Clear Victory for Chlamydia: The Subversion of Host Innate Immunity

Abstract

As obligate intracellular bacterial pathogens, members of the Chlamydia genera are the pivotal triggers for a wide range of infections, which can lead to blinding trachoma, pelvic inflammation, and respiratory diseases. Because of their restricted parasitism inside eukaryotic cells, the pathogens have to develop multiple strategies for adaptation with the hostile intracellular environment-intrinsically present in all host cells-to survive. The strategies that are brought into play at different stages of chlamydial development mainly involve interfering with diverse innate immune responses, such as innate immune recognition, inflammation, apoptosis, autophagy, as well as the manipulation of innate immune cells to serve as potential niches for chlamydial replication. This review will focus on the innate immune responses against chlamydial infection, highlighting the underlying molecular mechanisms used by the Chlamydia spp. to counteract host innate immune defenses. Insights into these subtle pathogenic mechanisms not only provide a rationale for the augmentation of immune responses against chlamydial infection but also open avenues for further investigation of the molecular mechanisms driving the survival of these clinically important pathogens in host innate immunity.

Keywords: Chlamydia; immune recognition; innate immune cells; innate immune response; survival and growth.

Figure 1

The taxonomy of Chlamydia. The phylum Chlamydiae comprises a single class, Chlamydia, containing two orders, Chlamydiales and Parachlamydiales. The order Chlamydiales encompasses four families, Candidatus Actinochlamydiaceae, Candidatus Clavichlamydiaceae, Chlamydiaceae, and the unclassified Chlamydiales. The family Chlamydiaceae contains the best-known human and animal chlamydial pathogens, such as C. trachomatis, C. pneumoniae, C. psittaci, and C. muridarum. The other order, Parachlamydiales, encompasses six families.

Figure 2

Innate immune recognition of Chlamydia. Chlamydial infection can be recognized by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), NLRs, and cGAS, which elicit strong host innate immune responses and the release of several pro-inflammatory cytokines. TLR1/2 and TLR2/6 recognize chlamydial lipopeptide/lipoprotein, and TLR4 recognizes chlamydial LPS and HSP60. Upon binding of cognate ligands, the MyD88-dependent pathway, which is common to all TLR signaling (with the exception of TLR3) is immediately activated. Whether TLR3 is involved in the recognition of chlamydial infection remains to be elucidated. The chlamydial peptidoglycan binds to the NLRs and induces the production of pro-inflammatory cytokines via nuclear factor-κB (NF-κB) or activator protein 1 (AP-1) signaling. The stimulation of cGAS by Chlamydia spp. DNA leads to the dimerization and activation of IRF3, which then translocates into the nucleus and promotes the transcription of type I IFN and IFN-inducible genes. Chlamydial components also bind to the ephrin receptor A2 (EPHA2), which in turn triggers the activation of PI3K-downstream signaling, favoring the proliferation and survival of Chlamydia.