Biology subjects

Frishberg, A.

Publications and source records attributed to Frishberg, A..

2 recordsLinked to original sources

bioRxiv2022

Distinct gene programs underpinning 'disease tolerance' and 'resistance' in influenza virus infection

When challenged with an invading pathogen, the host defense response is engaged to eliminate the pathogen (resistance) and to maintain health in the presence of the pathogen (disease tolerance). However, the identification of distinct molecular programs underpinning disease tolerance and resistance remained obscure. We exploited transcriptional and physiological monitoring across 33 mouse strains, during in vivo influenza virus infection, to identify two host-defense gene programs - one is associated with hallmarks of disease tolerance and the other with hallmarks of resistance. Both programs constitute generic responses in multiple mouse and human cell types. Our study describes the organizational principles of these programs and validates Arhgdia as a regulator of disease-tolerance states in epithelial cells. We further reveal that the baseline disease-tolerance state in macrophages is associated with the pathophysiological response to injury and infection. Our framework provides a paradigm for the understanding of disease tolerance and resistance at the molecular level.

systems biology↗

bioRxiv2021

Multiple trajectory alignment reconstructs disease dynamics for discovery and clinical benefit

Diseases change over time, both phenotypically and in underlying driving molecular processes. Though understanding disease progression dynamics is critical for diagnostics and treatment, capturing these dynamics is difficult, due to their complexity and the high heterogeneity between individuals. We developed TimeAx, an algorithm which builds a comparative framework for capturing disease dynamics using high-dimensional short time-series data. We demonstrate TimeAx utility by studying disease progression dynamics for multiple diseases and data types. Notably, for urothelial bladder cancer tumorigenesis, we identified a stromal pro-invasion point on the disease progression axis, characterized by massive immune cell infiltration to the tumor microenvironment and increased mortality. Moreover, the continuous TimeAx model differentiated between early and late tumors within the same tumor subtype, uncovering novel molecular transitions and potential targetable pathways. Overall, we present a powerful approach for studying disease progression dynamics, providing improved molecular interpretability and clinical benefits for patient stratification and outcome prediction.

systems biology↗