Sepsis poses grave health concerns with no effective prevention or cure. The key stumbling block is the highly complex nature of the disrupted innate leukocyte homeostasis. Disrupted sepsis monocyte homeostasis is reflected in a dramatic early upswing of inflammatory processes followed by a late-phase compensatory tolerance. Disrupted neutrophil homeostasis in sepsis patients is cardinally represented by ?migratory paralysis? in which septic neutrophils lose migratory potential toward bacterial products while retaining migration toward sterile tissues, due to preferential reduction of FPR2 and induction of CCR5. Septic neutrophils also have reduced potential for generating neutrophil extra-cellular trap (NET). Collectively, these disrupted innate leukocyte homeostasis may compromise host defense and exacerbate multi-organ inflammation. However, mechanisms underlying monocyte priming and neutrophil paralysis are poorly understood. Due to their highly dynamic natures, current experimental systems in vitro or animal models in vivo fail to properly capture the disrupted leukocyte homeostasis. The PI?s past systems analyses with experimental and computational approaches reveal a model system that recapitulates the disrupted human leukocyte homeostasis in vitro and in vivo by applying subclinical super-low dose lipopolysaccharide (LPS). In sharp contrast to the effects of widely used higher dosages LPS which preferentially facilitate monocyte tolerance, Dr. Li?s lab documented that super- low dose LPS ?primes? monocytes for prolonged ?run-away? inflammation. In addition, Li lab observed that super- low dose LPS ?programs? neutrophils into a paralytic state, mimicking septic neutrophils with reduced FPR2, reduced potential of bacterial killing and elevated CCR5. Monocyte priming and neutrophil paralysis by super- low dose LPS can be observed in human blood leukocyte ex vivo. With the cecal ligation and puncture sepsis model, Li lab demonstrated exacerbated sepsis mortality in mice pre-conditioned with super-low dose LPS. Mechanistically, Li lab observed that super-low dose LPS potently reprograms monocytes and neutrophils by disrupting key homeostatic events and molecules. Based on these intriguing observations, the long-term goal is to understand the disrupted innate immune dynamics responsible for the elevated morbidity and mortality of sepsis. As a crucial first step, our key objective is to better understand the mechanisms responsible for the disrupted homeostasis in monocytes and neutrophils. This project plans to test the central hypothesis that monocyte priming and neutrophil paralysis during sepsis are caused by the disruption of key homeostatic molecules and processes.
Aim 1 will test the hypothesis that the disruption of homeostatic molecules such as RelB is responsible for the monocyte priming conducive for increased sepsis mortality.
Aim 2 will reveal the fundamental cellular and molecular mechanisms responsible for neutrophil paralysis.
Aim 3 will test whether that alteration of leukocyte dynamics may exacerbate, while restoration of leukocyte homeostasis may attenuate sepsis pathogenesis.

Public Health Relevance

The goal of this project is to characterize novel mechanisms underlying the disrupted homeostasis of innate monocytes and neutrophils, as well as a novel strategy to modulate innate leukocyte homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI136386-02
Application #
9600056
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Minnicozzi, Michael
Project Start
2017-11-15
Project End
2022-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Virginia Polytechnic Institute and State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24061