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The emergence of antibiotic-resistant microorganisms (AMR) poses a threat to global health. Fast and accurate diagnosis is key to contain the rise of AMR, limit its spread and provide adequate treatment to patients. However, classic microbiology approaches are often inadequate in timely detection of infections. Here we propose to pilot the clinical usability and explore the commercial potential of a novel molecular approach able to detect AMR independent of the drug resistance mechanism or the presence of known markers.Based on our discovery that changes in mRNA degradation inform about strain-specific response to antimicrobials, we will develop a simplified molecular kit to measure AMR. The proposed strategy will be fast (<4h), use instruments present in most laboratories and be compatible with current diagnostic workflows. We will validate this approach and assess its utility in collaboration with the healthcare sector. Next, we will explore its future implementation in the context of the new EU regulation for In vitro Diagnosis. During this project we aim to obtain sufficient preliminary data to spin-off this technology to the Swedish biotech sector.In summary, we aim to develop a simplified platform to provide fast diagnosis for bacterial infections and actionable recommendation for antibiotic usage. Our work has the potential to dramatically accelerate diagnosis, improve patient survival, and contribute to individualized and rational use of antibiotics.

Virus-caused infections are a leading cause of illness around the world. Rapid diagnosis of infectious diseases is critical for appropriate and timely treatment of infected patients, for disease surveillance and to prevent the rapid spread of infectious diseases. Here we propose to develop a novel and scalable approach for label-free electric detection of virus. We will use a modified RT-LAMP to amplify viral genetic material and self-assemble the product into DNA nanoballs. Next, the generated nanoballs will be detected by measuring changes in electric impedance as they flow passively through a microfluidic channel. We expect that the combination of RT-LAMP and DNA nanoball generation provides higher specificity and sensitivity than current approaches. By avoiding the need of fluorescence and by using electric impedance that can be easily miniaturized, we aim to develop an affordable point of care system. We will validate this approach with SARS-CoV-2 and demonstrate its wide applicability and intrinsic flexibility by applying it to multiple pathogens (HIV, Influenza, RSV, measles…). Finally, we will benchmark this approach and validate its utility in collaboration with a hospital clinical microbiology laboratory. In summary, we propose to develop a new diagnostic method that has the potential to provide a sensitive, cheap and scalable point-of-care system to help address the growing diagnostic challenges in the coming decades.

We have recently discovered a novel mechanism by which, in response to low nutrient conditions, most ribosomes experience a -1 ribosome frameshift. This process affects most genes causing a drastic acceleration of mRNA decay and the production of aberrant proteins. Here we aim to improve our mechanistic understanding of this process using genomic and proteomic methods.First, we will characterize the accumulation of Ct truncated aberrant proteins derived from nutrition-induced frameshift events and their impact on cellular fitness. As our preliminary data shows that this phenomenon occurs also in cancer cells under amino acid starvation, we will characterize the impact of nutrition-induced frameshift in cancer regulation. We will focus on understanding how frameshift events result in the generation of cancer neoantigens.  Preliminary evidence suggest that older cells are more prone to experience nutrition-induced frameshift. Thus, we will study this using aging models for yeast and humans. Finally, as the level of nutrition-induced frameshift can be easily modulated, we will pilot the development of novel intervention strategies to increase the expression of neoantigens in cancer cells and minimise proteostasis problems during aging.In essence, our project aims to illuminate a novel layer of gene expression regulation and examine its manipulation for combating cancer and age-related diseases.