ac.uk | Twitter @MRC_LMS

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