Genetic variation in Chlamydia trachomatis and their hosts: impact on disease severity and tissue tropism

Abstract

Chlamydia trachomatis infections are a global health problem. This obligate intracellular bacterial pathogen comprises lymphogranuloma venereum (L1-L3), ocular (A-C) and genital (D-K) serovars. Although genetically similar, each serovar group differs in disease severity and tissue tropism through mechanisms that are not well understood. It is clear that host genetic differences also play a role in chlamydial disease outcome and key host polymorphisms are beginning to emerge from both human and experimental animal studies. In this review, we will highlight pathogen and host genes that link genetic diversity, disease severity and tissue tropism. We will also use this information to provide new insights that may be helpful in developing improved management strategies for these important pathogens.

Figure 1. Classification of Chlamydia trachomatis based on tissue tropism

Chlamydia trachomatis is divided into the oculogenital and LGV biovars. The ocular (A–C) and genital (D–K) serovars infect conjuctival and genital epithelia, respectively, while LGV (L1–L3) spreads systemically in macrophages and other host cell types via lymph nodes. LGV: Lymphogranuloma venerum.

Figure 2. Genetic variation as an adjustment to environmental changes

Genetic variation allows Chlamydia trachomatis to exploit diverse niches within a host (tissue tropism) and to avoid, escape or resist host responses. Consequently, new Chlamydia genotypes arise within the population and the potential for strain selection with increased virulence is possible.

Figure 3. Consequences of genetic variation for key Chlamydia trachomatis virulence factors

Genetic variation (lightning bolts) results in serovar-specific differences in invasiveness, evasion of host responses and tissue tropism. (A) Tarp variation alters the number of actin-binding domains and the rate of internalization. (B) Variation in IncA results in nonfusogenic inclusions. (C) IncG, a result of gene duplication within the Inc-family, interacts with the host protein 14-3-3β preventing initiation of apoptosis by the host cell. (D) Mutation in the partial trp operon results in nonfunctional tryptophan synthase unique to ocular Chlamydia trachomatis isolates. ‘?’ indicates that a ‘receptor’ or binding partner of Chlamydia EBs is not fully known and may be different between different chlamydial species. EB: Elementary body; RB: Reticulate body.

Figure 4. Trp synthase in different Chlamydia trachomatis serovars

All ocular serovars sequenced thus far harbor a nonfunctional trpRBA operon, whereas trpRBA is functional for all sequenced genital serovars. For ocular serovars, mutations may result either in a truncated TrpA or in a nonsynonymous point mutation that results in incorporation of an amino acid that inhibits function. Point mutations have been described for serovars E, F, G and Ia for trpA (e.g., change at C177Y) and serovars L1–L3 (change at Q178E); however, these mutations do not impact TrpA function. Nonsynonymous point mutations are represented by black lines while deletion mutations and their effect on TrpA are represented by the gray line. Not drawn to scale.

Figure 5. Contribution of host factors to Chlamydia trachomatis disease severity

Influence of genetic variation in host epithelial and immune cells on Chlamydia trachomatis infection and potential TFI induction. (A) Specific HLA*DQ alleles are correlated to TFI induction. (B) TFI patients carry an IL-10 promoter polymorphism. Cells from these individuals tend to produce less IL-10, more IFNγ and more TNF-α when leukocytes are stimulated in vitro. (C) IFN-γ induces IDO, which degrades tryptophan, an essential amino acid for both Chlamydia and the host cell. This may lead to dampening of the immune system, from a productive to a nonproductive chlamydial growth phenotype, which has been suggested to be associated with chronic infection and increased disease severity. IDO: Indoleamine 2,3-dioxygenase; TFI: Tubal factor infertility.