Spirochaetes

1. Spirochaetes

2. Spirochaetes- Introduction • Spirochetes are simple bacteria, with less than 1000 genes • Each type has a characteristic helical shape • Some are tightly coiled like a telephone cord, while others are more open • Three major families • Brachyspiraceae • Leptospiraceae • Spirochaetaceae • Spirochetes are Gram-negative and with a flagellar bundle running through their periplasmic space • The spirochete flagella run in the perplasmic space, causing the cells to move / propel in a corkscrew fashion

3. Movement of Spirochaetes • These organisms can swim easily through gel-like materials that hinder most other flagellated organisms • ecological niches, such as sediments in pond and lake bottoms, • the gutsof certain arthropods • and the rumens of cows and sheep (a) Scanning electron micrograph of spirochetes, Treponemapallidum • (b) Diagram of axial filament wrapped • around a spirochete (c) Cross section of the spirochete, which reveals that the axial filament is composed of endoflagella

4. Syphilis- Prevalence and history • According to WHO, there are 12 million cases of syphilis each year • Very ancient disease and was much more virulent in XV-XVI centuries • Columbian hypothesis about the spread: disease started in Africa, Asia and then North America • It is suggested that soon syphilis changed from an acute, rapid and debilitating disease to a milder chronic infection- modern syphilis possibly due to selective pressure lead to the readjustement of the pathogens virulence • During early 1900, syphilis was estimated to affect 10% of US and Western population

5. Treponemapallidum- syphilis • The spirochete bacterium Treponemapallidum- the cause of syphilis • Syphilis is an STD i.e. spread mostly by sexual contact, except for congenital syphilis, which is spread from mother to fetus • Transmission by sexual contact requires exposure to moist lesions of skin or mucous membranes • Transmission of infection depends on the existence of infectious lesions (sores), which may or may not be visible

6. Therapy • No natural immunity to syphilis develops and past infection offers no protection to future exposure • Syphilis is relatively easily treated with antibiotics such as penicillin, usually given as consecutive daily intramuscular injections • Patients who are allergic to penicillin may be treated with tetracycline • The symptoms of syphilis occur in three stages called primary, secondary and late

7. Stages of Syphilis • The first sign of syphilis is a lesion known as a "chancre“- a clean, painless, induratedulcer • Common sites for the lesions include genitalia, rectum, urethra and mouth • May last for 1-5 weeks and may resolve itself Unresolved syphilis can lead to destruction of soft tissue and bone, heart failure, blindness and a variety of other conditions which may vary After 6 weeksother symptoms may occur such as tiredness, fever, sore throat, headaches, hoarseness, loss of appetite, hair loss and swollen glands two to six weeks and generally disappear

8. Evasion of host immune defenses • Lack o f endo and exotoxins: • No LPS • No cytotoxic proteins (no swelling or indentation) • Cultured cells with attached bacterium were observed to remain uneffected from 5-7 days • Invasion of "immune-privileged" tissues: • central nervous system, eye, and placenta • Lack of common surface antigens: • T. pallidum is that its cell has only rare integral proteins in its outer membrane, appro ximately 1% o f the number found in the outer membrane o f E. coli • Ability to maintain infection with few organisms • T. pallidum may also exploit its slow metabolism (30-33 hrs) to survive in tissues, even those that are not immune privileged • Bymaintaining infection with very few organisms in anatomical sites distant fro m one another, T. pallidum may prevent its clearance by failing to trigger the host's immune response, which was speculated to require a "critical antigenic mass"

9. Low iron requirement s, ability to obtain sequestered iron • Iron sequestration is one of the important defense mechanisms used by the infected host • The host's transferrin and lactoferrin proteins bind free iron making it unavailable to bacteria and impairing their growth. T. pallidum may be able to acquire iron from these host proteins • In addition it lacks an electron transport chain, which is made up o f enzymes that use iron as a cofactor, which decreases its overall demand for iron • It may also overcome the iron sequestration by using enzymes that need metals other than iron as their co-factors

10. Orchestrated regulation of expression of antigens • Regulation of expression of related proteins is referred to as phase variation and may be used by T. pallidum to down-regulate the expression of those Tprs against which an immune response has been mounted, while simultaneously up-regulating the expression of new Tprs, which are not recognized by the existing immune response • This strategy may help T. pallidum maintain chronic infection • Several genes that encode candidate outer membrane proteins belong to the tpr gene family which contains twelve genes that are divided into three subfamilies I, II, and III) • Antibody responses arise at different times after infection: anti-TprKantibodies are seen as soon as 17 days postinfectionand are robustly reactive at day 30 • while antibodies against the members of subfamilies I and II often are not detectable until 45 days after infection and reach peak titers at day 60 • The time of development o f antibodies to specific Tprs may reveal the timing of expression of the proteins that induced those antibodies

11. Antigenic variation o f TprK protein • Diverse tprK sequences have been demonstrated between subpopulations o f every T. pallidum strain within single host • Recent studies identifiedTprK as a membrane-localized protein • The tprK gene and predicted protein amino acid sequences are characterized by seven discrete variable (V) regions that are separated by stretches of conserved sequences • DNA sequence cassettes that correspond to V-region sequences were discovered in an area of the T. pallidum chromosome separate from the tprKgene • These cassettes are potential sequence donors and are presumed to replace portions of V-region sequences in the tprKgene • The TprKprotein elicits both cellular and humoral immunity in infected animals • Antibodies to TprK that arise in response to T. palliduminfection are specifically targeted to the V regions • Very slight changes of the amino acid sequence in a V region can abrogate the ability of antibodies to bind the V region • Thus, the host immunity may eliminate organisms that express TprK sequences against which specific antibodies have been developed but not for the new variation in TprK

12. Resistance to macrophages in subpopulation of the pathogen • Opsonizingagents are serum components, antibodies, o r the complement protein C3b, which make the pathogen recognizable to macro phages via specific cell surface receptors • Majority o f treponemes that multiplied in quantities at the site of initial infection usually are cleared by macrophages • However, a small subpopulation of the organisms persists and appears to resist ingestion by macrophages • T. pallidum antigens, including Tp92 and TprK, have been shown to induce production of opsonic antibodies • Antibodies against the VDRL (Venereal Disease Research Laboratory) antigen, a complex of cardiolipin, cholesterol, and lecithin, also increase the phagocytosis o f T. pallidumby macrophages • This phenomenon suggests that opsonic antibodies do not bind these organisms, thus allowing them to survive in the face of active immune clearance

13. Resistance to neutralization by antibodies • Besides opsonization, there are other functions of antibodies produced during T. palliduminfection • Antibodies developed against T. pallidumimmobilize organisms and block them from binding the host's cells • Administration of whole serum and fractionated IgGfrom long-term-infected rabbits delays lesion formation in challenged rabbits, but lesions develop at the inoculation site within days of discontinuing the treatment • This demonstrates that specific antibody alone, while inhibitory to the establishment of lesions, is not sufficient to kill T. pallidum and prevent infection

15. Immune evasion by Spirochaetes • Another spirochete, the tick-borne Borreliaburgdorferi, is the cause of Lyme disease, which occurs as a result of chronic infection by the bacterium • Some strains of B. burgdorferimay avoid lysis by complement by coating themselves in the complement-inhibitory protein factor H made by the host which binds to receptor proteins in the bacterium's outer membrane