Our group is interested in studying bacterial-host interactions, particularly the role of bacterial proteins that promote disease. These proteins may modify host cell signaling to aid replication, allow the pathogen to subvert the immune response, or enable colonization of the host and abiotic surfaces in a hospital setting. We apply integrated molecular and cellular approaches to characterize these bacterial molecules and how they modulate cellular functions to contribute to disease in both humans and animals.
Brucella targeting of cellular functions
Brucella is the cause of an important zoonotic disease worldwide, still endemic in many countries and re-emerging in wildlife. Brucella can replicate extensively within host cells by tightly controlling cellular functions. This occurs partly via a type IV secretion system (T4SS) that enables the translocation of bacterial proteins inside host cells. The identity and function of these proteins remain mostly uncharacterized.
We have several ongoing projects to characterize novel Brucella effector proteins exported into host cells during infection and identify the cellular signaling pathways targeted. We have recently identified an effector modulating endoplasmic reticulum-associated degradation (Luizet et al. PNAS 2021) and two others targeting the host nuclei, impacting the subcellular localization of nuclear proteins (Louche et al. Nat Communications 2023). We are combining molecular, biochemical and cellular approaches to determine their function, mode of action, cellular targets, and identify key functional domains.
A new intracellular niche for A. baumannii clinical strains
Most A. baumannii strains remain extracellular or are quickly degraded by host cells. Our recent work suggests that a few clinical strains are highly invasive, and some can efficiently multiply inside cells (Rubio et al. 2022). These include some strains designated as “hypervirulent” because they were associated with exceptionally high mortality rates in recent hospital outbreaks. Yet the host responses elicited by these strains, the bacterial factors involved and the impact of an intracellular niche on the host’s ability to counteract A. baumannii remain unknown.
We are investigating the host responses to different A. baumannii strains (extracellular vs. intracellular), in vitro and in vivo, combining cell biology and immunology-based assays. We also aim to identify the bacterial factors implicated using targeted approaches and genome-wide screens.
Bacterial TIR domain-containing proteins in pathogenesis
We are actively characterizing and comparing TIR-containing proteins from a select group of bacteria. The Toll/Interleukin-1 receptor (TIR) domain is a conserved intracellular domain present on TLR receptors and is shared by the downstream adaptor molecules. TLRs recognize pathogen-associated molecular patterns (PAMPs) and are essential for TLR signaling and innate immunity.
Bacterial TIR effectors have been implicated in the virulence of Brucella spp. and uropathogenic E. coli, highlighting their relevance in disease progression. We have characterized the role of PumA, involved in multi-drug resistant Pseudomonas aeruginosa PA7 virulence by controlling both TLR adaptors and cytokine receptor trafficking (Imbert et al. EMBO Journal 2017).
More recently, NADase activity has been assigned to TIR domains, and we have confirmed that translocated Brucella TIR effectors retain this activity, resulting in NAD depletion during infection (Coronas-Serna et al. PLoS Pathogens, 2019). We are currently investigating how bacterial TIR proteins are secreted and their regulation upon antibiotic treatment.
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