Research

Specific Research Projects
Project I: Pyroptosis and immunity
Infectious disease is one of the major cause of illness and the second leading cause of death world-wide. Understanding the host’s responses to microbes is fundamental to prevent and treat infectious diseases. Many disease-causing microbes release factors which kill macrophages to inhibit immune responses. We found that anthrax lethal toxin and components from influenza A virus cause rapid macrophage cell death known as “pyroptosis” which is induced by defective mitochondria. To date, the role and mechanism of pyroptosis are largely unknown. This research project examines the signaling/molecular mechanism of pyroptosis in macrophages and its role in anthrax and influenza A virus infections. Information obtained through this research will provide new therapeutic strategies in harnessing pyroptosis during bacterial and viral infections.
	LeTx rapidly induces pyroptosis through mitochondrial condensation and degradation. Mitochondrial localization of GFP-Bnip3L were visualized using confocal microscope in RAW264.7 cells after treating LeTx for 2 and 3 h in the presence or absence of proteasome inhibitor MG132 (20 µM). LeTx induced condensation or aggregation of Bnip3L (green) in mitochondrial membrane as early as 2 h post-LeTx treatment. Mitochondrial fusion or aggregation of fragmented mitochondria (arrow) was also readily detected in LeTx-treated cells before cytolysis. Mitochondrial potential (red) was greatly reduced after 3 h LeTx treatment
Project II: Epigenetic immune regulation by histone deacetylase 8 in macrophages
Epigenetics is a cellular mechanism that inheritably regulates gene expression without altering genomic DNA sequences during development and cell differentiation. Recent intense studies have focused on its role in development and cancers; however, much less information is available on its role in immune responses. Macrophages are key immune cells residing in all tissues, and play a key role in directly killing microbes and orchestrating subsequent immune responses. We found that a protein known as histone deacetylase (HDAC) 8 plays a key role in modulating macrophages in releasing inflammatory mediators known as cytokines. This study examines the mechanism of HDAC8 in regulating macrophage function and its role in bacterial infections. This research will provide fundamental and detailed insights how our immune cells interact with microbes through HDAC8, and the information obtained through this research will provide new strategies for treating various infectious and inflammatory diseases.
	A proposed mechanism of HDAC8 in immune suppression induced by anthrax lethal toxin (LeTx) and other virulence factors. Activation of PRRs by microbial components induce innate immune responses through activating various signaling modules including MAPKs, NF-κB and the inflammasome. However, various microbial virulence factors (bold italics) inhibit immune responses through targeting these signaling molecules. LeTx inhibits both TLR and NLR signaling events through preventing MAPKs and pyroptosis, respectively. HDAC8 plays a key role in immune suppression induced by LeTx, through targeting H3K27Ac and preventing enhancer activities.
Project III: Investigating the mechanisms of immunomodulatory effects of probiotics.
Commensal microbes live inside the host in symbiosis. Probiotics are live commensals that have been used for centuries to replenish normal or beneficial gut and urogenital microflora. This research project is to understand how the host maintains immunological symbiosis with commensals and what immunological effects probiotics have on the host. We found that the probiotic strain of Lactobacillus rhamnosus GR1 (GR1) and its secreted products have immunomodulatory effects on macrophages, dendritic cells, intestinal lamina propria cells and placental trophoblasts. GR1 as well as other strains of Lactobacillus rhamnosus preferentially and potently produce the immunomodulatory cytokine granulocyte colony-stimulating factor (G-CSF) in these cells, which may play important roles in maintaining immunological homeostasis of intestine and placenta. This research proposal is to further study the cellular and signaling mechanisms by which GR1, GR1-secreted factor(s) and G-CSF in modulating macrophage differentiation, activation and survival. Information obtained through this study will provide detailed information on how lactobacilli modulate macrophage activation and how G-CSF highly produced by lactobacillus-exposed macrophages affects myeloid cell differentiation, cell survival and gut homeostasis.
Martins A, Han J, Kim SO. IUBMB Life. 2010	Model of the role of G-CSF in the intestine. G-CSF may exert immunomodulatory effects in the intestine through multiple mechanisms. Intestinal G-CSF may be produced by macrophages or subepithelial myofibroblasts, induced or modulated by luminal bacteria or endogenous factors such as serum amyloid A (SAA). G-CSF can then act locally to strengthen the barrier protecting epithelial cells from injury-induced apoptosis and stimulating neutrophil effector function to aid in the clearance of translocated bacteria. At the same time, G-CSF may have immunoregulatory effects on macrophages, dendritic cells, as well as Th1 and Th17 responses.