Cross-species blood transcriptional correlates of BCG-mediated protection against tuberculosis include innate and adaptive immune processes
Name
194450.2-20251230152444-covered-4fa089109ce452e764bbb8648b44a723.pdf
Description
Published version
Size
5.23 MB
Format
Adobe PDF
Checksum (MD5)
a64a5749fe0301f71e0d7db8527bb982
Author(s)
Bridges, Kate
Awany, Denis
Gela, Anele
Mwambene, Temwa-Dango
Kurtz, Sherry L
Baker, Richard E
Elkins, Karen L
Sassetti, Christopher M
Scriba, Thomas J
Lauffenburger, Douglas A
Date Issued
November 25, 2025
Journal
JCI Insight
Publisher
American Society for Clinical Investigation
Version
Final published version
Abstract
The immune mechanisms induced by the Bacillus Calmette-Guérin (BCG) vaccine, and the subset of which that mediate protection against tuberculosis (TB), remain poorly understood. This is further complicated by difficulties in verifying vaccine-induced protection in humans. Although research in animal models, namely mice and nonhuman primates (NHPs), has begun to close this knowledge gap, discrepancies in the relative importance of biological pathways across species limit the utility of animal model–derived biological insights in humans. To address these challenges, we applied a systems modeling framework, Translatable Components Regression (TransCompR), to identify human blood transcriptional variability that could predict Mycobacterium tuberculosis challenge outcomes in BCG-vaccinated NHPs. These protection-associated pathways included both innate and adaptive immune activation mechanisms, along with signaling via type I IFNs and antimycobacterial Th cytokines. We further partially validated the associations between these mechanisms and protection in humans using publicly available microarray data collected from BCG-vaccinated infants who either developed TB or remained healthy during 2 years of follow-up. Overall, our work demonstrates how species translation modeling can leverage animal studies to generate hypotheses about the mechanisms that underlie human infectious disease and vaccination outcomes, which may be difficult or impossible to ascertain using human data alone.
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DOI of Published Version
https://doi.org/10.1172/jci.insight.194450
