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23rd Human Proteome Organization World Congress

Beyond a bird's eye view towards One Health: Demystifying proteogenomic landscape and organeller control of health to disease linking multi-host response

Keynote Lecture

Complex nature of the interactions between plant, animal, human and ecosystem renders multisectoral transdisciplinary approaches critical to address future food and health risks and challenges. Proteogenomics and organeller proteomics uncover new strategies for one health problems by facilitating discovery of molecular signature of disease and protein biomarkers to multi-host resistance. Fusarium sp., an ascomycetes fungus and multi-host pathogen is a causal agent of vascular wilt in plants, neuronal stress in worm and fusariosis in humans. Although precisely controlled innate immune response is governed by conserved cellular events in phylogenetically diverse hosts, underlying molecular mechanisms by which this process is regulated against multi-host pathogen remain unknown. We have established the proteo-genomics landscape of a food legume, chickpea and reanalysed the data for worm in healthy and disease state based on DDA library and SWATH-MS with a high-quality spectral library for rapid and deep profiling. Further, with an iTRAQ based workflow combining integrated transcriptomics and metabolomics, we also demonstrated multilayered analyses at the resolution of organellar proteomics and phosphor-proteomic and their application to reveal new insight on the immune signature and pathogenesis during fusariosis. Most excitingly, network analysis identified significant functional modules pointing toward fusarium responsive common mechanism of remodelling, homeostasis and cell death response through divergent regulatory pathways across kingdom.

Keynote lecture

Prof

Protein restriction reprograms the multi-organ proteomic landscape of mouse aging

One Health Approaches (Plant, Food, Nutrition, Animal, Environment)

Aging is a major risk for life-threatening diseases. In recent years, protein restriction (PR) has gained recognition as a viable and practical intervention for promoting healthy aging. However, considering the complexity of aging and the importance of assessing the effectiveness and safety of PR prior to implementation, it is essential to delve into the molecular alterations occurring in different organs.While several extensive transcriptomics studies on aging covering five to 23 organs have been conducted, the need for proteomics studies remains crucial due to the limited correlation between transcripts and proteins. However, the existing proteomic investigations have primarily focused on no more than ten organs at just two time points, excluding vital organs including the adrenal glands, lymph nodes, and reproductive organs. Additionally, the two-time-point approach may introduce biases by confounding the effects of aging with those of diseases. Moreover, the impact of PR on multiple organs and the optimal timeframe for intervention remain largely unexplored.To address these gaps, we conducted an extensive study involving the collection of 41 mouse organs at eight distinct time points spanning the mouse lifespan and implemented a dietary intervention with varying protein intake for different age and sex groups. We also obtained plasma samples from both mice and humans to investigate the systemic effects of aging and PR. We applied Pulse Data-Independent Acquisition (PulseDIA) for analyzing all 2,565 tissue samples and Tandem Mass Tag (TMT) for the 592 depleted plasma samples.We observed tissue-specific expression patterns of aging hallmarks and identified 36 proteins that consistently changed across multiple organs, with immunoglobulins and serpins demonstrating particular significance. Notably, many of these changes started prior to maturation. PR mitigate age-related molecular changes in a tissue-specific manner, including epigenomic modifications in the urinary system and protein phosphorylation alterations in brown adipose tissue, brain, and seminal vesicle. Our findings were supported by Reduced-representation bisulfite sequencing, phosphoproteomics, and staining experiments. These molecular changes indicated improved health conditions under PR, such as reduced cancer risks in the bladder and enhanced adipose function through increased thermogenesis. Importantly, initiating PR during middle age yielded the most profound effects. Furthermore, our analysis of human and mouse plasma proteomic data indicated improved cardiovascular health under PR, although extreme low protein intake showed signs of increased inflammation.In summary, our study provides the most comprehensive molecular insights to date regarding aging and PR effects in multiple organs. This work expands our understanding of PR as a geroprotective intervention, highlights the potential benefits and risks, and identifies the optimal time frame for PR interventions.

Oral presentation

Prof.

Reversing antifungal resistance through disruption of ClpX

Fungal disease impacts the lives of almost a billion people across the globe. The opportunistic human fungal pathogen, Cryptococcus neoformans, causes cryptococcal meningitis in immunocompromised individuals with high fatality rates in response to limited treatment options. Moreover, the emergence of azole-resistant isolates in the clinic following prolonged treatment regimes, environmental fungicide exposure, and fungal evolution, threatens the outcome of current therapeutic options, endangering the survival of infected individuals. By quantitatively characterizing the proteomes of fluconazole-susceptible and -resistant C. neoformans strains using state-of-the-art tandem mass spectrometry, we defined ClpX, an ATP-dependent unfoldase, as a target to overcome resistance. We discovered that disruption of ClpX through deletion or inhibition re-introduces fluconazole susceptibility into the resistant strains, rendering treatment effective once again. We further explored the mechanism of susceptibility and determined interruption to heme biosynthesis and ergosterol production associated with ClpX. Our results contribute to the understanding of novel mechanisms driving fluconazole resistance and provide support for targeting proteins as a therapeutic strategy to combat resistance.

PECA, proteome integral solubility alteration for chemical safety, a tool for target identification, and exposome impact analysis within the One Health framework

The EU's zero pollution ambition for 2050 is to reduce pollution to levels no longer harmful to human and environmental health. Current research has predominantly focused on human health, leaving a significant gap in understanding how these exposures affect animal health. This knowledge gap has consequences, as animal health is intricately linked to human health through the One Health concept. The lack of high-throughput methods to analyse the effects of the exposome on animal health not only endangers animal welfare but could pose risks to food safety and, consequently, human health.As we present here, the Proteome Integral Solubility Alteration for Chemical Safety (PECA) implements the PISA assay for a fast and sensitive chemical safety assessment within the One Health concept. The modification aims: i) constrain the proteome of analysis on the globular native proteome; ii) increase the completeness of the target analysis by combining different principles that induce alteration in protein stability: temperature, acid or salt concentration; iii) select a temperature, acid, salt concentration that increases target identification while reducing sample requirement, iv) introduce lessons learnt from single-cell proteomics to reduce steps, time, and sample loss in sample preparation.Here, we showed that PECA, as a simplified PISA assay, can identify proteins interacting with environmental chemicals, providing insights into the mechanism of action and predicting potential adverse effects. We first applied the method to determine protein targets of chemicals from human cell lines from the liver, skin, and endothelium, which are relevant to predicting the impact. Finally, we confirmed the method's applicability by analysing farm animal tissues. PECA aligns with the One Health concept by examining the broad impact of chemicals across different organisms, which is crucial for safeguarding the health of all species and ensuring the integrity of our food supply.Funding: This work has been performed with funding from Cristobal Lab from the ERA-NET Marine Biotechnology project CYANOBESITY, which FORMAS, Sweden grant nr, cofounds. 2016-02004. The project GOLIATH has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 825489; IKERBASQUE, Basque Foundation for Science; Basque Government Research Grant IT-476-22 and LiU verification grant.

Conference room 1-2

Session

One health approaches

Session
One health approaches

Appointment

Chairs

Program

SessionOne health approaches

Appointment

Chairs

Program

Session
One health approaches