Year: 2025
Type: preprint
Abstract: Persistent human-adapted microbes can act as immunological “keystones,” organizing host defense across tissues and shaping vulnerability under immune perturbation. More generally, tissue immunity is calibrated by persistent niche-resident organisms that tune compartment-specific thresholds of cytotoxicity and peripheral tolerance; keystone organisms represent the apex subset with multi-niche scope. Here we operationalize keystone organisms as pathogens whose containment requires coordinated engagement of multiple immune arms and whose residence is structured across anatomical niches. Using 18 curated immunological and evolutionary traits across 43 organisms, unsupervised analyses resolved four reproducible archetypes and identified a compact keystone set dominated by persistent herpesviruses and Mycobacterium tuberculosis . We then translated the clinical literature into a pathogen×immune-perturbation×niche tensor capturing where and when each organism emerges under defined immune deficits. We quantified “diagnostic breadth” with two complementary summaries: immune breadth (diversity of perturbations associated with emergence) and niche breadth (diversity of anatomical sites). Clinical emergence patterns perfectly separated trait-defined keystones from all other organisms and highlighted expanded niche breadth as the primary discriminator, whereas immune breadth showed no significant group separation. Finally, a mechanistic model integrating barrier disruption, latent reservoir activation, and tissue-resident immune control predicted clinical emergence from first principles—without fitting parameters to individual pathogens—and ranked true emergences 2.9-fold above chance among its highest-confidence predictions. Together, these results link evolutionary adaptation to clinically readable patterns of reactivation, motivate archetype-aware surveillance under immunosuppression, and provide a framework for immunogen design that prioritizes conserved, functionally constrained targets. Because the clinical tensor is literature-curated and sparse, “perfect separation” refers to keystone-vs-other discrimination within this dataset and is not a claim of universal out-of-sample performance.
Authors: Amir Asiaee, Natalie Mallal, Elizabeth Phillips, Simon Mallal
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: Mechanisms of Immune Activation in Hypertension, Improving Prediction of Drug Action, HIV-1 adaptation to HLA-restricted immune responses, Immunogenetic predictors of active and incipient TB in HIV-negative and -positive close TB contacts, G5283026267, G5373364349, G5459587482, Causal Effect Estimation of Regulatory Molecules, G6877476418, G8763671412, G8927845304, Tennessee Center for AIDS Research (TN-CFAR), The intersection of immunity and cardiovascular diseases, Cancer Center Support Grant, Vanderbilt-coordinated human Virome Collaborative Center (V2C2), Pharmacogenomics of HIV Therapy, NATIENS: A Phase III Randomized Double Blinded Study to Determine the Mechanisms and Optimal Management of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
OpenAlex ID: W4413491754