Biology subjects

Steinfeldt, T.

Publications and source records attributed to Steinfeldt, T..

3 recordsLinked to original sources

bioRxiv2023

Dual role of Toxoplasma gondii ROP5 and ROP18 for NLRP3 inhibition

Inflammasome activation leads release of IL-1{beta}, a proinflammatory cytokine that drives antimicrobial immune responses. Toxoplasma gondii has been shown to activate the NLRP3 inflammasome but the trigger has not yet been identified. Here we provide evidence that vacuolar disruption is a prerequisite for NLRP3 activation. T. gondii type I ROP5 and ROP18 protect the parasitophorous vacuolar membrane (PVM) and thereby inhibit inflammasome activation and IL-1{beta} release. Besides protection of the PVM, we demonstrate an additional function of ROP5 and ROP18 for NLRP3 inhibition. We demonstrate the molecular mechanism of this inhibition includes direct interaction with GBP5. In conclusion, T. gondii ROP5 and ROP18 inhibit IL-1{beta} production by protection of the intracellular replicative niche of the parasite and by actively subverting NLRP3 activation. Our findings provide further insight into the intricate mechanisms governing inflammasome activation and inhibition, enhancing our understanding of the complex dynamics during T. gondii infection. O_FIG O_LINKSMALLFIG WIDTH=155 HEIGHT=200 SRC="FIGDIR/small/558105v1_ufig1.gif" ALT="Figure 1"> View larger version (78K): org.highwire.dtl.DTLVardef@10a71b2org.highwire.dtl.DTLVardef@ae753eorg.highwire.dtl.DTLVardef@19365e7org.highwire.dtl.DTLVardef@74d9c_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

IFN-lambda is protective against lethal oral Toxoplasma gondii infection

Interferons are essential for innate and adaptive immune responses against a wide variety of pathogens. Interferon lambda (IFN-{lambda}) protects mucosal barriers during pathogen exposure. The intestinal epithelium is the first contact site for Toxoplasma gondii (T. gondii) with its hosts and the first defense line that limits parasite infection. Knowledge of very early T. gondii infection events in the gut tissue is limited and a possible contribution of IFN-{lambda} has not been investigated so far. Here, we demonstrate with systemic interferon lambda receptor (IFNLR1) and conditional (Villin-Cre) knockout mouse models and bone marrow chimeras of oral T. gondii infection and mouse intestinal organoids a significant impact of IFN-{lambda} signaling in intestinal epithelial cells and neutrophils to T. gondii control in the gastrointestinal tract. Our results expand the repertoire of interferons that contribute to the control of T. gondii and may lead to novel therapeutic approaches against this world-wide zoonotic pathogen.

immunology↗

bioRxiv2021

A Novel in vitro Model for Mature Toxoplasma gondii Bradyzoites Reveals their Metabolome and a Diminished Role of the Mitochondrial Tricarboxylic Acid Cycle

The apicomplexan parasite Toxoplasma gondii forms bradyzoite-containing tissue cysts that cause chronic and drug-tolerant infections. However, current in vitro models do not allow long-term culture of these cysts to maturity. Here, we developed a human myotube-based in vitro culture model of functionally mature tissue cysts that are orally infectious to mice and tolerate exposure to a range of antibiotics and temperature stresses. Metabolomic characterization of purified cysts reveals global changes that comprise increased levels of amino acids and decreased abundance of nucleobase- and tricarboxylic acid cycle-associated metabolites. In contrast to fast replicating tachyzoite forms of T. gondii these tissue cysts tolerate exposure to the aconitase inhibitor sodium fluoroacetate. Direct access to persistent stages of T. gondii under defined cell culture conditions will be essential for the dissection of functionally important host-parasite interactions and drug evasion mechanisms. It will also facilitate the identification of new strategies for therapeutic intervention.

microbiology↗