Invertebrates, though only relying on innate immunity, have shown an unanticipated ability to mount highly specific responses to invading pathogens. We sought to unravel the molecular mechanisms behind pathogen strain-specific responses by studying the interaction between C. elegans and different strains of the Gram-positive pathogen Bacillus thuringiensis. A transcriptomic analysis identified that 9% of the response to infection is distinct between the two tested pathogen strains (BT18247 and BT18679), which produce different crystal pore-forming toxins. Promoter region motif enrichment analysis revealed the involvement of the GATA transcription factor gene
elt-2 as the central regulator of pathogen strain-specific responses.
elt-2 RNAi knockdown caused high susceptibility to the strain BT18679; yet surprisingly it caused high tolerance to strain BT18247 (i.e., low mortality in spite of high bacterial load). Through epistasis analysis we found that the
p38-MAPK pathway acts either in parallel to or directly interacts with
elt-2 in regulating resistance to BT18679, but is not required for tolerance to BT18247.
elt-2-mediated defense against BT18679 likely depends on the expression of putative immune effectors, such as the saposin-like protein-encoding gene
spp-8. In contrast, the increased tolerance to BT18247 after
elt-2 knockdown is likely due to changes in lipid metabolism and differential regulation of detoxification genes, as evidenced by a transcriptome analysis of
elt-2(RNAi) worms. Moreover, we found that
elt-2 genetically interacts with the nuclear hormone receptors
nhr-99 and
nhr-193 in regulating tolerance to BT247, emphasizing a potential link to lipid metabolism. In conclusion, this study demonstrates that
elt-2 coordinates highly specific interactions between C. elegans and different B. thuringiensis strains. In cooperation with additional host factors,
elt-2 promotes resistance to BT18679 infection, while it negatively regulates tolerance to BT18247. In general, our findings highlight to what extent and how invertebrates can produce highly fine-tuned, pathogen strain-specific defense responses.