Host nectin-1 is required for efficient Chlamydia trachomatis serovar E development

Abstract

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.

Damage/Danger Associated Molecular Patterns (DAMPs) Modulate Chlamydia pecorum and C. trachomatis Serovar E Inclusion Development In Vitro

“…In contrast, herpes simplex virus type-2 mediated down-regulation of host nectin-1 protein appears to induce C . trachomatis persistence [ 37 ]. The involvement of these modes of action has not yet been investigated in the context of DAMP-induced persistence/chlamydial stress, and currently, evaluation of possible modes of action for DAMP-induced persistence/chlamydial stress has been limited.…”

Host Nectin-1 Promotes Chlamydial Infection in the Female Mouse Genital Tract, but Is Not Required for Infection in a Novel Male Murine Rectal Infection Model

“…In this case, deletion of the nectin-1 gene would make little difference in rectal shedding, since nectin-1 is low in those tissues already. If nectin-1 levels regulate chlamydial development, as our in vitro [ 23 ] and in vivo ( Fig 1 ) observations suggest, this could explain the differences observed in GI and genital tract shedding.…”

“…Although Wyrick et al used integrin-specific neutralizing antibodies to determine that integrins were not required for chlamydial entry, they did not determine whether chlamydial development or production of infectious EB were altered [ 29 ]. Additionally, cell culture experiments demonstrate that nectin-1 ablation has more effect on infectious EB development than on entry/inclusion formation [ 23 ]. Therefore, it remains possible that nectin/αvβ3 integrin interaction might be required for chlamydial development at some step after initial infection [ 29 ].…”

“…Due to the ubiquitous expression of nectins, it is no surprise that nectin-1 also functions as a co-receptor for the Herpes Simplex Virus (HSV) gD protein on host epithelial cells and neurons [ 21 ]. HSV gD/nectin interaction also removes nectin-1 from the host cell surface [ 22 , 23 ]. Previous work in our lab demonstrated that HSV super-infection of Chlamydia infected cells significantly reduced EB production [ 23 , 24 ] and suggested that the loss of host nectin-1 was responsible for inhibition of chlamydial development [ 23 ].…”

“…HSV gD/nectin interaction also removes nectin-1 from the host cell surface [ 22 , 23 ]. Previous work in our lab demonstrated that HSV super-infection of Chlamydia infected cells significantly reduced EB production [ 23 , 24 ] and suggested that the loss of host nectin-1 was responsible for inhibition of chlamydial development [ 23 ]. We subsequently observed that that chlamydial inclusion size and production of infectious EB was significantly reduced in nectin-1 knockdown cells, confirming a role for host nectin-1 in chlamydial development–at least in culture [ 23 ].…”