Biology subjects

Iverson, T. M.

Publications and source records attributed to Iverson, T. M..

3 recordsLinked to original sources

bioRxiv2025

Sialic Acid Identity Modulates Host Tropism of Sialoglycan-binding Viridans Group Streptococci

Microbial interactions with multiple species may expand the range of potential hosts, supporting both pathogen reservoirs and zoonotic spillover. Viridans group streptococci interact with host cells by engaging protein-attached glycosylations capped with terminal sialic acids (sialoglycans). One potential origin for host tropism of these streptococci arises because humans exclusively synthesize the N-acetylneuraminic acid (Neu5Ac) form of sialic acid, while non-human mammals synthesize both Neu5Ac and a hydroxylated N-glycolylneuraminic acid (Neu5Gc). However, the link between binding preference for these sialic acids and preference for host has not been tested experimentally. Here, we investigate sialoglycan-binding by Neu5Ac/Neu5Gc cross-reactive Siglec-like binding regions (SLBRs) from two strains of streptococci, Streptococcus gordonii strain Challis (SLBRHsa) and Streptococcus sanguinis strain SK36 (SLBRSrpA). Structural and computational analyses of SLBRHsa identified molecular details for the binding of disaccharides capped in Neu5Ac or Neu5Gc. Engineering SLBRHsa and SLBRSrpA for narrow selectivity to synthetic Neu5Gc-terminated glycans shifted the binding preference from authentic human plasma receptors to plasma receptors from rat sources. However, host receptor preference did not fully recapitulate purified Neu5Ac/Neu5Gc-capped sialoglycan preference. These findings suggest that sialic acid identity modulates, but does not uniquely determine, host preference by these streptococci. This work refines our understanding of host specificity and challenges prevailing assumptions about the relative role of sialic acids in host tropism.

pathology↗

bioRxiv2020

Structure based virtual screening identifies novel competitive inhibitors for the sialoglycan binding protein Hsa

Infective endocarditis (IE) is a cardiovascular disease often caused by bacteria of the viridans group of streptococci, which includes Streptococcus gordonii and Streptococcus sanguinis. Previous research has found that a serine-rich repeat (SRR) proteins on the S. gordonii bacterial surface play a critical role in pathogenesis by facilitating bacterial attachment to sialyated glycans displayed on human platelets. Despite its important role in disease progression, there are currently no anti-adhesive drugs available on the market. Here, we performed structure-based virtual screening using an ensemble docking approach followed by consensus scoring to identify novel inhibitors against the sialoglycan binding domain of the SRR adhesin protein Hsa from the S. gordonii strain DL1. In silico cross screening against the glycan binding domains of closely related SRR proteins from five other S. gordonii or S. sanguinis strains was also performed to further reduce false positives. Using our in silico screening strategy we successfully predicted nine compounds which were able to displace the native ligand (sialyl-T antigen) in an in vitro assay and bind competitively to adhesin protein Hsa ([~]20% hit rate).

microbiology↗

bioRxiv2019

Selectivity and engineering of the sialoglycan-binding spectrum in Siglec-like adhesins

The Siglec-like Serine-Rich Repeat (SRR) adhesins mediate bacterial attachment to mammalian hosts via sialoglycan receptors. Here, we combine structural, computational, biochemical, and phylogenetic approaches to elucidate the determinants of the sialoglycan-binding spectrum across the family of Siglec-like SRR adhesins. We further identified mutable positions that disproportionately affect sialoglycan selectivity, as demonstrated by increases in binding to alternative ligands of 2- to 3-orders of magnitude. Biologically, these studies highlight how bacteria nimbly modulate the receptor interaction during coevolution of host and pathogen. These studies additionally created binding proteins specific for sialyl-T antigen or 6S-sialyl LewisX that can recognize glycosylation of human plasma proteins. The engineered binding proteins can facilitate the characterization of normal cellular glycan modifications or may be used as diagnostic tools in disease states with altered glycosylation.\n\nSignificanceThe ability of bacteria to bind selectively to host receptors underlies both commensalism and pathogenesis. Here, we identify the molecular basis for receptor selectivity in streptococci that bind to sialoglycan receptors. This revealed how to convert these adhesins into selective probes that measure triand tetrasacharides within the context of larger glycosylations. These probes that can be used in a laboratory with no specialized equipment and can be used to address biological questions relating to sialoglycan-dependent signaling and adhesion.

biochemistry↗