Advances in genetically engineered and humanized mouse models for dissecting sepsis mechanisms and therapeutic response.

Abstract

Sepsis remains a major cause of global mortality, yet translation from preclinical studies to effective targeted therapies has been limited. A key barrier is that conventional animal models incompletely capture human immune circuitry and patient heterogeneity. Recent progress in mouse genetics, CRISPR/Cas-based genome editing, conditional alleles (Cre-loxP), and next-generation humanized platforms has expanded the toolkit for functional interrogation of host pathways that shape sepsis outcomes. Germline and cell-type-restricted perturbations have helped map roles for pattern-recognition signaling, inflammasome modules, cell-death effectors, and immune checkpoints, while also showing that the same pathway can produce different phenotypes depending on cellular context. Cross-species differences in innate immune gene networks and caspase biology motivate validation in humanized systems and integration with human genetic evidence. Emerging "wildling" and genetically diverse panels provide complementary approaches to model environmental exposure and host variation. Coupling these platforms with single-cell multi-omics and endotype stratification can link genotype-to-phenotype mechanisms with biomarker-informed therapeutic testing.