A zebrafish leprosy model identifies interferon and plasminogen signaling as survival determinants in mycobacterial infection

A recent study has identified two key factors that determine survival in mycobacterial infections, using zebrafish as a model organism. Leprosy, caused by Mycobacterium leprae, is a skin and nerve infection with many associated genes whose functions remain unclear. Traditional animal models lack the genetic flexibility and disease recapitulation needed for research. However, zebrafish exhibit human-like responses to M. leprae, including inflammation and neurodegeneration, making them a promising model.

Researchers used RNA sequencing to examine gene expression in chronically infected adult zebrafish, identifying regulated zebrafish orthologs of human leprosy-associated genes, such as interferon, IL-6, IL-10, IL-4, TNF superfamily members, and others previously not linked to leprosy. Tuberculoid leprosy (T-lep) genes were largely downregulated, while lepromatous leprosy (L-lep) genes were upregulated. Pathway differences were observed between early and late infection stages.

In rag1 mutant zebrafish, lacking T and B cells, T-lep genes were downregulated, indicating that adaptive immunity is necessary for their expression. To validate key pathways and genes, researchers used qPCR with zebrafish infection by M. marinum:PGL-1, a model pathogen capable of expressing M. leprae genes. Multiplex CRISPR was employed to simultaneously mutate multiple zebrafish genes, screening 17 genes and identifying isg15 and serpine1 as those increasing mortality in infections.

These findings confirm that type I interferon and plasminogen activation are crucial for survival in mycobacterial diseases in both humans and zebrafish, and demonstrate the potential of multiplex CRISPR in identifying host defense mediators in vivo.