PAMPs, DAMPs and SAMPs: Host Glycans are Self‐Associated Molecular Patterns, but subject to Microbial Molecular Mimicry

Abstract

It has long been known that Pathogen-Associated Molecular Patterns (PAMPs, e.g., lipo-oligosaccharides, LOS) and Danger-Associated Molecular Patterns (DAMPs, e.g., fragments of endogenous hyaluronan) can be glycans or modified glycans. We have more recently emphasized that host glycans can also serve as Self-Associated Molecular Patterns (SAMPs), e.g., sialic acid-bearing glycans that are recognized by CD33-related Siglecs on innate immune cells to dampen responses, or by complement Factor H to dampen complement-mediated activation. However, several commensal or pathogenic organisms have evolved successful molecular mimicry of sialylated SAMPs, so as to hijack these mechanisms and suppress innate immune responses against them. Paired activating CD33rSiglecs have emerged in some lineages, presumably to counter hijacking by microbial molecular mimicry of sialylated SAMPs. Meanwhile, sialylated host SAMPs also have to evolve rapidly to escape from other pathogens that utilize them as targets to initiate infection. The ongoing pressures of these often-competing selection forces can explain our finding that the sialic-acid binding domains of CD33rSiglecs and Factor H show much higher than expected Ka/Ks ratios (an excess of non-synonymous substitutions changing encoded amino acids, over synonymous substitutions). Examples can also be found of lineage-specific complete loss of sialic binding e.g., via mutation of an essential arginine residue in some CD33rSiglec binding pocket––or even whole-sale elimination of the binding domain e.g., alternate splicing out of the amino-terminal V-set domain of CD33/Siglec-3. Such evolutionary changes can be either fixed or polymorphic within a given species. Further complexity arises because CD33rSiglec and Factor H can be directly engaged via protein:protein interactions, both with endogenous proteins such as Hsp70 and Vimentin, and with surface proteins of commensals e.g., the PorB protein of N. gonorrhea. The overall outcome is inter-species or intra-species variations in the intensity of innate immune responses, which can be reflected in relative susceptibility or resistance to infectious agents and/or harmful aggravation of endogenous inflammatory diseases. Perhaps because of the major changes in the sialome resulting from inactivation of the CMAH gene in the Homo lineage leading to humans, these and many other types of evolutionary changes appear to be very prominent in our species and in our pathogen regimes. This presentation will provide an overview of these topics and examples of our recent work in these areas. Varki, A.: Since there are PAMPs and DAMPs, there must be SAMPs? Glycan “self-associated molecular patterns” dampen innate immunity, but pathogens can mimic them. Glycobiology, 21:1121-1124, 2011. Padler-Karavani, V., Hurtado-Ziola, N., Chang, Y.-C., Sonnenburg, J., Ronaghy, A., Yu, H., Verhagen, A., Nizet, V., Chen, X., Varki, N., Varki, A., Angata, T.: Rapid Evolution of Binding Specificities and Expression Patterns of Inhibitory CD33-related Siglecs in Primates. FASEB J. 28:1280-93, 2014. Laubli, H. and Varki, A. Sialic acid–binding immunoglobulin-like lectins (Siglecs) detect self-associated molecular patterns to regulate immune responses. Cell. Mol. Life Sci. Springer, International. 2019.