Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor

Abstract

Burkholderia pseudomallei is a Gram-negative soil bacterium that infects both humans and animals. Although cell culture studies have revealed significant insights into factors contributing to virulence and host defense, the interactions between this pathogen and its intact host remain to be elucidated. To gain insights into the host defense responses to B. pseudomallei infection within an intact host, we analyzed the genome-wide transcriptome of infected Caenorhabditis elegans and identified ∼6% of the nematode genes that were significantly altered over a 12-h course of infection. An unexpected feature of the transcriptional response to B. pseudomallei was a progressive increase in the proportion of down-regulated genes, of which ELT-2 transcriptional targets were significantly enriched. ELT-2 is an intestinal GATA transcription factor with a conserved role in immune responses. We demonstrate that B. pseudomallei down-regulation of ELT-2 targets is associated with degradation of ELT-2 protein by the host ubiquitin-proteasome system. Degradation of ELT-2 requires the B. pseudomallei type III secretion system. Together, our studies using an intact host provide evidence for pathogen-mediated host immune suppression through the destruction of a host transcription factor.innate immunity | ubiquitin-proteosomal system

GATA transcription factor as a likely key regulator of the Caenorhabditis elegans innate immune response against gut pathogens

“…Such expression analyses have been performed with mutants of the p38 MAPK, JNK MAPK, TGF-␤ and the ILR cascades (for example pmk-1(km25) for p38 MAPK (Bond et al, 2014), jun-1(gk557) for JNK (Uno et al, 2013), dbl-1(ctIs40) overexpression for TGF-␤ (Roberts et al, 2010) and daf-16(mu86) for ILR (Murphy et al, 2003)). Similar expression analysis was performed for mutants of GATA transcription factors, including a mutant for the GATA transcription factor gene elt-2, which is known to contribute to immunity against some gut-infecting pathogens such as Pseudomonas aeruginosa, Salmonella typhimurium, Enterococcus faecalis, Cryptococcus neoformans or Burkholderia pseudomallei (Kerry et al, 2006;Shapira et al, 2006;Lee et al, 2013). ELT-2 is the major transcriptional regulator in the C. elegans intestine, controlling the constitutive expression of most of the genes necessary for maintenance of intestinal function (McGhee et al, 2009).…”

Detection of Burkholderia pseudomallei toxin-mediated inhibition of protein synthesis using a Caenorhabditis elegans ugt–29 biosensor

“…Lee et al 4. had previously demonstrated that ugt–29 was the most robustly induced C. elegans phase II detoxification gene following B. pseudomallei infection of worms.…”

Novel multi-component vaccine approaches for Burkholderia pseudomallei

“…The inability of antibody to provide high-level protection against B. pseudomallei may also reflect the intracellular lifestyle of the organism. In contrast, there is evidence from studies in Caenorhabditis elegans that the bacterium might recruit the ubiquitin-proteasome system to degrade a GATA transcription factor required for host immune defence [85]. Manipulation of the major histocompatibility complex (MHC) class I processing pathway is a common mechanism by which viral pathogens avoid the induction of protective CD8 + T cell responses [82,83].…”