Biology subjects

Chalasani, S.

Publications and source records attributed to Chalasani, S..

4 recordsLinked to original sources

bioRxiv2024

Toxoplasma gondii PROP1 is critical for autophagy and parasite viability during chronic infection

Macroautophagy is an important cellular process involving lysosomal degradation of cytoplasmic components, facilitated by autophagy-related proteins (ATGs). In the protozoan parasite Toxoplasma gondii, autophagy has been demonstrated to play a key role in adapting to stress and persistence of chronic infection. Despite limited knowledge about the core autophagy machinery in T. gondii, two PROPPIN family proteins (TgPROP1 and TgPROP2) have been identified with homology to Atg18/WIPI. Prior research in acute stage tachyzoites suggests that TgPROP2 is predominantly involved in a non-autophagic function, specifically apicoplast biogenesis, while TgPROP1 may be involved in canonical autophagy. Here, we investigated the distinct roles of TgPROP1 and TgPROP2 in chronic stage T. gondii bradyzoites, revealing a critical role for TgPROP1, but not TgPROP2, in bradyzoite autophagy. Conditional knockdown of TgPROP2 did not impair bradyzoite autophagy. In contrast, TgPROP1 KO parasites had impaired autolysosome formation, reduced cyst burdens in chronically infected mice, and decreased viability. Together, our findings clarify the indispensable role of TgPROP1 to T. gondii autophagy and chronic infection. ImportanceIt is estimated that up to a third of the human population is chronically infected with Toxoplasma gondii; however, little is known about how this parasite persists long term within its hosts. Autophagy is a self-eating pathway that has recently been shown to play a key role in parasite persistence, yet few proteins that carry out this process during T. gondii chronic infection are known. Here, we provide evidence for a non-redundant role of TgPROP1, a protein important in the early steps of the autophagy pathway. Genetic disruption of TgPROP1 resulted in impaired autophagy and chronic infection of mice. Our results reveal a critical role for TgPROP1 in autophagy and underscore the importance of this pathway in parasite persistence.

microbiology↗

bioRxiv2024

TgATG9 is required for autophagosome biogenesis and maintenance of chronic infection in Toxoplasma gondii

Toxoplasma gondii is a ubiquitous protozoan parasite that can reside long-term within hosts as intracellular tissue cysts comprised of chronic stage bradyzoites. To perturb chronic infection requires a better understanding of the cellular processes that mediate parasite persistence. Macroautophagy/autophagy is a catabolic and homeostatic pathway that is required for T. gondii chronic infection, although the molecular details of this process remain poorly understood. A key step in autophagy is the initial formation of the phagophore that sequesters cytoplasmic components and matures into a double-membraned autophagosome for delivery of the cargo to a cells digestive organelle for degradative recycling. While T. gondii appears to have a reduced repertoire of autophagy proteins, it possesses a putative phospholipid scramblase, TgATG9. Through structural modeling and complementation assays, we show herein that TgATG9 can partially rescue bulk autophagy in atg9{Delta} yeast. We demonstrated the importance of TgATG9 for proper autophagosome dynamics at the subcellular level using three-dimensional live cell lattice light sheet microscopy. Conditional knockdown of TgATG9 in T. gondii after bradyzoite differentiation resulted in markedly reduced parasite viability. Together, our findings provide insights into the molecular dynamics of autophagosome biogenesis within an early-branching eukaryote and pinpoint the indispensable role of autophagy in maintaining T. gondii chronic infection.

microbiology↗

bioRxiv2017

Neural mechanisms driving hunger-induced changes in sensory perception and behavior in Caenorhabditis elegans

Animals integrate changes in external and internal environments to generate behavior. While neural circuits detecting external cues have been mapped, less is known about how internal states like hunger are integrated into behavioral outputs. We use the nematode C. elegans to decode how changes in internal nutritional status affects chemosensory behaviors. We show that acute food deprivation leads to a reversible decline in repellent, but not attractant, sensitivity. This behavioral change requires two conserved transcription factors MML-1 (Mondo A) and HLH-30 (TFEB), both of which translocate from the intestinal nuclei to the cytoplasm upon food deprivation. Next, we identify insulin-like peptides INS-23 and INS-31 as candidate ligands relaying food-status signals from the intestine to other tissues. Furthermore, we show that ASI chemosensory neurons use the DAF-2 insulin receptor, PI-3 Kinase, and the mTOR complex to integrate these intestine-released peptides. Together, our study shows how internal food status signals are integrated by transcription factors and intestine-neuron signaling to generate flexible behaviors. Author SummaryWe have all experienced behavioral changes when we are hungry - the pang in our stomach can cause us to behave erratically. In particular, hungry animals, including humans, are known to pursue behaviors that involve higher risk compared to when they are well-fed. Here we explore the molecular details of this behavior in the invertebrate animal model C. elegans. This behavior, termed sensory integration, shows that C. elegans display reduced copper sensitivity when hungry. Copper is toxic and repellant to C. elegans; reduced avoidance indicates that these animals use riskier food search behaviors when they are hungry. Luckily, like us, this behavioral change is reversible upon re-feeding. This hunger-induced behavioral change is not due to increased attraction to food or depletion of fat stores, but rather insulin signaling between the intestine and specific neurons. We use genetic tools, microscopy, and behavioral tests to determine that this risky behavior involves sensation of "lack of food" in the intestine, release of signaling molecules, and engagement with sensory neurons. Our work highlights new and potentially evolutionarily conserved ways in which intestinal cells and neurons communicate leading to largescale behavioral change, providing further support for the importance of the gut-brain-axis.

neuroscience↗

bioRxiv2017

Predator-secreted sulfolipids induce fear-like defense responses in C. elegans

Animals respond to predators by altering their behavior and physiological states, but the underlying signaling mechanisms are poorly understood. Using the interactions between Caenorhabditis elegans and its predator, Pristionchus pacificus, we show that neuronal perception by C. elegans of a predator-specific molecular signature induces instantaneous escape behavior and a prolonged reduction in oviposition. Chemical analysis revealed this predator-specific signature to consist of a class of sulfolipids, produced by a biochemical pathway required for developing predacious behavior and specifically induced by starvation. These sulfolipids are detected by four pairs of C. elegans amphid sensory neurons that act redundantly and recruit cyclic nucleotide-gated (CNG) or transient receptor potential (TRP) channels to drive both escape and reduced oviposition. Specific abolishment of predator-evoked C. elegans responses by the anti-anxiety drug sertraline as well as functional homology of the delineated signaling pathways suggests a conserved or convergent strategy for managing predator threats.

neuroscience↗