Interaction of Herpes Simplex Virus (HSV)
glycoprotein D (gD) with the host cell surface during Chlamydia trachomatis/HSV
co-infection stimulates chlamydiae to become persistent. During viral entry, gD interacts with one of 4 host co-receptors: HVEM (herpes virus entry mediator),
nectin-1,
nectin-2 and 3-O-sulfated
heparan sulfate. HVEM and
nectin-1 are high-affinity entry receptors for both HSV-1 and HSV-2.
Nectin-2 mediates HSV-2 entry but is inactive for HSV-1, while 3-O-sulfated
heparan sulfate facilitates HSV-1, but not HSV-2, entry. Western blot and RT-PCR analyses demonstrate that HeLa and HEC-1B cells express
nectin-1 and
nectin-2, but not HVEM. Because both HSV-1 and HSV-2 trigger persistence, these data suggest that
nectin-1 is the most likely co-receptor involved.
Co-infections with
nectin-1 specific HSV-1 mutants stimulate chlamydial persistence, as evidenced by aberrant body (AB) formation and decreased production of elementary bodies (EBs). These data indicate that
nectin-1 is involved in viral-induced chlamydial persistence. However, inhibition of signal transduction molecules associated with HSV attachment and entry does not rescue EB production during C. trachomatis/HSV-2
co-infection. HSV attachment also does not activate Cdc42 in HeLa cells, as would be expected with viral stimulated activation of
nectin-1 signaling. Additionally, immunofluorescence assays confirm that HSV
infection decreases
nectin-1 expression. Together, these observations suggest that gD binding-induced loss of
nectin-1 signaling negatively influences chlamydial growth. Chlamydial
infection studies in
nectin-1 knockdown (NKD) HeLa cell lines support this hypothesis. In NKD cells, chlamydial inclusions are smaller in size, contain ABs, and produce significantly fewer infectious EBs compared to C. trachomatis
infection in control HeLa cells. Overall, the current study indicates that the actions of host molecule,
nectin-1, are required for successful C. trachomatis development.