Materiały źródłowe

• #1 The pathogenesis of syphilis: the Great Mimicker, revisited – PubMed

  https://pubmed.ncbi.nlm.nih.gov/16362988/

  Syphilis is a chronic sexually transmitted infection caused by Treponema pallidum subspecies pallidum. […] Understanding of disease pathogenesis and how host-pathogen interactions influence the course of disease have been compromised by the facts that the organism cannot be grown in vitro and, as an exclusively human pathogen, inferences made from animal models are of limited applicability. […] Many questions remain about how T. pallidum biology contributes to distinctive features of syphilis, such as its ability to persist in the presence of a brisk host response or its propensity for neuro-invasion and congenital transmission. […] While biological functions are suggested for only about 55% of T. pallidum’s 1041 open reading frames, even these relatively early studies offer important insights into syphilis pathogenesis.

• #2 Syphilis | SpringerLink

  https://link.springer.com/10.1007/978-3-642-30144-5_109

  Syphilis is an infection that has intrigued scientists, baffled clinicians, and terrified patients for centuries. […] The protean clinical manifestations, long periods of asymptomatic infection, and lifelong persistence of syphilis suggest a highly complex relationship between Treponema pallidum and the hosts immune response. […] The extreme fragility of the causative bacterium and the inability to cultivate it in vitro have impeded progress in identifying and understanding the important virulence factors. […] Despite these difficulties, the post-genomic era has yielded a new understanding of the molecular interactions of T. pallidum and the host. […] In this chapter, we present our current understanding of the mechanisms of syphilis pathogenesis in the context of a discussion of the clinical stages of syphilis.

• #3 Syphilis | SpringerLink

  https://link.springer.com/10.1007/978-3-642-30144-5_109?fromPaywallRec=true

  Syphilis is an infection that has intrigued scientists, baffled clinicians, and terrified patients for centuries. […] The protean clinical manifestations, long periods of asymptomatic infection, and lifelong persistence of syphilis suggest a highly complex relationship between Treponema pallidum and the hosts immune response. […] Despite these difficulties, the post-genomic era has yielded a new understanding of the molecular interactions of T. pallidum and the host. In this chapter, we present our current understanding of the mechanisms of syphilis pathogenesis in the context of a discussion of the clinical stages of syphilis.

• #4 Syphilis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/229461-overview

  Three genera of spirochetes cause human infection: […] The particular spirochete responsible for syphilis is Treponema pallidum. […] T pallidum is a fragile spiral bacterium 6-15 micrometers long by 0.25 micrometers in diameter. Its small size makes it invisible on light microscopy; therefore, it must be identified by its distinctive undulating movements on darkfield microscopy. It can survive only briefly outside of the body; thus, transmission almost always requires direct contact with the infectious lesion. […] In acquired syphilis, T pallidum rapidly penetrates intact mucous membranes or microscopic dermal abrasions and, within a few hours, enters the lymphatics and blood to produce systemic infection. […] Studies in rabbits show that spirochetes can be found in the lymphatic system as early as 30 minutes after primary inoculation, suggesting that syphilis is a systemic disease from the outset.

• #5

  https://www.meddean.luc.edu/lumen/meded/mech/cases/case21/syphilis.htm

  Treponema pallidum is the causative agent of syphilis. […] The spirochete reaches the subepithelial tissues through inapparent breaks in the skin or possibly by passage between the epithelial cells of a mucous membrane. It multiplies locally with a generation time of about 30 hours; although the primary lesion is local, the organism also disseminates rapidly to local lymph nodes and then to other organs by way of the bloodstream. […] The basic pathologic lesion is an endarteritis. The small arterioles show swelling and proliferation of their endothelial cells. This reduces or obstructs local blood supply and probably accounts for the necrotic ulceration. […] The manifestations may appear as early as 5 years after infection, but characteristically occur after 15 to 20 years. Meningovascular syphilis involves vascular changes of the meninges associated with increased cells and protein in the cerebrospinal fluid and focal neurologic changes.

• #6 Core Concepts – Syphilis – Self-Study Lessons – National STD Curriculum

  https://www.std.uw.edu/go/comprehensive-study/syphilis

  The etiologic agent in syphilis is Treponema pallidum from the Greek terms trepo (to turn) and nema (thread) and the Latin term pallida (pale). Treponema pallidum belongs to the spirochete class and is a corkscrew-shaped, motile microaerophilic bacterium that cannot be viewed by normal light microscopy. Isolation of T. pallidum was first performed using a live rabbit-model in vivo system, but subsequently, successful cultivation and propagation of T. pallidum has been achieved using in vitro tissue culture. This spirochete bacterium is thin (0.1 to 0.18 micrometers in diameter) and 6 to 20 micrometers in length. Treponema pallidum has been erroneously described as a gram-negative bacterium, but this organism lacks lipopolysaccharide (LPS), a hallmark of gram-negative organisms. […] The major routes of transmission for T. pallidum are sexual (during the primary and secondary stages of syphilis) and hematogenous (in utero via transplacental spread to a fetus). During sexual transmission, T. pallidum enters the body via skin and mucous membranes through macroscopic and microscopic abrasions during sexual contact. Persons who acquire T. pallidum are contagious to their sex partners throughout the primary and secondary stages of infection (when lesions or rash are present). Some patients may be asymptomatic and diagnosed with latent syphilis, but may have more subtle undetected manifestations, such as a small localized rash or mucosal lesions that are not visible, such as lesions in the anal canal. Although sexual transmission of T. pallidum usually results from contact with genital mucosal membranes, it can also occur at other sites, including the mouth, anorectal areas, and cutaneous lesions. Maternal transmission predominantly occurs via transplacental passage of T. pallidum during maternal spirochetemia; less often, transmission can occur if the newborn has contact with maternal genital lesions at the time of delivery. In contrast to sexual transmission of syphilis, which nearly always occurs in the early stages of syphilis, vertical transmission can occur during any stage of syphilis. Other forms of hematogenous transmission of T. pallidum are rare: transfusion-associated syphilis has been virtually eliminated in the United States, and transmission through needle-sharing with injection drug use is infrequent. […] Neurosyphilis occurs when T. pallidum invades the central nervous system, and this may occur at any stage of syphilis; neurosyphilis is categorized as early neurosyphilis and late neurosyphilis. Ocular and otic involvement can occur with early or late infection.

• #7 Pathogenesis of Syphilis

  https://www.caister.com/hsp/abstracts/trep/10.html

  Venereal syphilis is caused by Treponema pallidum, a noncultivatable, microaerophilic spirochete and obligate human pathogen. T. pallidum utilizes glycolysis for energy production, has extremely limited biosynthetic capacity, and possesses limited tolerance for environmental stress. Transmission of T. pallidum occurs in a high percentage of individuals exposed to primary or secondary syphilitic lesions. T. pallidum is extremely invasive. Invasion at the local site occurs shortly after inoculation, while hematogenous dissemination occurs well before the appearance of the primary lesion (chancre). Penetration of the blood-brain barrier by T. pallidum, a distinctive aspect of human disease, is common during early syphilis and, in untreated individuals, sets the stage for the subsequent development of neurological complications (neurosyphilis). Clinical manifestations result from the inflammatory responses elicited by spirochetes and spirochetal constituent (e.g., lipoproteins) locally and systemically. Clearance of spirochetes from sites of infection is accomplished by activated macrophages most likely in concert with opsonic antibodies. The limited surface antigenicity of T. pallidum is thought to be a major factor in the spirochete’s ability to establish persistent infection; selection of tprK sequence variants also may contribute to immune evasion. As with other spirochetal pathogens, motility is thought to be critical for treponemal invasiveness. The lack of orthologs for well characterized virulence determinants in the T. pallidum genome emphasizes the uniqueness of the bacterium’s parasitic strategies. Genetic approaches for identifying treponemal virulence determinants are beginning to emerge.

• #8 Pathogen Safety Data Sheets: Infectious Substances – Treponema pallidum – Canada.ca

  https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/treponema-pallidum-pathogen-safety-data-sheet.html

  Treponema pallidum is a spiral-shaped, microaerophilic, non-spore-forming, motile bacterium, measuring 620 m in length and 0.10.2 m in diameter. […] Due to its double-membrane structure, T. pallidum is often described as a Gram-negative bacterium, but its outer membrane lacks lipopolysaccharides and has a markedly different phospholipid composition than the outer membranes of typical Gram-negative bacteria. […] This paucity of surface-exposed pathogen-associated molecular patterns (PAMPs) enables T. pallidum to avoid triggering innate host surveillance mechanisms, facilitating local replication and early dissemination. […] Its limited surface antigenicity promotes the evasion of adaptive immune responses (i.e., antibody recognition), facilitating persistence. […] Small amounts of surface-exposed lipoproteins potentially enhance infectivity, including Tp0751, a laminin-binding lipoprotein and zinc-dependent metalloproteinase capable of degrading clots and the extracellular matrix.

• #9 Syphilis – Sexually Transmitted Bacterial Diseases – Bacterial Diseases – Infectious Diseases – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.18.96.6.4.

  1. Pathogenesis: T pallidum can invade the hosts tissues using its motility and ability to adhere to multiple types of cells and extracellular matrix proteins. T pallidum also stimulates production of extracellular matrix metalloproteinases in the hosts cells, which facilitates tissue penetration. Cellular and humoral immune responses in syphilis are induced mainly by highly immunogenic proteins of the endoflagella, such as FlaA, FlaB1, FlaB2, and FlaB3. […] The majority of syphilitic lesions are likely due to inadequate, enhanced immune response (nonspecific and specific) induced by the bacteria.

• #10 Syphilis – Clinical Features – Management – TeachMeObGyn

  https://teachmeobgyn.com/sexual-health/sexually-transmitted-infections/syphilis/?utm_source=chatgpt.com

  In addition to sexual transmission, the infection can also be transmitted from mother to fetus via the placenta (congenital syphilis) and through infected blood products. […] The motile Treponema pallidum enters through a break in the skin or through intact mucous membranes. The bacteria divide and an infectious hard ulcer (chancre) subsequently forms at the site of contact after an incubation period of 2-3 weeks. This is the first stage of acquired symptomatic syphilis: primary syphilis. […] If left untreated, T. pallidum can persist and cause systemic damage via obliterating arteritis. This is where endothelial cells of the vessels excessively proliferate causing the lumen of the vessels to become narrowed. This can then result in ischaemia at the tissues supplied by these arteries which leads to the symptoms associated with syphilis.

• #11

  https://www.jci.org/articles/view/57173

  To establish infection, T. pallidum adheres to epithelial cells and extracellular matrix components of the skin and mucosa. Several T. pallidum proteins mediate adherence, including TP0155 and TP0483, which bind to matrix fibronectin and to both soluble and matrix forms of fibronectin, respectively. […] T. pallidum replicates at the site of initial inoculation, dividing once every 30-33 hours, inducing a local inflammatory response that results in a painless chancre approximately 3-6 weeks after initial infection. […] Although T. pallidum has structural similarities to classical Gram-negative bacteria, such as having outer and inner membranes and a periplasmic space, it lacks lipopolysaccharide, a potent proinflammatory glycolipid, and does not produce any known toxic proteins. Therefore, most of the symptoms and tissue damage related to syphilis are due to activation of the host inflammatory and immune responses.

• #12 Syphilis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/229461-overview

  Regardless of the stage of disease and location of lesions, histopathologic hallmarks of syphilis include endarteritis (which in some instances may be obliterative in nature) and a plasma cell-rich infiltrate. Endarteritis is caused by the binding of spirochetes to endothelial cells, mediated by host fibronectin molecules bound to the surface of the spirochetes. […] The syphilitic infiltrate reflects a delayed-type hypersensitivity response to T pallidum, and in certain individuals with tertiary syphilis, this response by sensitized T lymphocytes and macrophages results in gummatous ulcerations and necrosis. […] Antigens of T pallidum induce host production of treponemal antibodies and nonspecific reagin antibodies. Immunity to syphilis is incomplete. […] For example, host humoral and cellular immune responses may prevent the formation of a primary lesion on subsequent infections with T pallidum, but they are insufficient to clear the organism.

• #13 A 2021 Update on Syphilis: Taking Stock from Pathogenesis to Vaccines

  https://www.mdpi.com/2076-0817/10/11/1364

  Although syphilis is a very old disease, its pathogenesis is not fully understood, diagnosis may be difficult and, lastly, few therapeutic or prophylactic options are available at the moment. […] TP is characterized by a rare outer membrane and a slow replication rate (about 33 h) with a dynamic regulation of TP genes, which is important for its successful colonization, dissemination, and invasion in hosts. […] Antigenic variation through gene conversion during infection seems to be the mechanism by which TP avoids the host immune response, allowing for prolonged infection and persistence even in the case of a robust host response. […] TP is presumed to penetrate through small skin lesions, but the exact mechanisms by which TP enters cells is not known. […] TP is one of the few pathogens capable of crossing specialized endothelial barriers such as the retinal, placental, and blood-brain barriers. […] Whether HIV infection alters the natural history of syphilis or vice-versa remains controversial.

• #14 The pathology of syphilis | Pathology Learning Centre

  https://health.uct.ac.za/pathology-learning-centre/disease-themes-syphilis-isifo-sedolobha-disease-town/pathology-syphilis

  Most of the pathology of syphilis is the consequence of widespread microscopic vascular compromise caused by obliterative endarteritis. Its pathogenesis is not known but in the lesions treponemes are scarce while the inflammatory infiltrate response is intense, indicating that the immune response is instrumental. […] The course, stages, and pathology of human syphilis are determined by the balance between delayed-type hypersensitivity (DTH) and humoral immunity to the causative agent, Treponema pallidum. A strong DTH response is associated with clearance of the infecting organisms in a well-developed chancre, whereas a cytotoxic T-cell response or strong humoral antibody response is associated with prolonged infection and progression to tertiary disease (in 1/3 patients). Many of the protean symptoms/appearances of secondary and tertiary human syphilis are manifestations of immune reactions that fail to clear the organism, due to a lack of recruitment and, more importantly, activation of macrophages by sensitized CD4 T cells.

• #15 Syphilis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Syphilis_pathophysiology

  Syphilis uses fibronectin molecules to attach to the endothelial surface of the vessels in organs resulting in inflammation and obliteration of the small blood vessels causing vasculitis (endarteritis obliterans). Organism has slow replication rate (30-33 hrs) and evades the initial host immune response. It may seed to different organs of the body especially the cardiovascular system and central nervous system resulting in tertiary syphilis. […] Different stages of syphilis results from the interaction between the antigen and the host immune response. […] The initial infection in primary syphilis is limited due to Th1 response and lack of the antibody response. It is speculated that there is a shift from Th1 to Th2 response during secondary syphilis. […] Cytotoxic T cells and an incomplete humoral response is mainly responsible for persistence of infection and tissue damage in tertiary syphilis. Ineffective type 4 delayed hypersensitivity reaction containing macrophages and sensitized T cells is mainly responsible for the gumma formation in various organs.

• #16

  https://www.jci.org/articles/view/57173

  The interaction of TpN47 with TLR2 on the surface of macrophages induces the production of IL-12. […] The humoral immune response produces antibodies that function in opsonization and complement-mediated immobilization or neutralization. […] In the rabbit model, despite the presence of functional antibodies, passive immunization with immune serum fails to provide protective immunity against T. pallidum infection, demonstrating that cellular immunity is also required for protection. […] While CNS involvement of syphilis infection is classically considered as the tertiary stage of infection, invasion of the nervous system by T. pallidum and neurosyphilis occur within days or weeks of infection. […] Despite a host immune response that results in effective local clearance of T. pallidum from primary and secondary lesions, treponemes persist in many tissues without causing clinical signs or symptoms. This is termed the latent stage.

• #17 Treponema pallidum – Wikipedia

  https://en.wikipedia.org/wiki/Treponema_pallidum

  Treponema pallidumcan enter the host through mucosal membranes or open lesions in the skin and is primarily spread through sexual contact. […] The ability of T. pallidum to avoid host immune defenses has allowed for stealth pathogenicity. […] The treponemal outer membrane proteins are key factors for the bacterium’s pathogenesis, persistence, and immune evasion strategies. […] T. pallidum was found to rely on its host for many molecules typically provided by biosynthetic pathways, and it is missing genes responsible for encoding key enzymes in oxidative phosphorylation and the tricarboxylic acid cycle. […] These virulence factors are thought to contribute to the bacterium’s ability to evade the immune system and cause disease. […] The TP0965 protein is critical for membrane fusion in T. pallidum, and is located in the periplasm.

• #18 The pathogenesis of syphilis: the Great Mimicker, revisited – PubMed

  https://pubmed.ncbi.nlm.nih.gov/16362988/

  Antigenic variation through gene conversion has been hypothesized to be one mechanism of escaping immune surveillance, allowing for prolonged infection and persistence in the presence of a robust host response. […] In pregnancy, intense inflammatory responses and prostaglandins induced by fetal infection may be responsible for fetal death or pre-term delivery and severe growth retardation or other manifestations of congenital syphilis. […] Understanding of the molecular targets of these immune responses may facilitate the development of vaccines for syphilis.

• #19

  https://www.jci.org/articles/view/57173

  Recent evidence suggests that T. pallidum organisms may be able to evade the acquired immune response by antigenic variation of bacterial surface proteins, consistent with the resistance to phagocytosis of those select treponemes that survive bacterial clearance of the primary lesion. […] Antigenic variation is well described in related spirochetes that cause relapsing fever and Lyme disease, each of which also has a multistage clinical course. […] Molecular studies of TprK show that new variants arise by segmental gene conversion, with the new sequences coming from a large repertoire of donor sites located elsewhere on the chromosome. […] The resulting changes in exposed variable regions of TprK enable the organism to evade antibody binding and opsonophagocytosis.

• #20 Syphilis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK534780/

  Syphilis is a systemic, bacterial infection caused by the spirochete Treponema pallidum. The infection progresses through 4 stages (primary, secondary, latent, and tertiary) and can affect virtually every organ system in the body, even many years or even decades after the original infection. […] The untreated infection progresses through 4 stages (primary, secondary, latent, and tertiary) and can affect multiple organ systems, often many years or even decades after the original infection. […] The classic primary syphilis clinical presentation is a solitary nontender genital chancre in response to invasion by the T pallidum. However, patients can have multiple non-genital chancres, such as on the digits, nipples, tonsils, and oral mucosa. These lesions can occur at any site of direct contact with the infected lesion and are accompanied by tender or nontender lymphadenopathy.

• #20 Syphilis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK534780/

  The clinical manifestations of secondary syphilis result from hematogenous dissemination of the infection and are protean: condyloma lata (papulosquamous eruption), lesions on the hands and feet, macular rash, diffuse lymphadenopathy, headache, myalgia, arthralgia, pharyngitis, hepatosplenomegaly, alopecia, and malaise. […] Both primary and secondary lesions resolve without treatment, and the patient enters either an early or latent phase in which no clinical manifestations are present. The infection can only be detected at this stage with serological testing. Some patients in this stage will progress to the tertiary stage, characterized by cardiovascular syphilis, late neurosyphilis (tabes dorsalis, syphilitic paresis), and late benign syphilis. […] The infiltrate in syphilis is a delayed hypersensitivity reaction to T pallidum. The infiltrate typically consists of plasma cells, lymphocytes, and histiocytes. It is often perivascular and typically demonstrates swelling of the endothelium that can eventually lead to ischemia and even complete arterial occlusion. […] The steady increase in the incidence of syphilis cases in the US and globally since 2000 makes it a resurging epidemic that requires additional attention and resources for earlier diagnosis and treatment.

• #21 Syphilis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/229461-overview

  Primary syphilis is characterized by the development of a painless chancre at the site of transmission after an incubation period of 3-6 weeks. […] Secondary syphilis develops about 4-10 weeks after the appearance of the primary lesion. During this stage, the spirochetes multiply and spread throughout the body. […] Currently, tertiary syphilis disease is rare. When it does occur, it mainly affects the cardiovascular system (80-85%) and the CNS (5-10%), developing over months to years and involving slow inflammatory damage to tissues. […] Gummatous syphilis is characterized by granulomatous lesions, called gummas, which are characterized by a center of necrotic tissue with a rubbery texture. […] Neurosyphilis has several forms. If the spirochete invades the CNS, syphilitic meningitis results.

• #22 Syphilis | GLOWM

  https://www.glowm.com/section-view/heading/Syphilis/item/30

  The pathogenesis of syphilis is not completely understood but is characterized across all stages by vasculitis (endarteritis and periarteritis) and, in gummatous lesions, by granulomas. After sexual exposure, Treponema pallidum subspecies pallidum invades the body through mucous membranes or abraded skin. It rapidly attaches to host cells and begins to multiply. Within hours, organisms appear within regional lymph nodes and disseminate to multiple organs through the circulation using their corkscrew motility to escape through the tight junctions of vascular endothelium. The primary ulcerative lesion, or chancre, develops at the site of inoculation with the recruitment of a dense perivascular infiltrate of mononuclear cells, which includes HIV target cells such as CD4+ lymphocytes, as well as plasma cells and histiocytes. This usually occurs within 2-6 weeks after infection but is dependent on inoculum size, with large inocula (e.g., 10^7 organisms) resulting in chancre formation within a week.

• #23 Introduction to Sexually Transmitted Diseases and Syphilis (

  http://web.biosci.utexas.edu/field/mic361a/mic361/std%20trep.htm

  b. Secondary Syphilis: The ulcer heals spontaneously, but the organisms continue to disseminate in the tissues, localizing in blood vessels and spreading to skin, liver, joints, muscle and brain. […] […] c. After secondary syphilis: About 1/3 of cases progress to cure without treatment. About 1/3 of cases remain latent (3-30 years) with no clinical signs of disease. […] […] d. Congenital Syphilis: An infected woman can transfer T. pallidum to the fetus after the 3rd month of pregnancy. Transmission in utero may result in the birth of an asymptomatic infant or in miscarriage, stillborn birth, or death of the fetus. […] […] 6. Unanswered questions: […] a. Why does the primary chancre heal? […] b. Why don’t the body’s defense mechanisms prevent secondary syphilis? […] c. How do the organisms survive in the body for such long periods of time?

• #24 Secondary Syphilis: Pathophysiology, Clinical Manifestations, and Diagnostic Testing

  https://www.mdpi.com/2674-0710/2/2/6

  Secondary syphilis is a stage of the disease with the most exuberant local and systemic clinical manifestations. […] The basis of the pathogenesis of secondary syphilis underscores the unique mechanisms by which Treponema pallidum utilizes to escape immune recognition while simultaneously induces inflammation. […] T. pallidum utilizes adherence mechanisms to bind to epithelia and underlying fibronectin, as well as laminin; after dissemination through the bloodstream, the spirochete invades tissues via inter-junctional penetration, which allows it to escape to the skin. […] The clinical manifestations of secondary syphilis result from the local inflammatory response elicited by syphilis spirochetes replicating within tissues. […] T. pallidum provokes an intense inflammatory response in the skin, with the presence of various cytokines (IFN-γ and TNF-α), chemokines (CCL2 and CXCL10), macrophage and dendritic cell (DC) activation markers (CD40 and CD86), Fc-mediated phagocytosis receptors (FcγRI and FcγR3), and IFN-β and effector molecules associated with CD8 and NK cell cytotoxic responses. […] Despite the overt inflammation, immune cells are inefficient in phagocytosing these spirochetes. […] The immune evasiveness of T. pallidum is also demonstrated by the fact that its infection does not lead to immunity against reinfection, and repeated episodes of syphilis may occur.

• #25 Syphilis | GLOWM

  https://www.glowm.com/section-view/heading/Syphilis/item/30

  The signs and symptoms of secondary syphilis are caused by the dissemination and proliferation of treponemes in affected tissues. This dissemination and deposition of lymphocytes and plasma cells in the dermis, which characterizes secondary syphilis, begins during the formation of the primary chancre, but the manifestations appear approximately 4-12 weeks after initial infection. The deposition of circulating immune complexes in affected organs, such as the liver or kidneys, also is a major factor in the pathogenesis of the lesions of secondary syphilis. […] Both the latent and tertiary stages of syphilis are characterized by the presence of treponemes in tissues. However, the pathogenesis of these stages is not completely understood, and the pathogenic trigger that causes progression from the latent to tertiary stage continues to be investigated. During the latent stage of syphilis, treponemes present in tissues exhibit little to no replication. This period of quiescence results from a relative equilibrium between treponemal activity and host response that does not invoke acute disease. A waning of the host immune response may break this equilibrium and lead to the increased treponemal activity of tertiary syphilis. The pathogenesis of tertiary syphilis is characterized by the inflammatory invasion of treponemes in major organs, such as the brain, heart, eyes, and skin, and activation of a delayed-type hypersensitivity response.

• #26 Pathogen Safety Data Sheets: Infectious Substances – Treponema pallidum – Canada.ca

  https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/treponema-pallidum-pathogen-safety-data-sheet.html

  Symptomatic manifestations include cardiovascular syphilis, which can present as aortitis, angina, aortic regurgitation, coronary artery stenosis or aneurysms, gummatous syphilis, characterized by granulomatous or ulcerative lesions occurring in a variety of organs, or late neurosyphilis. […] Neurosyphilis can occur at any time after initial infection; T. pallidum may be frequently identified in the cerebrospinal fluid (CSF) of patients with early disease, although most patients with early syphilis and CSF abnormalities are asymptomatic. […] Early symptomatic neurosyphilis can manifest as symptomatic syphilitic meningitis, characterized by severe headache, confusion, nausea, vomiting, and neck stiffness. […] T. pallidum subsp. endemicum causes endemic syphilis, also known as bejel. […] T. pertenue is the causative agent of yaws and causes primary, secondary, and tertiary lesions.

• #27 Pathogenesis and Clinical manifestations of Treponema pallidum

  https://microbenotes.com/pathogenesis-and-clinical-manifestations-of-treponema-pallidum/

  This primary lesion always heals spontaneously, but 210 weeks later, the secondary lesions appear. […] The lesions of secondary syphilis are highly infectious and these lesions gradually resolve and a period of latent infection is entered, in which no clinical manifestations are evident, but serological evidence of infection persists. […] Tertiary syphilis is the tissue-destructive phase that appears 10 to 25 years after the initial infection in upto 35% of untreated patients. […] It is a slowly progressive, destructive, inflammatory disease that may affect any organ. […] The three most common forms are neurosyphilis, cardiovascular syphilis and gummatous syphilis a rare granulomatous lesion of the skeleton, skin or mucocutaneous tissues. […] Treponemes can cross the placental barrier from the bloodstream of an infected mother and cause disease in the fetus where unborn fetus may develop an asymptomatic infection or symptomatic infection with damage to the bone and teeth, deafness, neurosyphilis, or neonatal death.

• #28 Syphilis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Syphilis_pathophysiology

  Syphilis is associated with increased transmission of HIV. The underlying mechanism may be related to the accumulation of dendritic cells containing CCR5 co-receptors at the site of infection, the same receptor entity binding the HIV. […] On microscopic histopathological analysis, characteristic findings of syphilis depends on the stage of the disease: […] Small vessel inflammation (endarteritis obliterans). Granulomatous lesions (gumma) containing central necrosis, inflammatory cells, such as lymphocytes, macrophages, plasma cells and fibroblasts.

• #29 Neurosyphilis: Overview of Syphilis of the CNS, Pathophysiology of Syphilis, Epidemiology of Syphilis

  https://emedicine.medscape.com/article/1169231-overview

  Syphilis is a sexually transmitted disease caused by Treponema pallidum, with human beings as the only host. […] Syphilitic infection of the nervous system results in the most chronic, insidious meningeal inflammatory process known. Invasion of the CNS occurs early in the course of untreated syphilis. […] The pathogenesis of neurosyphilis is similar to that in the rest of the body. Parenchymal involvement ensues. […] The pathogenesis is primarily obliterative endarteritis of terminal arterioles with resultant inflammatory and necrotic changes. […] The pathogenesis of the Jarisch-Herxheimer reaction is unclear. […] The pathogenesis of necrotizing neurosyphilis is considered the quaternary form of syphilis.

• #30 Neurosyphilis – UpToDate

  https://www.uptodate.com/contents/neurosyphilis

  Neurosyphilis begins with invasion of the cerebrospinal fluid (CSF), a process that probably occurs shortly after acquisition of T. pallidum infection. The organism can be identified in the CSF from approximately one-quarter of untreated patients with early syphilis. Specific strains of T. pallidum may be more likely to cause neurosyphilis. […] Unlike other bacteria that can infect the CSF, invasion of CSF with T. pallidum does not always result in persistent infection, as spontaneous resolution may occur in some cases without an inflammatory response. In other cases, spontaneous resolution may occur after a transient meningitis.

• #31 Syphilis – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/sexually-transmitted-infections-stis/syphilis

  The spirochete spreads in the bloodstream, producing widespread mucocutaneous lesions, lymph node swelling, and, less commonly, symptoms in other organs. […] Neurosyphilis has several forms: Asymptomatic neurosyphilis, Meningovascular neurosyphilis, Parenchymatous neurosyphilis, Tabes dorsalis. […] Most patients with tabes dorsalis are thin and have characteristic sad facies and Argyll Robertson pupils (pupils that accommodate for near vision but do not respond to light). […] Ocular syndromes can affect virtually any part of the eye; they include interstitial keratitis, uveitis (anterior, intermediate, and posterior), chorioretinitis, retinitis, retinal vasculitis, and cranial nerve and optic neuropathies. […] Patients with ocular syphilis are at risk of neurosyphilis. […] For ocular syphilis, otic syphilis, or neurosyphilis, one of the following is recommended: Aqueous penicillin 3 to 4 million units IV every 4 hours (penetrates the central nervous system best but may be impractical).

• #32 Syphilis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/229461-overview

  Meningovascular syphilis occurs as a result of damage to the blood vessels of the meninges, brain, and spinal cord, leading to infarctions causing a wide spectrum of neurologic impairments. […] The rate of HIV and syphilis co-infection is high. More than 50% of MSM with syphilis are also infected with HIV, and this number increases with each recurrence.

• #33

  https://www.meddean.luc.edu/lumen/meded/mech/cases/case21/syphilis.htm

  The most characteristic lesion of late cardiovascular syphilis is the development of an aneurysm of the ascending and transverse segments of the aortic arch as a result of gummatous changes in the middle coat of the aorta and loss of elasticity. This aneurysm can lead to aortic valve incompetence, pressure necrosis of structures adjacent to the aorta, or rupture of the aorta. […] The isolated gumma is a granulomatous reaction to T. pallidum infection. It occurs most often in skin, bones, or joints, but may involve any organ. […] In the early stages of syphilis, the patient rapidly becomes immune to reinfection, but immunity is short-lived if the patient is successfully treated. In the later stages, immunity to reinfection is more solid and continues after treatment.

• #34 Syphilis – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/syphilis/

  Spirochetes invade the body disseminate systemically within hours bind to endothelial cells inflammatory reaction endarteritis and perivascular inflammatory infiltrates. […] Treponema bacteria (particularly during stages I and II) are highly contagious. […] Aortitis, ascending aortic aneurysm (thoracic aortic aneurysm), syphilitic mesaortitis, aortic root dilation and insufficiency. […] Due to Treponema-induced vasculitis of the vasa vasorum of the large vessels (especially the aorta), resulting in vessel wall atrophy, and thereby, aneurysm formation.

• #35 Syphilis | GLOWM

  https://www.glowm.com/section-view/heading/Syphilis/item/30

  As in adults, the pathogenesis of congenital syphilis results from an obliterative endarteritis characterized by perivascular mononuclear and plasma cell infiltrates, intimal hyperplasia, and bloated, hyperplastic endothelial cells. Both treponemal lipoproteins and intact, motile organisms activate vascular endothelium.

• #36 SciELO – Public Health – Maternal syphilis: pathophysiology and treatment Maternal syphilis: pathophysiology and treatment

  https://www.scielosp.org/article/bwho/2004.v82n6/433-438

  The organism has genes for 22 different lipoproteins, which may elicit strong inflammatory responses. […] However, many questions remain unanswered because despite the genomic sequencing the functions of more than 40% of the genes in the sequence are as yet unknown. […] Fetal infection is a result of haematogenous spread from an infected mother, although transmission at the time of delivery can result from direct contact with infectious genital lesions of the mother. […] Haematogenous spread is dependent upon the occurrence of maternal spirochaetaemia. […] Since the early stage of syphilis is characterized by spirochaetaemia, the probability of transmission to the fetus is nearly 100% if the mother has early syphilis. […] The main factors that determine the probability of fetal transmission are stage of maternal syphilis and duration of exposure in utero.

• #37 LSHTM LSHTM Research Online

  https://researchonline.lshtm.ac.uk/4696/

  In pregnancy, intense inflammatory responses and prostaglandins induced by fetal infection may be responsible for fetal death or pre-term delivery and severe growth retardation or other manifestations of congenital syphilis. […] Understanding of the molecular targets of these immune responses may facilitate the development of vaccines for syphilis.

• #38 SciELO – Public Health – Maternal syphilis: pathophysiology and treatment Maternal syphilis: pathophysiology and treatment

  https://www.scielosp.org/article/bwho/2004.v82n6/433-438

  It is useful to review the manifestations of fetal involvement and to note that the microscopic appearance of syphilitic lesions is similar whether manifested in the fetus, adult or infant. […] These typical lesions reflect an inflammatory response, and have suggested to some researchers an important role for cytokines in the pathophysiology of disease secondary to syphilis. […] Additional work has suggested that the interaction of T. pallidum with vascular endothelium may be an important early event in the host immune response, resulting in initiation of an inflammatory cascade. […] The pathology suggests multi-organ involvement, with an extensive inflammatory response. […] The importance of treating maternal syphilis early in gestation was demonstrated by Gust et al. […] To reduce perinatal mortality by 70%, all pregnant women with syphilis must be treated before 21 weeks of gestation. […] There is much to be learned about pathophysiology of syphilis during pregnancy.

• #39 An analysis of the clinical features of children with early congenital Syphilis and Syphilitic Hepatitis | BMC Pediatrics | Full Text

  https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-021-02932-5

  The infection rate of congenital syphilis is gradually increasing, the clinical manifestations of some children with congenital syphilis are abnormal liver function, which is given the clinical diagnosis of syphilitic hepatitis. […] Syphilitic hepatitis is liver damage caused by Treponema pallidum, which mostly occurs in late syphilis. […] The key to the treatment of syphilitic hepatitis lies in the complete elimination of Treponema pallidum. […] The specific causes of infantile hepatitis include infectivity, immunity, heredity, and metabolism, as well as poisons or drugs. Syphilis is an infectious cause of infantile hepatitis, accounting for about 1.2%. […] The pathogenesis of syphilitic hepatitis has not been fully elucidated. Ridruejo et al. found that liver biopsies of patients with syphilitic hepatitis had lymphocytic infiltration in the portal area, hepatocyte necrosis, noncaseating granuloma, and intrahepatic bile duct inflammation. Therefore, the underlying mechanism may be that the autoimmune response mediated by Treponema pallidum, or related immune complexes, directly damages the portal vein system, liver cells, and the intrahepatic bile duct system, leading to the onset of hepatitis.

• #40 An analysis of the clinical features of children with early congenital Syphilis and Syphilitic Hepatitis | BMC Pediatrics | Full Text

  https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-021-02932-5

  Liver function examinations of the 51 children with syphilitic hepatitis before treatment indicated that liver damage caused by the syphilis infection was often due to the increase of ALT, AST, and bilirubin, and the decrease of proteins, especially albumin. After the diagnosis of syphilis, the children underwent standard treatment with penicillin, which in many cases had significant therapeutic effects, with rapid improvement in symptoms, and the obvious recovery of liver function, manifested by clear improvement in alanine aminotransferase, aspartate aminotransferase, albumin, and bilirubin.

• #41 Syphilis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/syphilis/symptoms-causes/syc-20351756

  Disease that spreads to the eye is called ocular syphilis. It can cause eye pain or redness, vision changes, blindness. […] These may include bulging and swelling of the aorta the body’s major artery and other blood vessels. Syphilis also may damage heart valves. […] Syphilis sores on the genitals raise the risk of catching or spreading HIV through sex. A syphilis sore can bleed easily. This provides an easy way for HIV to enter the bloodstream during sex. […] If you’re pregnant, you could pass syphilis to your unborn baby. Congenital syphilis greatly raises the risk of miscarriage, stillbirth or your newborn’s death within a few days after birth.

• #42 Introduction to Sexually Transmitted Diseases and Syphilis (

  http://web.biosci.utexas.edu/field/mic361a/mic361/std%20trep.htm

  d. Are the organisms extracellular or intracellular? […] e. Does the specific immune response contribute to disease? Is the damage done in tertiary syphilis due to an overactive delayed type hypersensitivity response or do antibodies play a role? […] […] D. Treatment: Penicillin G effective at all stages of disease. A single injection can eradicate T. pallidum and cure early syphilis. No resistance to penicillin.

• #43 A large screen identifies beta-lactam antibiotics which can be repurposed to target the syphilis agent | npj Antimicrobials and Resistance

  https://www.nature.com/articles/s44259-023-00006-3

  Syphilis, caused by the spirochete Treponema pallidum subsp. pallidum (hereafter called T. pallidum), is re-emerging as a worldwide sexually transmitted infection. A single intramuscular dose of benzathine penicillin G is the preferred syphilis treatment option. […] We reasoned that other -lactams may be equally or more effective at targeting the disease-causing agent, Treponema pallidum, but have yet to be discovered due to a previous lack of a continuous in vitro culture system. […] Our studies not only identified additional potential therapeutics in the resolution of syphilis, but provide techniques to study the complex biology of T. pallidum, a spirochete that has plagued human health for centuries. […] The primary treatment option for early syphilis is a single intramuscular dose of the -lactam benzathine penicillin G (also known as benzathine penicillin), which could pose several problems.

• #44 A large screen identifies beta-lactam antibiotics which can be repurposed to target the syphilis agent | npj Antimicrobials and Resistance

  https://www.nature.com/articles/s44259-023-00006-3

  We reasoned that there are other -lactams with similar or greater efficacy against T. pallidum, relative to benzathine penicillin G, but have yet to be discovered. […] We determined the relative in vitro efficacy of 89 -lactams found in a commercially available compound library. […] The efficacy of a particular type of -lactam to treat a bacterial infection is largely based on outer membrane penetrance and the affinity for one or more essential PBPs in PG synthesis. […] We further broke down each group by generation and found striking trends. […] Our initial screen yielded many promising candidates, which we went on to analyze further. […] Minimum inhibitory concentration (MIC) calculations are the gold standard for determining the efficiency of a treatment in the context of antimicrobials.

• #45 A large screen identifies beta-lactam antibiotics which can be repurposed to target the syphilis agent | npj Antimicrobials and Resistance

  https://www.nature.com/articles/s44259-023-00006-3

  PBPs, the target of -lactams, catalyze transglycosylase and transpeptidase reactions required for cell elongation and division, respectively. […] We reasoned that this scenario could be circumvented by analyzing purified PG. […] To determine how and/or if selected -lactams impact T. pallidum PG synthesis at the cellular level, we co-incubated cultures with HADA and each compound at a final concentration of 2 times the MIC. […] Our studies uncovered several compounds that may be appropriate to treat syphilis in a clinical setting. […] The high degree of efficacy at low nanomolar concentrations of the compounds, with several compounds having lower MICs compared to benzathine penicillin G, make them strong candidates for future in vivo studies. […] The four other -lactams we identified as being highly active against T. pallidum were cephalosporins, albeit to a lesser extent than the penicillin group. […] A wealth of T. pallidum knowledge has been produced despite the experimental challenges attributed to a lack of a stable in vitro culture system.

• #46 Syphilis: antibiotic treatment and resistance | Epidemiology & Infection | Cambridge Core

  https://www.cambridge.org/core/journals/epidemiology-and-infection/article/syphilis-antibiotic-treatment-and-resistance/D8519DE049A3F96B18C7F29A50E5D437

  Syphilis is a chronic, multi-stage infectious disease that is usually transmitted sexually by contact with an active lesion of a partner or congenitally from an infected pregnant woman to her fetus. […] The emergence of clinically significant azithromycin resistance in Treponema pallidum subsp. pallidum, the syphilis agent, has resulted in treatment failures, thus precluding the routine use of this second-line drug. […] Factors involved in syphilis pathogenesis are poorly understood. […] Despite documented erythromycin resistance in T. pallidum Street strain 14, there was considerable enthusiasm early on for the use of azithromycin for treatment of syphilis, particularly for resource-limited settings where the burden of syphilis is high and the use of injectable drugs is problematic.

• #47 Syphilis: antibiotic treatment and resistance | Epidemiology & Infection | Cambridge Core

  https://www.cambridge.org/core/journals/epidemiology-and-infection/article/syphilis-antibiotic-treatment-and-resistance/D8519DE049A3F96B18C7F29A50E5D437

  However, during 2002-2003, treatment failures were observed in eight patients in San Francisco, California. […] Macrolide-resistant T. pallidum with the A2058G mutation is now present in several areas of the USA, Canada, Europe, and China and has been reported recently in Sydney, Australia. […] The persistence of low levels of azithromycin in tissues for weeks after treatment for unrelated infections is likely to allow for selection of resistant mutants of T. pallidum that arise de novo. […] Thus, azithromycin-resistant T. pallidum strains may be able to persist in sexual networks. […] The A2058G mutation is stable in the absence of selective pressure. […] Thus, point mutations at the relevant position in one or both copies of the T. pallidum 16S rRNA gene could result in doxycycline resistance. […] Addressing the resurgence of syphilis and the emergence of macrolide-resistant T. pallidum will require effort on several fronts.

• #48 Syphilis: Cause, Symptoms, Diagnosis, Treatment & Prevention

  https://my.clevelandclinic.org/health/diseases/4622-syphilis

  Your healthcare provider treats syphilis with antibiotics. Antibiotics are a type of medication that treats bacterial infections. Penicillin is the most commonly used medication for syphilis. How much medication you need and how long you take it depends on your syphilis stage and symptoms. […] Yes. Your healthcare provider can treat syphilis with antibiotics. Antibiotics will cure the infection, but theres no way to repair organs damaged by syphilis.

• #49 Syphilis | Nature Reviews Disease Primers

  https://www.nature.com/articles/nrdp201773

  Treponema pallidum subspecies pallidum (T. pallidum) causes syphilis via sexual exposure or via vertical transmission during pregnancy. T. pallidum is renowned for its invasiveness and immune-evasiveness; its clinical manifestations result from local inflammatory responses to replicating spirochaetes and often imitate those of other diseases. […] Strong advocacy and community involvement are needed to ensure that syphilis is given a high priority on the global health agenda. More investment is needed in research on the interaction between HIV and syphilis in MSM as well as into improved diagnostics, a better test of cure, intensified public health measures and, ultimately, a vaccine. […] The review provided a very informative summary of the interaction of T. pallidum and its human hosts.

• #50

  https://www.jci.org/articles/view/57173

  Syphilis is a fascinating and perplexing infection, with protean clinical manifestations and both diagnostic and management ambiguities. Treponema pallidum subsp. pallidum, the agent of syphilis, is challenging to study in part because it cannot be cultured or genetically manipulated. Here, we review recent progress in the application of modern molecular techniques to understanding the biological basis of this multistage disease and to the development of new tools for diagnosis, for predicting efficacy of treatment with alternative antibiotics, and for studying the transmission of infection through population networks. […] Despite the difficulties in working with T. pallidum, much has been learned about the molecular basis of syphilis pathogenesis. For each stage of infection, we review the most closely related steps of pathogenesis.

• #51 Genetic engineering of Treponema pallidum subsp. pallidum, the Syphilis Spirochete | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009612

  Despite more than a century of research, genetic manipulation of Treponema pallidum subsp. pallidum (T. pallidum), the causative agent of syphilis, has not been successful. The lack of genetic engineering tools has severely limited understanding of the mechanisms behind T. pallidum success as a pathogen. […] A better understanding of T. pallidum biology and syphilis pathogenesis would help devise better control strategies for this infection. […] Here, we report a transformation protocol that allowed us to replace a specific region of the T. pallidum genome containing a pseudogene (i.e., a non-functional gene) with a stably integrated kanamycin resistance gene. […] Our work provides evidence that transformation and genetic manipulation of T. pallidum is attainable. This is a significant step forward in the field. Our discovery opens numerous possibilities, including classical genetic studies in this pathogen, the long-awaited application of functional genomics techniques, and even the possibility of targeting virulence factors responsible for immune evasion and persistence to obtain an attenuated strain to inform vaccine development efforts.

• #52 Genetic engineering of Treponema pallidum subsp. pallidum, the Syphilis Spirochete | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009612

  Given the significant impact of syphilis on human health, there is great interest in deepening our understanding of the molecular mechanisms underlying its pathogenesis. In turn, this could lead to improved strategies for disease control and vaccine development. A critical step in this direction is the identification of treponemal factors that contribute to virulence. […] The result that the ratio between the kanR gene and tp0574 was higher than originally expected was intriguing and worth discussing in the context perhaps of molecular detection assays for T. pallidum. […] We demonstrate that genetic engineering of the syphilis spirochete is possible with a relatively simple method that has the potential to transform our way to approach the study of T. pallidum biology and syphilis pathogenesis.

• #53

  https://journals.lww.com/stdjournal/fulltext/2024/11000/new_pathways_in_syphilis_vaccine_development.15.aspx

  The high prevalence of syphilis worldwide and the recurring global shortages of benzathine penicillin G underscore the necessity for novel measures to control syphilis transmission. […] The syphilis field has been searching for a subunit vaccine capable of conferring a near-complete level of protection in animal experiments. This vaccine ideally would be appealing to industry partners and could be transitioned to clinical trials within a matter of years. […] Studies on T. pallidum biology have flourished and focused on the antigenic composition of the T. pallidum outer membrane and the role of outer membrane proteins (OMPs) in syphilis pathogenesis. […] Given that T. pallidum clearance during infection is mediated by phagocytosis of opsonized pathogen cells by activated macrophages, the OMPs of the syphilis spirochete are regarded as primary targets for vaccine development efforts.

• #54

  https://journals.lww.com/stdjournal/fulltext/2024/11000/new_pathways_in_syphilis_vaccine_development.15.aspx

  The presumptive features of an effective syphilis vaccine include the ability to induce opsonic antibodies and strong cellular responses to the vaccinogen, specifically by T-helper 1 response cells. […] T. pallidum biology also poses a unique challenge for vaccine development. Because of the paucity of surface-exposed antigens, multiple OMP epitopes must be targeted to facilitate pathogen recognition, particularly for antigens whose expression is not constitutive and can be regulated or altered through phase variation at the transcriptional or translational level or through other still unknown mechanisms. […] The UConn/Duke CRC U19 syphilis vaccine program was founded on an understanding of the molecular architecture of the T. pallidum outer membrane derived from years of investigation of this fragile, protein-poor lipid bilayer.

• #55

  https://journals.lww.com/stdjournal/fulltext/2024/11000/new_pathways_in_syphilis_vaccine_development.15.aspx

  As in other diderm bacteria, OMPs in T. pallidum adopt a -barrel conformation in which ECLs bridge neighboring -strands; antibodies that promote clearance of spirochetes must target ECLs. […] An in-depth exploration of the antigenic targets and their variants within T. pallidum OMPs on a global scale will provide valuable insights into the immunogens capable of eliciting opsonic antibodies and help inform future studies of potentially protective mechanisms for vaccine development.

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