Endosulfatases SULF 1 and SULF 2 limit C hlamydia muridarum infection

Summary The first step in attachment of C hlamydia to host cells is thought to involve reversible binding to host heparan sulfate proteoglycans ( HSPG s), polymers of variably sulfated repeating disaccharide units coupled to diverse protein backbones. However, the key determinants of HSPG structure that are involved in C hlamydia binding are incompletely defined. A previous genome‐wide D rosophila 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 SULF 1 or SULF 2, human endosulfatases, which remove 6‐ O sulfates from HSPGs , modulate C hlamydia infection. Ectopic expression of SULF 1 or SULF 2 in HeLa cells, which decreases cell surface HSPG sulfation, diminished C . muridarum binding and decreased vacuole formation. ShRNA depletion of endogenous SULF 2 in a cell line that primarily expresses SULF 2 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 SULF 2 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.