Treponematoses from the Great Pox to the Tuskegee Syphilis Study

11/9/20

Treponematoses From the Great Pox to the Tuskegee Syphilis Study

Sick: 10,000 years of health and disease

What is treponematosis?

• Treponema • Cork-screw shaped bacterial genus in the phylum Spirochaetes • Genus of >30 host-associated bacteria, mostly oral and gut microbiome associated, to date mostly isolated from insects and mammals • Well known species: • Treponema succinifaciens: gut commensal that aids in mammalian digestion • Treponema denticola: oral pathobiont associated with periodontal disease • Treponema pallidum: skin pathogen causing treponematosis • Treponema pallidum • Pathogen causing skin disease that can become invasive • Treponema pallidum ssp. pallidum: Syphilis • Treponema pallidum ssp. pertenue: Yaws • Treponema pallidum ssp. endemicum: Bejel • Treponema carateum*: Pinta

Treponema pallidum identified as cause of syphilis ca. 1905 Treponema pallidum subspecies are >99.8% identical

*No genome is available for pinta, so its species designation is uncertain 2

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What is treponematosis? • Yaws • Found primarily in hot and humid tropical regions • Primarily transmitted in childhood (<15 years) via skin-to-skin contact with lesions • Associated with poverty and low sanitation • Typically begins as a large lesion (mother yaw) on the leg or foot • Primarily affects skin and bone • Bejel • Found primarily in hot and dry regions • Primarily transmitted in childhood (<15 years) via skin-to-skin contact with lesions, also contaminated drinking vessels and eating utensils • Associated with poverty and low sanitation • Also called endemic syphilis; often mistaken for leprosy • Typically begins as an unobserved oral lesion • Progresses to affect oral and nasal cavity mucosa and bone • Pinta • Found in warm and dry tropical America (but not reported in >20 years) • Transmitted among children and adults • Typically begins as lesions on the limbs • Generally restricted to skin and leads to depigmentation • Syphilis • Global distribution • Sexually transmitted and congenital (acquired in utero) • Less commonly transmitted by skin-to-skin contact • Typically begins as a genital lesion • Progresses to affect skin, bone, and central nervous system

Where is treponematosis?

Syphilis is global

Note: No pinta cases have been reported in 21st century; however there is no monitoring program 4

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Stages of treponematosis

• Stage 1: Primary • All treponematoses begin as skin or mucous membrane lesions • Dissemination is local, near point of transmission • Yaws: mother yaw, typically on foot or leg after ~21 day incubation • Bejel: typically unobserved oral lesions after 2-3 month incubation • Pinta: lesions on limbs after 1-2 month incubation • Syphilis: lesion on genitals, anal region or oral cavity, typically after 2-6 week incubation; spontaneously heals after 3-6 weeks

• Stage 2: Secondary • Infection disseminations systemically • Disseminated lesions in skin and mucosal membranes • Yaws: daughter yaws appear, can occur up to 2 years after primary infection; bone periostitis and osteitis can form, especially in fingers and toes; fever and malaise; heals spontaneously after weeks or months; can periodically relapse for a period of up to ~ 5 years • Bejel: mucosal lesions in oral cavity, tonsils, tongue and nasopharynx; non- itchy skin eruptions; periostitis and osteitis cause nocturnal bone pain; heals spontaneously after 6-9 months • Pinta: skin lesions appear months or years after primary infection and typically lasts 2-4 years • Syphilis: 4-10 weeks after primary infection, lesions form in oral cavity and on skin; many different manifestations, including rash, hair loss, headache, malaise, organ involvement, optic nerve inflammation, joint inflammation, more; goes latent but relapses in ~25%

Stages of treponematosis

• Latent Phase • Infection goes latent (dormant) in the body • No symptoms, no transmission • Most cases do not progress beyond this point • Stage 3: Tertiary • Systemic infection, serious and life threatening • Yaws: 10% progress to tertiary; periostitis of bones (saber shin), gummatous nodules, destruction of palate and nasal septum, collapse of nasal bridge; goundou formation • Bejel: most cases progress to tertiary; progression to tertiary sooner than in yaws; otherwise similar clinical features; also depigmentation and hyperpigmentation; focus of destruction is the oral cavity and nasopharynx • Pinta: progresses shortly after secondary phase; continues to only affect skin • Syphilis: ~30% progress to tertiary; typically occurs 3-15 years after initial infection; can lead to gummatous lesions, neurosyphilis, and cardiovascular syphilis; not infectious during this stage

Gerard de Lairesse

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What is treponematosis?

• Although long held to be distinct diseases caused by distinct species, genomic analysis increasingly indicates that they are caused by variants (subspecies or ecotypes) of the same species • Each subspecies is capable of producing symptoms indistinguishable from the others under specific circumstances • Differences in clinical symptoms may be primarily due to the age and manner of transmission • Specific gene variants or gene/loss events may be responsible for specific symptoms or disease courses, but the relationship between genes and pathology are still very poorly understood

Syphilis Suddenly appears in historical records in 15th/16th century

• Italian War of 1494: first accounts of syphilis in Naples • “Great pox” (as opposed to smallpox) • Jean Fernelius (Paris): “lues venera” (venereal pest), promoted mercury treatment (long in use since medieval period for various ailments) • Girolamo Fracastoro: “syphilis” • Named after the character of Syphlis in his poem, “Syphilis sive Morbus Gallicus (1530), about a man who enraged Apollo and was punished

• Like the 1918 influenza, it gets blamed on different populations based on national prejudices: • Italy, Germany, UK: “French disease” • France: “Neapolitan disease” • Russia: “Polish disease” • Poland: “German disease” • Denmark, Portugal, North Africa: “Spanish disease” • Turkey: “Christian disease” • India: Muslims blamed Hindus, and Hindus blamed Muslims • “in the end everyone blamed Europeans” 8

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Syphilis treatments Guaiacum • Treatment with extracts from the American tree Guaiacum officinale • Acts as purgative, was advertised as a “blood cleaner”, patients wrapped in blankets and encouraged to sweat out disease* • Used 1500s century onwards in Europe, earlier in Americas Mercury • In use since medieval times in Europe and circum-Mediterranean, through early 20th century • Ointments, pills mercury vapor inhalation Bismuth • Bismuth salts administered starting 1884 • Less toxic than mercury and slightly more bactericidal than mercury Arsenic • Salvarsan: arsphenamine • Discovered by Paul Ehrlich in 1907, therapeutic use beginning 1910 • First modern antimicrobial • Effective for early stage disease with a single injectable dose • However: side effects • In use through 1940s when gradually replaced by penicillin; but remained cheaper and easier to access than penicillin Penicillin • Discovered by Alexander Fleming in 1928, therapeutic use began in 1942 • Penicillin G (benzylpenicillin intravenous) • Fewer side effects but some allergies • Effective with a single injectable dose 9

Syphilis treatments

• Fever has long been noted to have positive therapeutic effects for neurosyphilis. Turpentine, mercury, Salmonella typhi (typhoid fever!), and Plasmodium vivax (malaria!) have been administered as treatments for syphilis because of their ability to produce fever.

• Julis Wagner-Jauregg discovered beneficial effects of malaria on syphilis in 1917 and received 1927 Nobel Prize for Physiology and Medicine for the discovery.

Wagner-Jauregg (blue arrow) watching a transfusion from a malaria patient (rear) to a neurosyphilis victim (center) in 1934

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Origin of syphilis

Four main hypotheses • Columbian hypothesis Columbian hypothesis • Pre-Columbian hypothesis Current data • Unitarian hypothesis • Evolutionary hypothesis

Pre-Columbian hypothesis

Unitarian hypothesis

Evolutionary hypothesis 11

Archaeology of Treponematoses

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Contributions of genomics

• Recent expansion of syphilis, with MRCA around 1744

Contributions of ancient DNA

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Still a puzzle?

French troops arriving in Naples, Italian War of 1494 15

Treponematoses today

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WHO eradication campaign

• WHO and UNICEF • 1950: 160 million yaws, 1 million bejel, 0.7 million pinta • 1952-1964: global eradication campaign using injectable benzathine penicillin (penicillin G) • 300M screened, 50M treated • Program phased out to allow remaining eradication to proceed under local control - failed • WHO, USAID, UNICEF, EEC Effect of a single dose of penicillin in • 1980 renewed effort, but failed to move 1950s beyond drawing board • WHO • 2012-2020: new global eradication campaign using azithromycin • Single dose of oral azithromycin as effective as injectable penicillin – first major advance in treatment in 60 years • Not on track to succeed: azithromycin antibiotic resistance

WHO eradication campaign

Modern treatments • Penicillin: 1929 (therapeutic use in 1942) • Pros: Effective, no known resistance despite decades of use • Cons: Requires cold chain and clean needles, trained personnel • Azithromycin: 1980 (therapeutic use in 1988) • Pros: Effective, oral pill, easily distributed to remote locations • Cons: Pathogen easily acquires resistance: Effect of a single dose of penicillin in A2058G/A2059G point mutation in 23 rRNA gene 1950s

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Antibiotic resistance

• Penicillin • Beta-lactam class of antibiotic • Inhibit cell wall biosynthesis of bacterium • Penicillin was first beta-lactam discovered; was produced by a rare variant of Penicillium rubens fungus • Discovered by Alexander Fleming in 1928 after a petri dish of Staphylococcus aureus bacteria became contaminated with a fungal colony over his holiday; he initially called it “mould juice” but eventually named it penicillin in 1929

Antibiotic resistance • Penicillin • Beta-lactam class of antibiotic • Inhibit cell wall biosynthesis of bacterium • Penicillin was first beta-lactam discovered; was produced by a rare variant of Penicillium rubens fungus • Discovered by Alexander Fleming in 1928 after a petri dish of Staphylococcus aureus bacteria became contaminated with a fungal colony over his holiday; he initially called it “mould juice” but eventually named it penicillin in 1929

Normal cell wall Peptidoglycan cell peptidoglycan wall disruption by synthesis penicillin

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Antibiotic resistance • Penicillin • Resistance requires set of changes that are unlikely to happen spontaneously • Typically acquired through horizontal gene transfer • Treponema do not easily take up new genes or plasmids through horizontal gene transfer • Thus, low chance of Treponema species acquiring resistance to beta-lactam antibiotics

Normal cell wall Peptidoglycan cell peptidoglycan wall disruption by synthesis penicillin

Antibiotic resistance

• Azithroymycin • Macrolide class of antibiotic • Interferes with translation of RNA • Prevents protein formation • Problem: minor mutations can prevent the action of azithromycin – resistance is easily acquired

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Antibiotic resistance

• Azithroymycin • A2058G/A2059G point mutation in 23 rRNA gene • Today, 90% of SS14 syphilis strains are azithromycin resistant • 25% of Nichols strains

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The Tuskegee Syphilis Study

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The Tuskegee Syphilis Study

• Tuskegee Syphilis Study • 1932 until 1970s

PRESENTATION: Vismaya, Grace, Leonardo