Spirochetes and Neisseria

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SPIROCHETES (Treponema, Borrelia and Leptospira)

Spirochetes are Gram negative bacteria that are long, thin, helical and motile. Axial filaments (a form of flagella) found between the peptidoglycan layer and outer membrane and running parallel to them, are the locomotory organelles.

Treponema pallidum and syphilis

T. pallidum is the causative agent of syphilis, a common sexually-transmitted disease found world-wide. It is generally transmitted by genital/genital contact. Transmission in utero or during birth can also occur. Syphilis, chronic and slowly progressive, is the third most common sexually transmitted disease. After initial infection, a primary chancre (an area of ulceration/inflammation) is seen in genital areas or elsewhere within 10-60 days. The organism, meantime, has penetrated and systemically spread. The patient has flu-like symptoms with secondary lesions particularly affecting the skin. These occur 2-10 weeks later. The final stage (if untreated) is tertiary syphilis (several years later). In primary and secondary syphilis organisms are often present in large numbers. However, as the disease progresses immunity controls bacterial replication and fewer organisms are seen. It is extremely difficult to detect spirochetes in tertiary syphilis. The systemic lesions of skin, central nervous system and elsewhere are suggestive of a delayed hypersensitivity reaction.

The organism cannot be cultured from clinical specimens. Thus, experimentally, syphilis is commonly studied in animal models. Also microscopic and serological methods are the only means of clinical diagnosis.

In primary syphilis (before immunity develops), the organisms are often present in sufficient numbers in exudates to be detected by dark field microscopy. In conventional light microscopy, the light shines through the sample and thin treponemes cannot be visualized. In dark field microscopy, the light shines at an angle and when reflected from the organism will enter the objective lens. The actively motile organisms appears brightly lit against the dark backdrop. Alternatively fluorescent antibody staining is used.

In secondary and tertiary syphilis, serological methods are usually used to detect syphilis. Screening methods are based on detecting serum antibodies to cardiolipin in patients (including VDRL test). The antibodies result from tissue injury, with autoimmunity developing to self components. Thus, there are many other diseases that result in anti-cardiolipin antibodies and false positives are common. However, these are cheap screening tests. More definitive diagnosis is achieved by detecting the presence of "specific" serum antibodies against treponemal antigens. These tests are more expensive and usually performed (as a definitive diagnosis) on sera previously shown to be positive after first detecting antibodies to cardiolipin.

No vaccine exists, but antibiotic therapy (usually penicillin G) is usually highly effective.

Rare (in the US) diseases caused by organisms related to T. pallidum are bejel, yaws and pinta.

Bejel

Bejel, also known as endemic syphilis, is not transmitted sexually but via contact, for example hands to broken skin. The disease can also be spread by sharing eating utensils. It is thus a disease of low income groups with poor hygiene. Depending on the route of transmission, skin or mucous membranes are the first to be infected but the bacterium can spread deeper to the bones. Thus, one sees sores in the mouth, throat and the nasal passages and the infected lesions can penetrate deep into the tissue causing major malformations of the face and limbs. This results in severe bone pain and there is also swelling of the lymph nodes. The T. pallidum organisms can be found in swabs of the sores.

Treatment of bejel, which can be completely curative, is similar to syphilis, that is penicillin G or tetracycline. Bejel is found in the Middle-East, Africa, Australia and central Asia.

Pinta

Pinta is another non-venereal, treponematous disease which is caused by T. carateum. It occurs in the New World, particularly the Caribbean, central America and northern South America. Pinta is the Spanish for "painted". Again, it is a disease of poor regions with sub-standard hygiene and is spread by personal contact through cuts in the skin. This results in scaly red lesions (hence the name) which form a lump at the site of the primary infection. Small satellite lesions form around the primary lesion and lymph node swelling is also seen. Some months after the primary infection, the patient experiences more scaly red lesions that are now flat and tend to itch. These are the pintids and occur around or distant from the site of the primary infection. The color of the pintids changes to blue black with time and then can lose pigmentation. Unlike bejel, the disease does not spread deep into the tissues and bones. Detection is is via serology or direct examination of lesion specimens under the light microscope.

Treatment of pinta is again curative and can be accomplished by a single injection of penicillin G.

Yaws

Yaws is another chronic treponematous disease of poor hygiene. It can be very disfiguring. It strikes mainly children in Africa, south Asia and northern South America. The causative agent is T. pertenue. As with pinta and bejel, spread is via direct contact through skin lesions. About a month after the infection, a papule forms at the infection site which transformsinto a crusted ulcer that takes months to heal. Painful swelling of the lymph nodes occurs. Later, soft growths appear on the face, buttocks and limbs. They can also occur in the bottoms of the feet causing the infected person to have a very characteristic walk which gives rise to the name of "crab yaws". Further formation of tumors and ulcers on the face can cause bone malformation and can be disfiguring. Microscopy (of samples from the lymph nodes) is diagnostic and there are various serological tests.

Treatment of yaws is also a single penicillin G injection which can be completely curative

Borrelia burgdorferi and Lyme disease

Lyme disease is caused by Borrelia burgdorferi and is a relatively newly recognized disease. It is found widely in the United States Although clinically first described in 1975, the role of a tick-borne spirochete. was not proven until 1983. These ticks infect a large array of wild life, particularly white footed mice. A tick bite leads to transmission of B. burgdorferi causing an erythematous skin rash in a few days along with a transient bacteremia leading to (weeks or months later) severe neurologic symptoms or polyarthritis. Cardiac problems may occur in a minority of cases. If antibiotic therapy is initiated early, a cure is usually achieved. However, late antibiotic administration (penicillin or tetracycline) is often ineffective.

Diagnosis. The organism is highly fastidious, growing extremely slowly in tissue culture (not bacteriological) media. The vast majority of body fluid or tissue samples from patients with Lyme disease do not yield spirochetes on culture. Lyme disease is thus usually diagnosed by detection of serum antibodies to B. burgdorferi. However, acutely antibodies may not occur in detectable titer, making early diagnosis difficult. Whilst late diagnosis, (as mentioned above) may lead to ineffective treatment. Many patients are unaware of having had a tick bite or a rash.

Etiology. The chronic arthritis clinically resembles rheumatoid arthritis. Live agent is almost never cultivated from the joint (in common with other forms of reactive arthritis such as Reiter's syndrome and rheumatic fever). However, small numbers of persistent spirochetes and borrelial antigens have been detected histologically in human tissues. Whether the organism persists in a viable form or not remains to be determined. Thus, there is no clear explanation for the immunopathologic stimulus for chronic tissue injury in Lyme arthritis.

Relapsing fever

There are less than 100 cases of relapsing fever per year in US. Relapsing fever (with associated bacteremia) is caused by other species of Borrelia which are transmitted by tick (B. hermsii, rodent host) and lice (B. recurrentis, human host) bites. The term relapsing fever is derived from the following repeating cycle. As an immune response develops the disease relapses. However, the antigens expressed change and the disease reappears. The organism is extremely difficult to culture and there is no serological test. The organism is generally detected by blood smear.

Leptospirosis
There are less than 100 cases per year in US. This flu-like or severe systemic disease is also a zoonotic infection. Leptospira (figure 15) are transmitted in water contaminated with infected urine from wild animals (including rodents) and farm animals and can be taken in through broken skin (e.g. bathing). Leptospira particularly infect the kidney (figure 16), brain and eye. They are the most readily culturable of the pathogenic spirochetes; but this is not routine and diagnosis is usually by serology.

NEISSERIA

Neisseria are Gram negative diplococci (pairs of cocci). These bacteria grow best on chocolate agar (so-called because it contains heated blood, brown in color); a modified (selective) chocolate agar commonly used is Thayer Martin. The colonies are oxidase positive (i.e. produce cytochrome oxidase) which is demonstrated by flooding the plate with a dye which on oxidation changes color.

N. gonorrhoeae (the "gonococcus")

N. gonorrhoeae, found only in man, is the causative agent of gonorrhea, the second most common venereal disease. The organism often causes an effusion of polymorphonuclear cells. A smear may show the presence of Gram negative cocci present in cells. However, culture is essential for definitive diagnosis.

A common feature of disseminated gonoccocal disease is arthritis. Although commonly considered a form of septic arthritis, in many cases gonococci cannot be isolated from the joint (i.e. they are "reactive" in nature). Dermatitis is also common.

Penicillin therapy is still usually effective. However, resistant strains producing beta lactamases are sufficiently common that alternatives are recommended for all gonococcal infections; this includes ceftriaxone (a beta lactamase-resistant cephalosporin). There is no vaccine since strains are highly variable in their external antigens (both outer membrane and pili). Both are involved in the initial adhesion of the organism to genital epithelium.

IgA proteases (also produced by N. meningitidis) are involved in successful colonization. As for many other bacterial infections, a role for both the lipopolysaccharide and peptidoglycan in tissue injury have been suggested. Exotoxins are not believed to be of importance in pathogenesis.

N. meningitidis (the "meningococcus")

This organism resides only in man. The majority of cases are sporadic cases most commonly seen among young children. Outbreaks occur usually among adults living in confined and crowded conditions (e.g. army barracks). Initial infection of the upper respiratory tract (involving binding by pili) leads to invasion into the bloodstream and from there to the brain. Indeed, it is the second most common cause of meningitis (pneumococcus is the most common). It is usually fatal if untreated but responds well to antibiotic therapy. Thus, rapid diagnosis is important. The organism is often detectable in spinal fluid (Gram negative diplococci within polymorphonuclear cells) or antigenically. Culture on Thayer Martin (or similar) agar is essential for definitive diagnosis. Penicillin is the drug of choice.

Meningococci vary antigenically and can be serogrouped with anti-capsular antibodies. The capsule is an important pathogenesis factor allowing inhibition of phagocytosis. A vaccine against these capsular antigens is available. However, effective immunization against the most common group B has not been achieved.

Non-pathogenic species morphologically resembling Neisseria are found in the normal flora of the oropharynx but can be differentiated from the pathogenic Neisseria readily. These occasionally cause opportunistic human disease (including pneumonia).