2025/11/01 by Kirsty M. Hooper · 1 voice
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · #Endoplasmic Reticulum Stress and Disease #Genetics, Aging, and Longevity in Model Organisms #Invertebrate Immune Response Mechanisms
paper · doi:10.1242/dmm.052765
openalex publication_date 2025/11/01 · openalex created_date 2025/11/27 · openalex updated_date 2026/05/06
Host responses to infection are primarily focused on fighting the pathogen, but certain responses aim to reduce the indirect impact of infection on host survival and fitness, known as immune tolerance. Altering lipid metabolism is one such method, but its role in immune tolerance is not fully understood. Bone morphogenetic proteins (BMPs), including DBL-1 in Caenorhabditis elegans, are known to regulate innate immunity and lipid metabolism, but any overlap in these DBL-1-dependent mechanisms has yet to be investigated.In this study, Yamamoto, Savage-Dunn and colleagues exposed wild-type and dbl-1 mutant C. elegans to non-pathogenic Escherichia coli or pathogenic Serratia marcescens to investigate DBL-1/BMP-dependent changes in lipid metabolism. By using Oil Red O fat staining, they determined that the dbl-1 mutants, but not wild types, initially had increased fat stores at 6 h, but by 24 h had significantly decreased intestinal fat stores, following exposure to S. marcescens compared to that following exposure to E. coli control. The authors then found that pathogen exposure in wild-type C. elegans, but not in dbl-1 mutants, altered lipid droplet number and size, which presumably maintained total fat stores.Moving forward, the authors employed RNA sequencing of whole C. elegans to reveal 122 genes that were upregulated in wild-type animals upon pathogen exposure but not in dbl-1 mutants. Interestingly, this category of pathogen-induced BMP-dependent genes was highly enriched for lipid metabolism genes, including genes involved in fatty acid desaturation and elongation, and β-oxidation. The authors then found that maoc-1 mutant C. elegans, with impaired β-oxidation, had no significant defects in survival upon exposure to pathogenic bacteria, suggesting that β-oxidation has only a minor role in immune tolerance. Next, the authors investigated fatty acid desaturases and found that fat-4 fat-1 and fat-6;fat-7 mutant C. elegans had severe decreases in survival when exposed specifically to the pathogenic bacteria. As fat-4 fat-1 and fat-6;fat-7 mutants are deficient in polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs), respectively, the authors supplemented C. elegans with these fatty acids and found that MUFA, but not PUFA, supplementation improved the survival of dbl-1 mutants after exposure to pathogen.This study has revealed a link between the immune and metabolic functions of BMP signalling that is likely to be conserved. It has yet to be conclusively determined whether these changes in lipid metabolism aid host survival by directly fighting the bacteria or through immune tolerance, or a combination of both. Regardless, this research encourages the development of new therapeutic strategies for infectious disease, especially in patients with metabolic disease who have increased risk of severe infections.