The Chlamydia pneumoniae Invasin Protein Pmp21 Recruits the EGF Receptor for Host Cell Entry

Abstract

Infection of mammalian cells by the strictly intracellular pathogens Chlamydiae requires adhesion and internalization of the infectious Elementary Bodies (EBs). The components of the latter step were unknown. Here, we identify Chlamydia pneumoniae Pmp21 as an invasin and EGFR as its receptor. Modulation of EGFR surface expression evokes correlated changes in EB adhesion, internalization and infectivity. Ectopic expression of EGFR in EGFR-negative hamster cells leads to binding of Pmp21 beads and EBs, thus boosting the infection. EB/Pmp21 binding and invasion of epithelial cells results in activation of EGFR, recruitment of adaptors Grb2 and c-Cbl and activation of ERK1/2, while inhibition of EGFR or MEK kinase activity abrogates EB entry, but not attachment. Binding of Grb2 and c-Cbl by EGFR is essential for infection. This is the first report of an invasin-receptor interaction involved in host-cell invasion by any chlamydial species.

The Chlamydia pneumoniae Adhesin Pmp21 Forms Oligomers with Adhesive Properties

“…Pmps are known to share characteristic features with Type V autotransporters, including proteolytic processing (13,14,16,18,22). Recently, Pmp21 was shown to bind to the host's EGF receptor and to induce its own uptake; hence, Pmp21 acts both as an adhesin and as an invasin (28). Interestingly, the characteristic FXXN and GGA(I/L/V) motifs, which are known to occur in multiple copies exclusively in chlamydial Pmp proteins (14), have been shown to be crucial for Pmp21-mediated adhesion (22).…”

“…The images shown are representative for the whole grids (independent replicates n ϭ 2). (28). To analyze whether the monomeric and oligomeric D-Wt species have identical or different affinities for EGFR, we performed pulldown assays with D-Wt-O 1 and D-Wt-M. As positive control we used recombinant M-Pmp21 (28), whereas other controls were recombinant GST, the C. pneumoniae adhesin OmcB-BD (46), and the C. trachomatis adhesin and invasin Ctad1 (47) (Fig.…”

“…In addition, blocking experiments using recombinant Pmp proteins have provided direct evidence for the critical role of the Pmp proteins in chlamydial pathogenesis (22,27) More recently, the epidermal growth factor receptor (EGFR) was identified as the host receptor for the C. pneumoniae adhesin Pmp21, and binding to EGFR was shown to induce the uptake of the chlamydial EB, thus qualifying Pmp21 as an invasin (28).…”

Analysis of Humoral Immune Responses to Surface and Virulence-Associated Chlamydiaabortus Proteins in Ovine and Human Abortions by Use of a Newly Developed Line Immunoassay

“…Pmps are differentially expressed during the chlamydial developmental cycle (27,28) and are therefore suspected to play a role in antigenic diversity and evasion of the host immune response. Pmp21 of C. pneumoniae has been described as an invasion protein that recruits the epidermal growth factor receptor for host cell entry (29).…”

In Vitro Passage Selects for Chlamydia muridarum with Enhanced Infectivity in Cultured Cells but Attenuated Pathogenicity in Mouse Upper Genital Tract

“…Multiple putative chlamydial factors, such as the major outer membrane protein (MOMP) (10)(11)(12)(13), outer membrane complex (OMC) protein B (OmcB) (14)(15)(16), and the polymorphic membrane proteins (Pmps) (17)(18)(19), and host-derived factors, such as heparin sulfate (16,20), epidermal growth factor receptor (EGFR) (21), estrogen receptor (22), and insulin-like growth factor 2 receptor (23), have been proposed to mediate chlamydial interactions with host cells. However, the precise structural basis of the interactions between an EB and a host cell during chlamydial infection in animals and humans remains ill defined.…”