(Forum, Oct 24) To See the Unseen: Intravital imaging reveals key immune defense mechanisms against bloodstream bacterial infection & Management of Leukemia from Metabolic Perspectives


 Title I: To See the To See the Unseen: Intravital imaging reveals key immune defense mechanisms against bloodstream bacterial infection
Speaker: Post Dr. Zhutian Zeng(University of Calgary)
Venue: Room 513, Building B2, University Town Campus
Time: OCT. 24, Wednesday, 14:00-17:00
Abstract: Bloodstream bacterial infection is on the rise due to the wide spread use of indwelling intravenous catheters and immunosuppressive iatrogenic interventions. First-pass clearance of blood-borne bacteria is critical to control bloodstream infections and to prevent systemic dissemination. The liver has been well known as a blood-filtering organ capable of sequestering circulating bacteria via its vast pool of intravascular macrophages-Kupffer cells. However, the molecular mechanism underlying Kupffer cell mediated capture of circulating pathogens under shear conditions remains less understood. Taking advantage of high-speed real time intravital imaging, we visualized the dynamic process of bacterial capture by Kupffer cells, and revealed novel mechanisms utilized by Kupffer cells to catch bacteria. We observed a pattern recognition role for complement receptor-CRIg in the capture of circulating Gram-positive bacteria from the bloodstream by directly binding to the Lipoteichoic Acid (LTA) of Gram-positive bacteria, such as S. aureus. We also observed a sex-biased difference of Kupffer cells in capture circulating enteropathogenic E. coli (EPEC). While complement opsonization was indispensable for the capture of EPEC in male mice; however, a faster, complement-independent process involving abundant preexisting antibodies to EPEC was detected in female mice. These antibodies were elicited predominantly in female mice at puberty in response to estrogen regardless of microbiota-colonization conditions. Estrogen-driven antibodies were maternally transferrable to offspring and conferred protection during infancy. Thus, an estrogen-driven, innate antibody-mediated immunological strategy conferred protection to females and their offspring.
Title II: Management of Leukemia from Metabolic Perspectives
Speaker: Post Dr. Haobin Ye(University of Colorado)
Venue: Room 513, Building B2, University Town Campus
Time: OCT. 24, Wednesday, 14:00-17:00
Obese leukemia patients have a poorer prognosis compared to normal weight patients, suggesting that obesity-associated conditions protect leukemia cells/leukemia stem cells (LSCs) from chemotherapy. Further, obese population have a higher risk for leukemia, indicating that obesity promotes disease development and progression. However, the biological mechanisms underlying these phenomena remain unknown. In today’s presentation, the author introduces two studies that reveal the mechanisms for the phenomena mentioned above.
The first study has demonstrated that adipose tissue functions as a sanctuary for LSCs. Briefly, LSCs are found to be enriched in adipose tissue. Tranome comparisons show that compared to hematopoietic tissue-resident LSCs, adipose-resident LSCs display a pro-inflammatory gene signature, which leads to an inflamed state in adipose tissue, and consequently an increased lipolysis rate as evidenced by elevated serum fatty acids level. Lipolysis-derived fatty acids are utilized by two distinct pathways: 1) fatty acids-induced inflammation pathway and 2) fatty acid oxidation (FAO) pathway. Interestingly, a LSC subpopulation that has a high-level expression of the fatty acid transporter CD36 (CD36+ LSCs) displays a significantly higher FAO rate compared to CD36- LSCs and is strikingly enriched in adipose tissue. Further, CD36+ LSCs are more chemo-resistant compared to CD36- LSCs partially due to CD36-mediated FAO. More importantly, a CD36+ LSC subpopulation is also observed in primary human leukemia patient samples. Human CD36+ LSCs display a higher FAO rate and are chemo-resistant compared to CD36- LSCs. Collectively, this study shows that the interplay between leukemia cells and adipose tissue creates a unique microenvironment that supports the metabolic demands and survival of a distinct LSC population.
The second study demonstrates that leukemic disease causes aberrancies in multiple tissues including adipose tissue, pancreas, gut and gut microbiota to subvert the systemic glucose metabolism to support growth of leukemia cells. Briefly, leukemia mice are found to have characteristics of both type 2 and type 1 diabetes: insulin resistance and insulin defect, conditions that inhibit glucose utilization in normal tissues. Mechanistically, leukemia induces a high-level production of IGFBP1 from adipose tissue, which results in insulin resistance. Further, leukemic disease impairs gut functions causing loss of gut-derived serotonin and dysbiosis. Serotonin loss results in inhibition of insulin secretion and dysbiosis leads to insulin resistance and less production of microbiota-derived short chain fatty acids (SCFAs) such as butyrate and propionate. Supplementation of serotonin or SCFAs impedes leukemia progression. Importantly, combination of serotonin and SCFAs supplementations drastically reduce leukemic burden and prolong survival of leukemic mice by directly increasing the uptake and utilization of glucose in normal tissues. Together, these data demonstrate that restoration of normal glucose regulation may be a feasible strategy to suppress systemic growth of malignant cell types.
Taking together, these two studies suggest that interventions by targeting either intracellular metabolism of LSCs or systemic metabolism are effective means for disease management.

Announced by School of Matreials Science and Engineering