Discrete-state models identify pathway specific B cell states across diseases and infections at single-cell resolution.

ABSTRACT

Oxygen (O2) regulated pathways modulate B cell activation, migration and proliferation during infection, vaccination, and other diseases. Modeling these pathways in health and disease is critical to understand B cell states and ways to mediate them. To characterize B cells by their activation of O2 regulated pathways we develop pathway specific discrete state models using previously published single-cell RNA-sequencing (scRNA-seq) datasets from isolated B cells. Specifically, Single Cell Boolean Omics Network Invariant-Time Analysis (scBONITA) was used to infer logic gates for known pathway topologies. The simplest inferred set of logic gates that maximized the number of "OR" interactions between genes was used to simulate B cell networks involved in oxygen sensing until they reached steady network states (attractors). By focusing on the attractors that best represented sequenced cells, we identified genes critical in determining pathway specific cellular states that corresponded to diseased and healthy B cell phenotypes. Specifically, we investigate the transendothelial migration, regulation of actin cytoskeleton, HIF1A, and Citrate Cycle pathways. Our analysis revealed attractors that resembled the state of B cell exhaustion in HIV+ patients as well as attractors that promoted anerobic metabolism, angiogenesis, and tumorigenesis in breast cancer patients, which were eliminated after neoadjuvant chemotherapy (NACT). Finally, we investigated the attractors to which the Azimuth-annotated B cells mapped and found that attractors resembling B cells from HIV+ patients encompassed a significantly larger number of atypical memory B cells than HIV- attractors. Meanwhile, attractors resembling B cells from breast cancer patients post NACT encompassed a reduced number of atypical memory B cells compared to pre-NACT attractors.