23rd Human Proteome Organization World Congress

The interface between metabolism and immunity within a virus microenvironment

Keynote speaker

Keynote lecture

Prof

Professor

Immunoproteomic analysis of cellular and adaptive responses in naïve and recovered TB patients following intra-lung re-challenge with live BCG

Infectious Biology Insights

Tuberculosis disease (TB) remains a major global health challenge today, despite the availability of vaccine and an armoury of small molecule drugs. Notably, response rates to the century-old bacillus Calmette-Guerin (BCG) vaccine vary widely, for reasons that remain poorly understood. We have therefore developed a lung-oriented controlled human infection model of tuberculosis disease to better understand TB immunopathogenesis at the site of disease and across a spectrum of disease susceptibilities.We recruited 99 healthy South African participants who had previously either single or multiple bouts of TB disease, a latent TB infection, or who appeared to have sterilising immunity. Live BCG, sterile PPD and saline were bronchoscopically instilled into separate lung segments (n = 65). A control group (n = 34) underwent a single bronchoscopy without challenge. Bronchoalveolar lavage (BAL) samples were collected at baseline and 3 days after re-challenge and analysed using SWATH-based proteomics, as well as using mycobacterial protein- and lipid-microarrays, in order to quantify cellular immune responses and anti-microbial antibody signatures as a function of challenge and disease susceptibility.We quantified 4901 peptide IDs and 949 human protein IDs in the BAL samples through the SWATH-based analysis, with a data completeness of 79% across all samples. Differential expression was analysed in limma with Benjamin-Hochberg multiple testing correction, comparing baseline and 3 days post-rechallenge samples across the four disease susceptibility groups. We also quantified antigen-specific IgG and IgA titres in BAL and serum using custom mycobacterial protein NAPPA microarrays comprising 687 cell wall-associated antigens, as well as on home-made mycobacterial lipid microarrays.We observed that immune responses were highly compartment specific (BAL vs. blood) and localized to the challenged lung segments. We also found that cellular and humoral responses increased in magnitude with increasing disease susceptibility, but that these were highly heterogeneous within a challenge- and susceptibility group. In particular, integration of our multi-omic proteomic and antibody data demonstrates the presence of previously unrecognised sub-groups within the clinically-defined latent TB infection group and points to significant mechanistic differences in the immune responses upon re-exposure to the pathogen between these sub-groups. More specifically, STRING analysis of our data identifies a co-ordinated antigen-specific IgA- and neutrophil-driven response at the site of disease in one LTBI sub-group that is likely to be protective but which is absent in in the other LTBI sub-group. Collectively, our integrated proteomic data therefore sheds important new light on the latent TB infection state, with implications amongst others for control of TB transmission, as well as for WHO modelling of elimination of TB disease by 2050.

Oral presentation

Prof. Dr.

Population scale proteomics enables adaptive digital twin modelling in sepsis

Sepsis is one of the leading causes of mortality in the world. Currently, the heterogeneity of sepsis makes it challenging to determine the molecular mechanisms that define the syndrome. Here, we leverage population scale proteomics to analyze a well-defined cohort of 1364 blood samples taken at time-of-admission to the emergency department from patients suspected of sepsis. We identified panels of proteins using explainable artificial intelligence that predict clinical outcomes and applied these panels to reduce high-dimensional proteomics data to a low-dimensional interpretable latent space (ILS). Using the ILS, we constructed an adaptive digital twin model that accurately predicted organ dysfunction, mortality, and early-mortality-risk patients using only data available at time-of-admission. In addition to being highly effective for investigating sepsis, this approach supports the flexible incorporation of new data and can generalize to other diseases to aid in translational research and the development of precision medicine.

Organ atlas proteome mapping of cryptococcosis defines novel putative biomarkers and promising druggable targets for personalized health management

The ability to profile changes in both host and pathogen proteomes during infection provides a unique opportunity to identify novel mechanisms of interplay driving disease. Such information supports an improved understanding of a diseased state and promotes novel strategies for disease detection and treatment. Here, we profiled the interplay between the human fungal pathogen, Cryptococcus neoformans, and the mammalian host using high-resolution mass spectrometry-based proteomics to demonstrate the dynamic nature of infection and to define novel diagnostic biomarkers of disease. We established an in vivo murine model of cryptococcosis and profiled 13 clinically relevant organs, tissues, and fluids across a temporal continuum of disease. Tandem mass tags combined with high pH fractionation improved protein quantification and increased proteome coverage across 780 samples with the proteomic data curated and publicly available through our development of the "CProteo Atlas". We demonstrate the value of this resource by defining novel putative dual species biomarker signatures for detecting and monitoring progression of infection, as well as provide organ and temporal-specific drivers of disease. We also leverage our findings to reveal a novel putative druggable target with a key role in blood brain barrier crossing through in vitro and in vivo assays. Overall, we demonstrate dynamic proteome remodelling of cryptococcosis in a temporal and spatial-dependent manner to uncover new putative biomarkers and druggable targets of infection for informed detection, monitoring, and treatment of disease.

Conference room 1-2

Session

Proteomics in infectious diseases

Session
Proteomics in infectious diseases

Appointment

Chairs

Program

SessionProteomics in infectious diseases

Appointment

Chairs

Program

Session
Proteomics in infectious diseases