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<p>Host genetic background plays a decisive role in susceptibility to pathogens, and hybrid offspring often exhibit heterosis that surpasses parental phenotypes. However, the underlying regulatory mechanisms remain poorly understood. In this study, we generated an F1 hybrid mouse model by crossing highly susceptible BALB/c mice (maternal strain) with resistant C57BL/6 mice (paternal strain) to systematically investigate the immune regulatory strategies underlying heterosis during <i>Mycobacterium tuberculosis</i> infection. Our results demonstrate that F1 hybrid mice display pronounced heterosis following infection, characterized by a significantly reduced pulmonary bacterial burden, attenuated pathological damage, and enhanced infiltration of innate immune cells, particularly natural killer cells. Transcriptome sequencing (RNA-seq) revealed that F1 hybrids integrate parental genetic information via parent-of-origin effects: maternally expressed genes were predominantly enriched in signal transduction and immune dysregulation pathways, whereas paternally expressed genes were significantly associated with metabolic processes and homeostatic maintenance. Furthermore, by integrating padlock probe&#xa0;based single-nucleotide polymorphism (SNP) in situ hybridization, we demonstrate that this allelic expression bias is highly cell type&#xa0;specific. Notably, in infection-recruited macrophages and neutrophils, key genes such as <i>Plin2</i> (lipid metabolism) and <i>Tap2</i> (antigen presentation) exhibited a pronounced paternal allele&#xa0;biased expression pattern. Collectively, our findings indicate that hybrid offspring achieve coordinated optimization of immune defense and metabolic homeostasis by preferentially utilizing paternally derived genetic information within specific innate immune cell populations. This study provides new insights into the genetic basis of infectious disease susceptibility and the molecular mechanisms underlying heterosis.</p>

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Deciphering the immune heterosis mechanism against Mycobacterium tuberculosis infection in hybrid mice based on allele-specific expression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月27日

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  • Haoqi Wang,
  • Xianglong Shi,
  • Jinxia Dai,
  • Gang Cao,
  • Xiaofeng Wu

摘要

Host genetic background plays a decisive role in susceptibility to pathogens, and hybrid offspring often exhibit heterosis that surpasses parental phenotypes. However, the underlying regulatory mechanisms remain poorly understood. In this study, we generated an F1 hybrid mouse model by crossing highly susceptible BALB/c mice (maternal strain) with resistant C57BL/6 mice (paternal strain) to systematically investigate the immune regulatory strategies underlying heterosis during Mycobacterium tuberculosis infection. Our results demonstrate that F1 hybrid mice display pronounced heterosis following infection, characterized by a significantly reduced pulmonary bacterial burden, attenuated pathological damage, and enhanced infiltration of innate immune cells, particularly natural killer cells. Transcriptome sequencing (RNA-seq) revealed that F1 hybrids integrate parental genetic information via parent-of-origin effects: maternally expressed genes were predominantly enriched in signal transduction and immune dysregulation pathways, whereas paternally expressed genes were significantly associated with metabolic processes and homeostatic maintenance. Furthermore, by integrating padlock probe based single-nucleotide polymorphism (SNP) in situ hybridization, we demonstrate that this allelic expression bias is highly cell type specific. Notably, in infection-recruited macrophages and neutrophils, key genes such as Plin2 (lipid metabolism) and Tap2 (antigen presentation) exhibited a pronounced paternal allele biased expression pattern. Collectively, our findings indicate that hybrid offspring achieve coordinated optimization of immune defense and metabolic homeostasis by preferentially utilizing paternally derived genetic information within specific innate immune cell populations. This study provides new insights into the genetic basis of infectious disease susceptibility and the molecular mechanisms underlying heterosis.