Interaction of human Tamm–Horsfall glycoprotein with Bordetella pertussis toxin

Abstract

Tamm-Horsfall glycoprotein (THP), which is synthesized by renal tubular cells, is the most abundant protein in normal human urine. Although its physiological function remains unclear, it has been proposed that THP may act as a defence factor against urinary tract infections by inhibiting the binding of S-and P-fimbriated Escherichia coli to renal epithelial cells. Because THPrelated proteins are also found in the superficial layers of the oral mucosa, the authors investigated the ability of THP to interfere with the cytoadherence of pathogenic bacteria that colonize mucosal surfaces other than those of the urogenital tract. In this report, it is shown that THP binds to virulent Bordetella pertussis and reduces its adherence to both renal and pulmonary epithelial cells. This cytoadherence inhibitory effect was not observed with a B. pertussis mutant lacking the pertussis toxin (PTX) operon, and was dependent on the direct interaction of THP with the S2 subunit within the PTX B oligomer. The authors also show that the glycosylation moiety of THP is crucial for its binding to PTX. The THP-PTX interaction was exploited to develop an affinity chromatography method that allows a one-step purification of active PTX. These observations suggest that besides its anti-adherence activity, THP may also trap toxins produced by pathogenic bacteria that colonize mucosal surfaces.

Intact protein core structure is essential for protein-binding, mononuclear cell proliferating, and neutrophil phagocytosis-enhancing activities of normal human urinary Tamm–Horsfall glycoprotein

“…The daily excretion of THG ranges from 50-200 mg in humans [32]. The glycoprotein can interact with viral proteins [1], bacterial structure components [2], bacterial exotoxin [33], immunoglobulin light chains [14,15], complement component 1 and 1q [16], proinflammatory cytokine IL-1 [12], IL-2 [34] and TNF-α [12,13], and surface membrane proteins on human PMN, lymphocytes and monocytes [17][18][19][20][21]. Immunologically, THG not only activates PMN through binding to a single class of sialic acid-specific cell surface receptors [17] but enhances the release of IL-1, IL-6, and TNF-α from monocytes responsible for B and T lymphocytes proliferation [20,21].…”