Treponema pallidum, formerly known as Spirochaeta pallida, is a microaerophilic spirochete bacterium with subspecies that cause the diseases syphilis, bejel (also known as endemic syphilis), and yaws. It is known to be transmitted only among humans and baboons. The bacterium is helically coiled, typically measuring 6–15 μm in length and 0.1–0.2 μm in width.

T. pallidum exhibits minimal metabolic activity due to its lack of both a tricarboxylic acid cycle and processes for oxidative phosphorylation. The bacterium has cytoplasmic and outer membranes. When viewed under light microscopy, treponemes are visible only under dark-field illumination.

There are three subspecies of T. pallidum: T. p. pallidum, T. p. endemicum, and T. p. pertenue, each associated with distinct diseases.

Subspecies

Three subspecies of T. pallidum are known:

• Treponema pallidum pallidum, which causes syphilis
• T. p. endemicum, which causes bejel or endemic syphilis
• T. p. pertenue, which causes yaws

The three subspecies causing yaws, bejel, and syphilis are morphologically and serologically indistinguishable. Originally classified as separate species, DNA hybridization analysis indicates they belong to the same species. Treponema carateum, the cause of pinta, remains a separate species due to the unavailability of isolates for DNA analysis. Transmission of T. p. endemicum and T. p. pertenue is considered non-venereal. T. p. pallidum is the most invasive pathogenic subspecies, while T. carateum is the least invasive. T. p. endemicum and T. p. pertenue are intermediate in invasiveness.

Physiology

Treponema pallidum is a helically shaped bacterium with high motility, composed of an outer membrane, peptidoglycan layer, inner membrane, protoplasmic cylinder, and periplasmic space. It is often described as Gram-negative, but its outer membrane lacks lipopolysaccharide found in other Gram-negative bacteria. It possesses an endoflagellum (periplasmic flagellum) consisting of four main polypeptides, forming a core structure and sheath. The flagellum is located within the periplasmic space and wraps around the protoplasmic cylinder. The outer membrane of T. pallidum has minimal protein content, limiting antigenicity and immune recognition. Its cytoplasmic membrane is covered in lipoproteins. Treponema species have cytoplasmic filaments composed of the intermediate filament-like protein cytoplasmic filament protein A (CfpA), although their precise function remains unknown.

Outer Membrane

The outer membrane of T. pallidum presents challenges for research due to its low protein content, fragility, and limited gene sequences compared to other Gram-negative outer membranes. Genomic sequencing and advanced computational models have improved understanding of its pathogenesis, persistence, and immune evasion strategies. Outer membrane proteins are crucial for interaction with the host and immune evasion. T. pallidum is known as a "stealth pathogen" due to its unique outer membrane structure.

TP0326, TP0965, TP0453, TP0624

TP0326 is an ortholog of the β-barrel assembly machine Bam A, involved in inserting outer membrane proteins into the membrane. TP0965 is critical for membrane fusion in T. pallidum and contributes to endothelial barrier dysfunction in late-stage syphilis. TP0453 is an inner membrane-associated protein involved in nutrient uptake. TP0624, an Outer Membrane Protein A (OmpA) domain-containing protein, facilitates structural integrity and interactions between outer membrane proteins and the peptidoglycan layer.

Treponema Repeat Family of Proteins (Tpr)

Tprs, expressed during infection, consist of conserved N-terminal and C-terminal domains with a central variable region. TprK, with variable regions (V1–V7), undergoes antigenic variation to evade host immunity, allowing reinfection. Phase variation in TprF, TprI, TprG, TprJ, and TprL involves reversible changes in polymeric repeats to adapt to the microenvironment and evade immune responses.

Culture and Genome

Culturing T. pallidum in vitro has historically been challenging, limiting studies on its metabolism and antimicrobial sensitivity. Successful long-term cultivation was achieved in 2017 using epithelial cells from rabbits and a specific tissue culture medium. The genome of T. pallidum, sequenced in 1998, revealed its reliance on host-derived molecules and reduced metabolic capabilities. Its small genome and adaptation to mammalian tissue contribute to its pathogenicity and evasion of host defenses.

Clinical Significance

Clinical features of syphilis, yaws, and bejel progress through multiple stages affecting the skin, with early lesions highly infectious. Latent stages may persist for life or progress to destructive tertiary lesions affecting skin, bone, and cartilage. Syphilis in its tertiary stage can also impact the heart, eyes, and nervous system.