Biology subjects

Lu, K.-Y.

Publications and source records attributed to Lu, K.-Y..

5 recordsLinked to original sources

bioRxiv2024

A host-directed adjuvant resuscitates and sensitizes intracellular bacterial persisters to antibiotics

There are two major problems in the field of antimicrobial chemotherapy-antibiotic resistance and antibiotic tolerance. In the case of antibiotic tolerance, antibiotics fail to kill the bacteria as their phenotypic state affords them protection from the bactericidal activity of the antibiotic. Antibiotic tolerance can affect an entire bacterial population, or a subset of cells known as persister cells. Interaction with the host induces the formation of persister cells in numerous pathogens, with reactive oxygen and nitrogen species production being heavily implicated in the collapse of bacterial energy levels and entrance into an antibiotic tolerant state. Here, we developed a high-throughput screen to identify energy modulators for intracellular Staphylococcus aureus. The identified compound, KL1, increases intracellular bacterial energy and sensitizes the persister population to antibiotics, without causing cytotoxicity or bacterial outgrowth. We demonstrate that KL1 exhibits adjuvant activity in a murine model of S. aureus bacteremia and intracellular infection of Salmonella Typhimurium. Transcriptomic analysis and further studies on its mechanism of action reveal that KL1 modulates host immune response genes and suppresses the production of reactive species in host macrophages, alleviating one of the major stressors that induce antibiotic tolerance. Our findings highlight the potential to target intracellular persister cells by stimulating their metabolism and encourage larger efforts to address antibiotic tolerance at the host-pathogen interface, particularly within the intracellular milieu.

microbiology↗

bioRxiv2023

A Weakly Supervised U-Net Model for Precise Whole Brain Immunolabeled Cell Detection

Cell segmentations low precision due to the intensity differences hinders widespread use of whole brain microscopy imaging. Previous studies used ResNet or CNN to account for this problem, but are unapplicable to immunolabeled signals across samples. Here we present a semiauto ground truth generation and weakly-supervised U-Net-based Deep-learning precise segmentation pipeline for whole brain immunopositive c-FOS signals, which reveals the distinct neural activity maps with different social motivations.

neuroscience↗

bioRxiv2022

Inflammasome-mediated glucose limitation induces antibiotic tolerance in Staphylococcus aureus

Staphylococcus aureus is a leading human pathogen that frequently causes relapsing infections. Host-pathogen interactions have been shown to have substantial impacts on antibiotic susceptibility and the formation of antibiotic tolerant cells. In this study, we interrogate how a major S. aureus virulence factor, -toxin, interacts with macrophages to alter the microenvironment of the pathogen, thereby influencing its susceptibility to antibiotics. We find -toxin-mediated activation of the NLRP3 inflammasome induces antibiotic tolerance in the host cell cytoplasm. Induction of antibiotic tolerance is driven by increased glycolysis in the host cells, resulting in glucose limitation and ATP depletion in S. aureus. Additionally, inhibition of NLRP3 activation improves antibiotic efficacy in vitro and in vivo. Our findings identify interactions between S. aureus and the host that result in metabolic crosstalk that can determine the outcome of antimicrobial therapy.

microbiology↗

bioRxiv2020

A Systematic Analysis of Mosquito-Microbiome Biosynthetic Gene Clusters Reveals Antimalarial Siderophores that Reduce Mosquito Reproduction Capacity

Advances in infectious disease control strategies through genetic manipulation of insect microbiomes have heightened interest in microbially produced small molecules within mosquitoes. Herein, 33 mosquito-associated bacterial genomes were mined and over 700 putative biosynthetic gene clusters (BGCs) were identified, 135 of which belong to known classes of BGCs. After an in-depth analysis of the 135 BGCs, iron-binding siderophores were chosen for further investigation due to their high abundance and well-characterized bioactivities. Through various metabolomic strategies, eight siderophore scaffolds were identified in six strains of mosquito-associated bacteria. Among these, serratiochelin A and pyochelin were found to reduce female Anopheles gambiae overall fecundity likely by lowering their blood feeding rate. Serratiochelin A and pyochelin were further found to inhibit the Plasmodium parasite asexual blood and liver stages in vitro. Our work supplies a bioinformatic resource for future mosquito microbiome studies and highlights an understudied source of bioactive small molecules.

microbiology↗

bioRxiv2020

Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell death

Phosphatidylinositol 3-phosphate (PI(3)P) levels in Plasmodium falciparum correlate with tolerance to cellular stresses caused by artemisinin, a first-line malaria treatment, and environmental factors. However, the functional role of PI(3)P in the Plasmodium stress response and a possible mechanism of protection were unknown. Here, we used multiple chemical probes including PI3K inhibitors and known antimalarial drugs to examine the importance of PI(3)P under thermal conditions that recapitulate malaria fever. Live cell microscopy using both chemical and genetic reporters revealed that PI(3)P stabilizes the acidic and proteolytic digestive vacuole (DV) under heat stress. We demonstrate that heat-induced DV destabilization in PI(3)P-deficient P. falciparum precedes cell death and is reversible after withdrawal of the stress condition and the PI3K inhibitor. These phenotypes are not observed with an inactive structural analog of the PI3K inhibitor. A chemoproteomic and biochemical approach identified PfHsp70-1 as a parasite PI(3)P-binding protein. Targeting PfHsp70-1 with a small molecule inhibitor phenocopied PI(3)P-deficient parasites under heat shock. Furthermore, tunable knockdown of PfHsp70-1 showed that PfHsp70-1 downregulation causes DV destabilization and hypersensitizes parasites to heat shock and PI3K inhibitors. Our findings underscore a mechanistic link between PI(3)P and PfHsp70-1, and present a novel PI(3)P function in stabilizing the DV compartment during heat stress.

microbiology↗