Siglecs are members of lg superfamily lectins that recognize sialoside-containing structure. We have recently reported that CD24-Siglec G/10 interaction regulates inflammatory responses to danger-associated (DAMPs) but not pathogen-associated (PAMPs) molecular patterns and proposed this interaction as the foundation for self-nonself discrimination in innate immunity. However, since exposure to PAMPs may also cause release of DAMPs, it is challenging to distinguish septic from aseptic injuries. This paradox is partially reconciled by our recent discovery that sialidases encoded by pathogens disrupt the CD24-Siglec G interaction and exacerbate inflammation. However, this notion only applies to sialidase-producing pathogens. In order to expand the original concept to infections by non-sialidase-producing microbes, we hereby hypothesize that host sialidases are mobilized by PAMPs to disrupt sialoside-based pattern recognition. This hypothesis is supported by our preliminary data that a novel sialidase inhibitor 2,3-dehydro-2-deoxy-N-glycolylneuraminic acid (NeuGC2en) conferred 100% protection against lethal endotoxic shock. Since endotoxin has no microbes-derived sialidase, the inhibitor has to target the host sialidase. Therefore, the first ai of the study is to identify the host sialidase responsible for exacerbating inflammation. In addition, since the inhibitor protects WT, CD24-/- and Siglecg-/- mice equally well, its therapeutic effect must be independent of CD24-Siglec G interaction.
Our second aim i s therefore to identify the Siglec responsible protection against endotoxic shock. Our proposed studies will not only expand the horizon of sialoside-based pattern recognition in self-nonself discrimination in innate immune response, but also suggest novel therapeutic approaches for endotoxic shock, which is a major unmet medical challenge.

Public Health Relevance

Despite availability of antibiotics, the mortality and hospitalization of severe sepsis increased rapidly between 1993 and 2003, causing approximately 200,000 annual deaths in US alone. A major proportion of septic shock was caused by endotoxin (LPS)-producing gram-negative bacteria. Our proposed studies may provide a novel therapeutic approach for septic shock.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI105727-01A1
Application #
8770184
Study Section
Innate Immunity and Inflammation (III)
Program Officer
Minnicozzi, Michael
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Research Institute
Department
Type
DUNS #
City
Washington
State
DC
Country
United States
Zip Code
20010
Chen, Guo-Yun; Brown, Nicholas K; Zheng, Pan et al. (2014) Siglec-G/10 in self-nonself discrimination of innate and adaptive immunity. Glycobiology 24:800-6
Chen, Guo-Yun; Brown, Nicholas K; Wu, Wei et al. (2014) Broad and direct interaction between TLR and Siglec families of pattern recognition receptors and its regulation by Neu1. Elife 3:e04066