Endosulfatases SULF1 and SULF2 limit Chlamydia muridarum infection.

Abstract

The first step in attachment of Chlamydia to host cells is thought to involve reversible binding to host heparan sulfate proteoglycans (HSPGs), polymers of variably sulfated repeating disaccharide units coupled to diverse protein backbones. However, the key determinants of HSPG structure that are involved in Chlamydia binding are incompletely defined. A previous genome-wide Drosophila RNAi screen suggested that the level of HSPG 6-O sulfation rather than the identity of the proteoglycan backbone maybe a critical determinant for binding. Here, we tested in mammalian cells whether SULF1 or SULF2, human endosulfatases, which remove 6-O sulfates from HSPGs, modulate Chlamydia infection. Ectopic expression of SULF1 or SULF2 in HeLa cells, which decreases cell surface HSPG sulfation, diminished C. muridarum binding and decreased vacuole formation. ShRNA depletion of endogenous SULF2 in a cell line that primarily expresses SULF2 augmented binding and increased vacuole formation. C. muridarum infection of diverse cell lines resulted indownregulation of SULF2 mRNA. In a murine model of acute pneumonia, mice genetically deficient in both endosulfatases or in SULF2 alone demonstrated increased susceptibility to C. muridarum lung infection. Collectively, these studies demonstrate that the level of HSPG 6-O sulfation is a critical determinant of C. muridarum infection in vivo and that 6-O endosulfatases are previously unappreciated modulators of microbial pathogenesis.

• Authors: J H Kim, C Chan, C Elwell, M S Singer, T Dierks, H Lemjabbar-Alaoui, S D Rosen, J N Engel
• Journal: Cellular microbiology (Cell Microbiol) Vol. 15 Issue 9 Pg. 1560-71 (Sep 2013) ISSN: 1462-5822 [Electronic] India
• PMID: 23480519 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 John Wiley & Sons Ltd.

Chemical References

• Heparitin Sulfate
• SULF1 protein, human
• Sulf1 protein, mouse
• Sulfotransferases
• SULF2 protein, human
• Sulf2 protein, mouse
• Sulfatases

Topics

• Animals
• Bacterial Adhesion
• Chlamydia Infections (immunology, microbiology)
• Chlamydia muridarum (growth & development, immunology)
• Disease Models, Animal
• Disease Susceptibility
• HeLa Cells
• Heparitin Sulfate (metabolism)
• Humans
• Mice
• Mice, Knockout
• Pneumonia, Bacterial (immunology, microbiology)
• Sulfatases (deficiency, immunology)
• Sulfotransferases (deficiency, immunology, metabolism)