Pathogenic treponemes are clonal, unculturable, highly invasive bacteria that cause venereal syphilis, yaws, endemic syphilis and pinta — multi-stage infections that have many similarities, but can be differentiated based on clinical, epidemiological, geographical and, most recently, genomic criteria. Only Treponema pallidum subsp. pallidum is transmitted through sexual activity.
Key to the capacity of the syphilis spirochete for immune evasion and thus 'stealth pathogenicity' is its unusual outer membrane, which lacks lipopolysaccharide and contains an extremely low density of integral membrane proteins and a paucity of surface-exposed lipoproteins. The production of opsonic antibodies against low-abundance surface antigenic targets is believed to be essential for control of syphilitic infection.
In recent years, considerable progress has been made in defining the repertoire of β-barrel-forming rare outer membrane proteins of the syphilis spirochete and the mechanisms by which the bacterium seems to limit the exposure of surface molecules to the antibody-mediated defences of the host.
During the course of genomic reduction, T. pallidum has undergone adaptations that enable it to acquire all of its required nutrients from its obligate human host and optimize their usage in various niches, while coping with exogenous and endogenous stresses.
The genome of T. pallidum encodes several alternative sigma factors and other regulatory molecules or pathways that collectively point to a previously unsuspected capacity to intricately regulate gene expression in diverse microenvironments.
Comparative genomics has enabled investigators to identify 'hotspots' for sequence variation that probably explain differences in virulence potential and tissue tropisms among the pathogenic treponemes; many of these hotspots are located in proteins that are known or predicted to reside at the host–pathogen interface.
The past two decades have seen a worldwide resurgence in infections caused by Treponema pallidum subsp. pallidum, the syphilis spirochete. The well-recognized capacity of the syphilis spirochete for early dissemination and immune evasion has earned it the designation 'the stealth pathogen'. Despite the many hurdles to studying syphilis pathogenesis, most notably the inability to culture and to genetically manipulate T. pallidum, in recent years, considerable progress has been made in elucidating the structural, physiological, and regulatory facets of T. pallidum pathogenicity. In this Review, we integrate this eclectic body of information to garner fresh insights into the highly successful parasitic lifestyles of the syphilis spirochete and related pathogenic treponemes.
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The authors gratefully acknowledge support from the US National Institutes of Health (NIH) and the US National Institute of Allergy and Infectious Diseases (NIAID; grants AI26756 (to J.D.R.), AI56305 (to M.V.N.) and AI83640 (to X.F.Y.)); from the Connecticut Children's Medical Center (to J.D.R.), from the Ministry of Health of the Czech Republic (grant NT11159-5/2010 to D.S.); from the Grant Agency of the Czech Republic (grant P302/12/0574 to D.S.); and from the National Science Foundation of China (grant 81428015 to X.F.Y.). The authors also thank C. Brautigam and M. Saier for helpful discussions in relation to this manuscript; M. Caimano for many insightful comments and careful proofreading and editing; M. Ledoyt and C. Karanian for assistance with figures; and A. Cruz, J. Salazar and K. Dieckhaus for providing images of syphilitic lesions.
The authors declare no competing financial interests.
- Toll-like receptor 2
(TLR2). A pattern recognition receptor that recognizes various pathogen-associated molecular patterns, including bacterial lipoproteins.
- Opsonic antibodies
Antibodies that are directed against the surface-exposed epitopes of a pathogen that bind to Fc receptors on a phagocytic cell, which triggers internalization through phagocytosis.
Polytopic integral membrane proteins that mediate energy-dependent uptake of small molecules across the plasma membrane of Gram-positive bacteria and the cytoplasmic membrane of Gram-negative bacteria.
- ATP-binding cassette transporters
(ABC transporters). Transporters that couple the hydrolysis of ATP to the transport (usually import) of a substrate across the cytoplasmic membrane of Gram-negative bacteria and the plasma membrane of Gram-positive bacteria. Classical bacterial ABC transporters have a modular composition that consists of a substrate-binding protein, a dimeric membrane-bound permease and a dimeric nucleotide-binding protein that has ATPase activity.
Transporter proteins that use the sodium or electrochemical gradient across the cytoplasmic membrane to drive the co-directional import of substrates to the cytosolic compartment.
An organism that has lost the ability to synthesize molecules that are required for growth. Treponema pallidum subsp. pallidum is considered an extreme auxotroph because of its very limited biosynthetic capacity.
- Two-component systems
Systems that typically consist of a membrane-bound histidine kinase that senses a specific environmental stimulus and a cognate response regulator that mediates a cellular response, usually through the activation and/or repression of differentially expressed genes.
- Housekeeping sigma factor
A sigma factor that binds to the catalytic core of RNA polymerase and recognizes promoters of genes that are required for core functions in bacterial cells, such as maintenance and metabolism.
- Alternative sigma factors
Sigma factors that bind to the catalytic core of RNA polymerase, which displaces the housekeeping sigma factor, and re-direct transcription towards genes that are required to respond to a particular environmental stimulus, condition or stress.
- Heat shock response
The response of a bacterial cell to a sudden increase in temperature, which involves differential gene expression regulated through the alternative sigma factor σ32.
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Radolf, J., Deka, R., Anand, A. et al. Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen. Nat Rev Microbiol 14, 744–759 (2016). https://doi.org/10.1038/nrmicro.2016.141
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