TheC.elegansGATA transcription factorelt-2mediates distinct transcriptional responses and opposite infection outcomes towards differentBacillus thuringiensisstrains

The nematodeCaenorhabditis eleganshas been extensively used as a model for the study of innate immune responses against bacterial pathogens. While it is well established that the worm mounts distinct transcriptional responses to different bacterial species, it is still unclear in how far it can fine-tune its response to different strains of a single pathogen species, especially if the strains vary in virulence and infection dynamics. To rectify this knowledge gap, we systematically analyzed theC.elegansresponse to two strains ofBacillus thuringiensis(Bt), MYBt18247 (Bt247) and MYBt18679 (Bt679), which produce different pore forming toxins (PFTs) and vary in infection dynamics. We combined host transcriptomics with cytopathological characterizations and identified both a common and also a differentiated response to the two strains, the latter comprising almost 10% of the infection responsive genes. Functional genetic analyses revealed that the AP-1 component genejun-1mediates the common response to both Bt strains. In contrast, the strain-specific response is mediated by theC.elegansGATA transcription factor ELT-2, a homolog ofDrosophilaSERPENT and vertebrate GATA4-6, and a known master regulator of intestinal responses in the nematode.elt-2RNAi knockdown decreased resistance to Bt679, but remarkably, increased survival on Bt247. Theelt-2silencing-mediated increase in survival was characterized by reduced intestinal tissue damage despite a high pathogen burden and might thus involve increased tolerance. Additional functional genetic analyses confirmed the involvement of distinct signaling pathways in theC.elegansdefense response: the p38-MAPK pathway acts either directly with or in parallel toelt-2in mediating resistance to Bt679 infection but is not required for protection against Bt247. Our results further suggest that theelt-2silencing-mediated increase in survival on Bt247 is multifactorial, influenced by the nuclear hormone receptors NHR-99 and NHR-193, and may further involve lipid metabolism and detoxification. Our study highlights that the nematodeC.eleganswith its comparatively simple immune defense system is capable of generating a differentiated response to distinct strains of the same pathogen species. Importantly, our study provides a molecular insight into the diversity of biological processes that are influenced by a single master regulator and jointly determine host survival after pathogen infection. Author summary Although invertebrates possess a comparatively simple immune system, research over the past decades revealed that a complexity of different signaling processes interact to produce fine-tuned defense responses to various pathogenic challenges. To date, however, it is still largely unexplored to what extent invertebrates generate a differentiated response against different strains of a given pathogen species. Here, we used the nematodeC.elegansas a model to elucidate the common and, importantly, distinct defense responses directed at different strains of the same pathogen taxon,Bacillus thuringiensis(Bt), which vary in infection characteristics. We found that silencing of a single GATA transcriptional regulator causes protection against one Bt strain but sensitization against another. The protection is multifactorial and most likely mediated via tolerance (i.e., ability to limit cellular damage despite high pathogen burden), while sensitization results from decreased resistance (i.e., ability to limit pathogen burden through induction of antimicrobial effectors). Our work demonstrates that invertebrate defense responses against two different strains of the same pathogen species can be distinct, that they likely involve tolerance against one of the strains and are mediated by a single transcription factor as a central master switch.