Abstract
Chlamydia trachomatis is an obligate intracellular pathogen that can persist in the urogenital tract. Mechanisms by which C. trachomatis evades clearance by host innate immune responses are poorly described. CD1d is MHC-like, is expressed by epithelial cells, and can signal innate immune responses by NK and NKT cells. Here we demonstrate that C. trachomatis infection down-regulates surface-expressed CD1d in human penile urethral epithelial cells through proteasomal degradation. A chlamydial proteasome-like activity factor (CPAF) interacts with the CD1d heavy chain, and CPAF-associated CD1d heavy chain is then ubiquitinated and directed along two distinct proteolytic pathways. The degradation of immature glycosylated CD1d was blocked by the proteasome inhibitor lactacystin but not by MG132, indicating that degradation was not via the conventional proteasome. In contrast, the degradation of non-glycosylated CD1d was blocked by lactacystin and MG132, consistent with conventional cellular cytosolic degradation of N-linked glycoproteins. Immunofluorescent microscopy confirmed the interruption of CD1d trafficking to the cell surface, and the dislocation of CD1d heavy chains into both the cellular cytosol and the chlamydial inclusion along with cytosolic CPAF. C. trachomatis targeted CD1d toward two distinct proteolytic pathways. Decreased CD1d surface expression may help C. trachomatis evade detection by innate immune cells and may promote C. trachomatis persistence.
Highlights
Chlamydia trachomatis serovars D–K are common obligate intracellular pathogens that infect the columnar epithelia of the human urogenital mucosa (1, 2)
This study demonstrates that CD1d molecules are decreased on the surface of C. trachomatis-infected cells, CD1d mRNA levels were not altered when compared with those in non-infected cells
The three described isoforms of CD1d heavy chain (HC) protein were here observed in distinctive patterns that depended upon the infection status and the time after C. trachomatis infection
Summary
Chlamydia trachomatis serovars D–K are common obligate intracellular pathogens that infect the columnar epithelia of the human urogenital mucosa (1, 2). C. trachomatis targets upstream stimulation factor-1 for CPAF-mediated degradation, resulting in the inhibition of interferon ␥-inducible expression of MHC class II products (5). CD1d-restricted NKT cells can act directly on infected cells, killing the CD1d-expressing cell They promote interferon ␥ production by conventional NK cells and modulate adaptive immune cells by altering Th1/ Th2 polarization. The activation of CD1d-restricted invariant NKT cells in response to microbial invasion is antigen-dependent, but these antigens can be derived from the invading microbe or possibly host antigens (16 –18). Viewing the importance of CD1d in innate immune responses to microbes, we hypothesized that C. trachomatis may alter CD1d-mediated immune pathways and thereby avoid innate immune destruction of the infected cell by the host. We demonstrate that surface-expressed CD1d in human urethral epithelial cells is down-regulated by C. trachomatis infection, and this involves both CPAF-mediated and classic cytosolic proteasomal pathways
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