M. tuberculosis

Mykobakterien
24 November 2009
Dr. Bános Zsuzsa
Mykobakterien
Gattung
Art
Mycobacterium
M. tuberculosis P
M. africanum P
M. bovis P
M. leprae P
Atypische M. kansasii
(MOTT = NTM) M. avium-intracellulare
u. a.
Tab. 42.2 (Hahn)
Geschichte
Mumien: Knochen + Abszess
Hyppokrates: Tröpcheninfektion
Mittelalter: „Phtysis” (Schwindsucht)
Franz de le Boë (1614 – 1672)
„Tuberculum”
19. Jh. – 30% aller Todesfälle (Urbanisierung,
industrielle Revolution)
Johan Lukas Schönlein (1793 – 1864)
1832: Klinische Terminologie: Tuberkulose, Tbc
Fig.1 A tomb painting at Beni
Hasan showing a gardener with a
localized angular deformity of the
cervical-thoracic spine.
Tuberculosis in Ancient Egypt
The first evidence that human
tuberculosis was present in ancient Egypt
came from typical macroscopic osseous
changes in human remains, which were in
this instance the well preserved Egyptian
mummies. Likewise, one of the first
“cases” has already been described in
1910 by Sir Marc Armand Ruffer, the
“founder” of ancient Egyptian
paleopathology. The mummy of the
Amun´s priest Nesperhan presented with
typical ventral destruction of the lower
thoracic spine leading to the typical
gibbus formation of spinal tuberculosis.
Moreover, there are also historic Egyptian
representations which indicate the
possibility of tuberculosis deformity:
www.nanobiomed.de/_Media/fig1-6_textmedium.jpeg
1882: Robert Koch
Mycobacterium tuberculosis
1890: Tuberculin → 1930-s: diagnostisch!
1905: Nobel Preis (Robert Koch)
1906 : Albert Calmette and Camille Guèrin
Aktive Immunisierung BCG
www.nature.com/.../v6/n9/images/nri1920-f1.jpg
Geschichte
Geschichte
1921: erste Anwendung von BCG Vakzine
1930: Lübeck Katastrophe
(Mischung von virulenten ⇔ avirulenten Stämmen)
1930-s: screening programmes ⇒ Verminderung der
Morbidität
1945: II. Weltkrieg ⇒ wiederholte Erhöhung der Fälle
1946: Erste Antituberkulotikum (Streptomycin)
1992: WHO Global Problem
2006 – 2015 WHO Global Programme
1992: WHO Global Problem
2M Todesfälle/Jahr
8M neue Erkrankungen/Jahr
Therapieresistente und multiresistente Stämme
HIV Infektionen
BCG: Schutz in Kleinkinder nur vor Meningitis, in
Erwachsenen ungenügend
2006 – 2015 WHO Global Programme
Geschichte
Berühmte Patienten
Calvin, der Reformer
Cardinal Richelieu
Schriftsteller, Dichter
Schiller, Molière, Edgar Allan Poe, Anton Tsechow, Brontë
Schwester
Philosopher
Spinoza, Descartes, Rousseau
Musik
Chopin, Carl-Maria von Weber
Verdi: „La Traviata”
Puccini: „La Bohèm”
Thomas Mann: „Der Zauberberg”
www.ifpri.org/.../focus05/Map-Tuberculosis.gif
earthtrends.wri.org/images/tuberculosis_incid...
Figure 3. Absolute numbers of cases of active tuberculosis (TB) (2002) and
estimated absolute numbers of people living with HIV (2004) and distribution of
major HIV subtypes around the world.
The HIV-1 subtypes A−H and the HIV-2 subtypes N and O are shown. Sequence
differences between the subtypes mean that different subtype vaccines will be needed
for different parts of the world.
http://www.nature.com/nm/journal/v11/n4s/fig_tab/nm1221_F3.html
Mycobacterium tuberculosis, M. bovis
Morphologie
Säuerfeste Stäbchen
Ziehl-Neelsen Färbung
Kulturpräparat:
Cordbildung – Virulenzfaktor
Kultur
Löwenstein Jensen Medium, Šula Medium
Sichtbare Kolonien nach 4-8 Wochen
(Generationszeit: 12-18 Stunden!)
Mycobacterium tuberculosis.
Sputum, ZN Färbung.
Roche_231
FIGURE 33-1 Complex cell wall structure of mycobacteria.
Ligand für TLR 2
medmicro
Abb. 14-3. Hahn
Mycobacterium tuberculosis, M. bovis
Resistenz
Gegen physische und chemische Einwirkungen ist HOCH!
(ausgetrocknetes Sputum!)
Antigene, Feinstrukturen
Fettsäure: Mycolsäure
Tuberkuloproteine
Proteine, Polysaccharide, Glykolipide
Mycobacterium tuberculosis, M. bovis
Pathogenese, Infektion
Intrazelluläre Vermehrung in Makrophagen Î
Tuberkelbildung /Granulomen/ (Abb. 42.6. Hahn)
Infektionsquelle
Kranke Menschen (Tiere)
Kontaminierte Gegenstände
Übertragung
Tröpfcheninfektion
Peroral (Milch)
Kontakt (direkt, indirekt)
FIGURE 33-5
Principal
mechanisms of Tlymphocyte
activation or
destruction of
macrophages
following stimulation
by mycobacterial
antigens. Activation of
macrophages can
result in bacterial
killing while
cytotoxicity may
release bacteria from
phagocytes and allow
their
engulfment and
destruction by
activated
macrophages.
Medmicro
Fig.: Macrophages and tuberculosis bacteria. Macrophages are among the
most important defense protection of the body. Tuberculosis bacteria
however "hide" in the macrophages and are thus able to survive. Image:
MPI for Infection Biology/Volker Brinkmann
www.mpg.de/.../01/Kaufmann0104/Web_Zoom.jpeg
(Roitt 16.28)
Pathogenese
http://www.nature.com/nm/journal/v11/n4s/fig_tab/nm1221_F1.html
Figure 1. Different outcomes of M. tuberculosis infection and
underlying immune mechanisms.
M. tuberculosis enters the host within inhaled droplets. Three outcomes are
possible. (i) Immediate eradication of M. tuberculosis by the pulmonary
immune system. This alternative is rare to absent. (ii) Infection transforms
into tuberculosis. This frequently occurs in immunodeficient individuals, with
the notable example of HIV infection increasing the risk of developing
tuberculosis 800-fold. (iii) Infection does not transform into disease because
M. tuberculosis is contained inside granulomas. In the diseased individual,
M. tuberculosis is no longer contained because caseation of the lesion
results in dissemination and transmission of M. tuberculosis. After inhalation,
M. tuberculosis is engulfed by alveolar macrophages and DCs. In draining
lymph nodes, these cells present mycobacterial antigens to different T cell
populations. Antigen presentation probably involves cross-priming, allowing
transfer of mycobacterial antigens from infected macrophages to dendritic
cells. Antigen-specific CD4+ T cells, CD8+ T cells, γδT cells and CD1restricted T cells participate in protection. Most importantly, macrophages
are activated by IFN-γ and TNF- α. In addition, T cells may kill mycobacteria
present in macrophages by means of perforin and granulysin.
http://www.nature.com/nm/journal/v11/n4s/fig_tab/nm1221_F1.html
Mycobacterium tuberculosis, M. bovis
Pathogenese, Infektion
Intrazelluläre Vermehrung in Makrophagen Î Tuberkelbildung
/Granulomen/ (Abb. 42.6. Hahn)
Infektionsquelle
Kranke Menschen (Tiere)
Kontaminierte Gegenstände
Übertragung
Tröpfcheninfektion
Peroral (Milch)
Kontakt (direkt, indirekt)
FIGURE 33-3 Pathogenesis of tuberculosis.
Medmicro
sitemaker.umich.edu
FIGURE 33-4 Radiologic differences between
primary and post-primary tuberculosis.
Medmicro
Fig. 2.48-49-50 Pulmonary tuberculosis. Chest radiograph showing…
…consolidation and
cavitation of left
upper lobe.
…extensive
consolidation of the left
lung with partial
collapse. Less severe
changes are seen on
the right.
…early and limited
pulmonary disease.
Fig. 2.59 Postprimary
pulmonary tuberculosis.
Chest radiograph
showing far advanced
disease.
Mycobacterium tuberculosis, M. bovis
Krankheitsbilder
Tuberkulose (Tbc)
Lungentbc
Primäre Darmtbc
Hauttbc
Generalisierte Infektionen
Miliartbc
Meningitis tbc = Meningitis basillaris tuberculosa
Organmanifestationen
Immunität
Zelluläre Mechanismen
Fig. 2.46 Pulmonary tuberculosis. Histopathology showing dense
inflammatory infiltration, granuloma formation and caseous necrosis. By
courtesy of Dr. R. Bryan.
Same patient as Fig. 2.59
Fig. 2.60 Postprimary tuberculosis.
Autopsy appearance of lung showing extensive
caseous necrosis, particularly of the upper lobe
and the apical segment of the lower lobe.
Fig. 2.61 Autopsy appearance of larynx.
Fig. 2.58 Miliary
tuberculosis. Gross
specimen of lung
showing cut surface
covered with white
nodules, fairly uniform in
size, which are miliary
foci of tuberculosis. The
adjacent lobe shows
confluent consolidation.
Fig. 3.19
Fig. 3.20 Tuberculous meningitis. Autopsy specimen of the brain of a child showing a
sheet of white exsudate which encompasses and obscures the basal cranial nerves. By
courtesy of Dr. J.D. Balentine.
Fig. 3.21 Tuberculous meningitis. Cranial nerve palsies are very common. This patient’s
progress was generally satisfactory but he developed left III paralysis, shown here by ptosis
and lateral deviation of the left eye caused by unopposed action of the lateral rectus.
Fig. 4.67 Tuberculous enteritis.
Transverse ulceration and caseous
necrosis involving the intestinal wall
and adjacent lymph nodes. By
courtesy of Dr. J. Newman.
Fig. 8.44a
Tuberculosis
of the hip. This
Asian man had
been confined to
bed with pain and
swelling around his
right hip for at least
one year. There
was a large soft
tissue swelling
around the hip…
Fig. 8.44b
… and
radiographs
showed
total
destruction
of the
acetabulum
and head of
the femur,
with
calcification
in the soft
tissue
mass.
Fig. 8.44c At surgical drainage
large quantities of pus and
caseous material were
removed. Mycobacterium
tuberculosis was isolated from
this material.
Fig. 8.45 Cold abscess of the
chest wall. This painless indolent
swelling had been present for
several months. Radiographs
showed tuberculosis of the
underlying ribs.
Fig. 8.47 Tuberculosis f the knee.
This patient was a 27-year-old
Asian man whose knee had been
swollen for 18 months and who
had miliary shadowing on chest Xray. Mycobacterium tuberculosis
was isolated from synovial fluid.
Normal left psoas muscle
Right psoas greatly distended by pus
Fig. 8.49 Tuberculous psoas abscess. This
patient had been treated for tuberculous
spondylitis of the lower thoracic spine several
years previously. He re-presented with a
fluctuant swelling in his right groin and a plain
abdominal radiograph (left) showing a bulging
psoas which was confirmed on CT scan
(right).
Fig. 10.86 Lupus vulgaris. An indolent, slowly spreading, reddish-brown
plaque-like lesion characteristic of tuberculosis of the skin.
Haut-tuberkulose
www.ecureme.com/atlas/data/dis_images/Tubercu...
Fig. 10.87 Lupus
vulgaris. Biopsyproven cutaneous
tuberculosis
causing
destruction of the
pinna. By courtesy
of Dr. C.J. Ellis.
Fig. 10.88 Papulonecrotic tuberculid. Lesions on foot.
Fig. 1.76 Primary tuberculosis. Site of implantation of infection
beneath the upper eyelid. The patient shared a bed with a sister
who had open pulmonary tuberculosis.
Fig. 1.77 Primary tuberculosis of the conjunctiva. Enlargement of the
preauricular lymph node, from which Mycobacterium tuberculosis was isolated.
Fig. 1.78
Tuberculous
cervical
lymphadenitis.
Infection has spread
to the cervical
glands. (Same
patient as fig. 1.76)
Mycobacterium tuberculosis, M. bovis
Diagnose
Direkter Nachweis – ZN- und Auraminfärbung,
Amplifikationsmethoden
Kultivierung
Tierversuch (Meerschweinchen)
Tuberkulin-Hautreaktion
Überempfindlichkeitsreaktion Typ IV.
Fig. 2.43 Tuberculin test. Erythema and induration at site of intradermal
injection of 5 tuberculin units in a child with primary tuberculosis. This is an
unusually severe reaction. Mantoux method.
Mycobacterium tuberculosis, M. bovis
Prophylaxe
Schutzimpfung – BCG Vakzine
(Tab. 16.4 Hahn)
Neue Vakzinationsstrategien (bis 2015)
Expositions- und Chemoprophylaxe
http://www.nature.com/nm/journal/v11/n4s/fig_tab/nm1221_F4.html
Figure 4. The major components of the immune response can be stimulated
by different types of vaccine.
Prophylaxe
Neue Vakzine Kandidaten
(Hahn 16.4.4)
¾Subzelluläre Fragmente (Proteine)
• Antigen + Adjuvant
• Nackte DNA Vakzine
• Recombinant, carrier-expressing antigen
(Vektoren: Adeno-, Vacciniavirus, Salmonella, Shigella)
¾Bakterielle Vakzine (Lebendimpfstoffe)
• M. tuberculosis – Deletionsmutante, Auxotrophe Mutante
• BCG – rekombinant BCG (Zytolysin/Listeriolysin; Zytokine;
Überexpression von Antigene)
¾Prime-boost Vakzination
Grundimmunisierung: BCG; rBCG
Komplettierung eines unvollständigen Impfschutzes: selektierte
Ag
FIGURE 2 |
Prime-boost
vaccination
strategies.
www.nature.com/.../n6/images/nrmicro1419-f2.jpg
Mycobacterium tuberculosis, M. bovis
Therapie
Antituberkulotika! (INH, Rifampicin, Ethambutol,
Pyrazinamid u.a.)
9-12 Monate!
RESISTENZ!
First-Line
Treatment of
Tuberculosis (TB)
for Drug-Sensitive
TB
www3.niaid.nih.gov/.../0/tb1.jpg
www3.niaid.nih.gov/.../0/tb1.jpg
Multidrug-Resistant Tuberculosis (MDR TB) and Possible Effective Treatments
www3.niaid.nih.gov/.../0/tb1.jpg
Extensively
Drug-Resistant
Tuberculosis
(XDR TB)
Diminishing
Options for
Treatment
New Tuberculosis (TB) Drugs Under Development
www3.niaid.nih.gov/.../0/tb1.jpg
Mykobakterien
Gattung
Mycobacterium
Art
M. tuberculosis P
M. africanum P
M. bovis P
M. leprae P
Atypische
(MOTT = NTM)
M. kansasii
M. avium-intracellulare
u. a.
Tab. 42.2 (Hahn)
Fig. 10.91 Cutaneous vasculitis in atypical mycobacteriosis. There
is irregular scarring, telangiectasis and nodular thickening. The
patient was highly sensitive to tuberculin and developed an
axillary abscess from which Mycobacterium gordonae was grown.
Fig. 10.92 Atypical mycobacteriosis. Fish tank granuloma due to
Mycobacterium marinum over the dorsum of the wrist.
Fig. 10.93 Skin abscess due to Mycobacterium cheloneae at the site of selfadministered insulin injection in the thight of a diabetic patient. The syringe
was not sterilized adequately.
Mycobacterium leprae
Morphologie Säuerfeste Stäbchen
Ziehl-Neelsen Färbung
Kultur Nicht kultivierbar!
Tierversuch: Maus, 9 bändrige Gürteltier (Armadillo)
Krankheitsbild: Lepra (tuberkuloide, lepromatöse)
Hauttest: mit Lepromin
(Überempfindlichkeitsreaktion Typ IV.)
Diagnose: Direkter Nachweis (ZN Färbung)
Therapie: Dapson, Rifampicin, Clofazimine
FIGURE 33-7 Pathogenesis of leprosy.
Medmicro
Fig. 10.75 Lepromatous leprosy. Smear from nasal mucosa showing
numerous acid-fast bacilli. Ziehl-Neelsen stain. By courtesy of Dr. I. Farrell.
Fig. 10.76 Lepromatous leprosy. Histology of skin biopsy showing clumps of
acid-fast bacilli (stained red) in the dermis. ZN staining. By courtesy of Dr.
C.J. Ellis.
Fig. 10.78 Lepromatous
leprosy. Typical ‘leonine’
facies with thickened
infiltrated skin, widened
nosenand loss of
eyebrows. By courtesy of
Dr. D.A. Lewis.
W640 - Lepromatous leprosy
– nodule in eye
W639 - Lepromatous leprosy
– facies leonina
Fig. 10.80 Leprosy. Skin lesions of
borderline tuberculoid (BT) leprosy
showing raised erythematous
margin. The center of the lesion
was anaesthetic. A similar solitary
lesion is typical of tuberculoid (TT)
disease. By courtesy of Dr. C.J.
Ellis.
Fig. 10.85 Skin lesions of
borderline leprosy over
buttock of an African patient.
This is a typical site. The
skin is hypopigmented and
anaesthetic. By courtesy of
Dr. D.A. Lewis
W635 Tuberculoid leprosy – early lesions: macules show loss of
sensation and hypopigmentation
W638 Tuberculoid leprosy.
Thickening of the great
auricular nerve.
W636 Ulnar nerve lesion in
tuberculoid leprosy.
Characteristic picture of
the ‘main de predicateur’.
Fig. 10.81 Tuberculoid leprosy. Thickened lateral perineal nerve over the
ankle and foot. The depigmented lesion on the foot is a burn as a result of
anaesthesia. By courtesy of Dr. C.J. Ellis.
Fig. 10.82 Leprosy. Weakness of the small muscles of the right hand with
early clawing of the ring and little finger due to ulnar nerve lesion. The skin
lesion has a raised edge and anaesthetic centre. By courtesy of Dr. C.J. Ellis.
Fig. 10.83 Leprosy. Hands in advanced untreated leprosy showing gross
deformity and loss of tissue.
Late tuberculoid leprosy
Actinomyces,
Nocardia
Actinomycetaceae
ANAEROBE
Actinomyces
A. israelii
Actinomycose
A. naeslundi (Genospecies-1 und -2)
A. odontolyticus
Karies, Parodontitis
A. viscosus
A. bovis
Fig. 1.64 Actinomycosis. Gram stain from an actinomycotic lesion showing
gram-positive branching filaments of Actinomyces isrealii. By courtesy of A.E.
Prevost
Fäden von Actinomyces israelii. (Roche_3)
Actinomyces Drusen im Eiter. (Roche_1)
Actinomyces „Strahlenkranz” an der Peripherie (Roche_2)
Fig. 1.67 Actinomycosis. Histological appearance of the ‘sulphur granule’
(bacterial aggregation) in tissues.
Fig. 2.66 Actinomycosis – black-staining organisms in bronchial biopsy.
Grocott’s stain.
Fig. 3.72 Brain abscess. ‘Sulfur granules’ in necrotic inflammatory exudate in a
cerebellar abscess due to A. israelii. HE stain.
Fig. 3.73 Brain abscess. Actinomyces
israelii, filamentous gram-positive bacilli,
within inflammatory exsudate. Gram
staining. By courtesy of Dr. J.F. John, Jr.
FIGURE 34-1 Pathogenesis and disease sites of
three major forms of actinomycosis.
Medmicro
Fig. 1.65 Cervicofacial actinomycosis. Erythema and induration of the skin
overlying odontogenic infection. By courtesy of Mr. C. J. Meryon.
Fig. 1.66 Cervicofacial actinomycosis. Healed lesion showing a dimple at the
site of the previously discharging sinus. By courtesy of Mr. C. J. Meryon.
Faziale Aktinomykose. Roche_4
Zervikale Aktinomykose. Roche_5
Aktinomykose. Spätform mit
Fistelbildung. Roche_6
Fig. 2.65 Actinomycosis. Subcutaneous mass and sinus formation on the
chest wall. By courtesy of Dr. T.F. Sellers, Jr.
Fig. 7.92 Pelvic actinomycosis. Portion of an intrauterine contraceptive device
(lippes loop) studded with ‘molar-tooth’ colonies of A. israelii. By courtesy of
Dr. A.E. Prevost
FIGURE 34-5 Pathogenesis of actinomycotic mycetoma.
Medmicro
W667
Madura foot
caused by
Actinomyces
and Fungi
imperfecti.
AEROBE
Nokardien
Gattung
Nocardia
Art
N. madurae
N. asteroides
N. brasiliensis
Streptomyceten
Gattung
Streptomyces
Art
S. griseus (Streptomycin)
S. venezuelae (Chloramphenicol)
S. aureofaciens (Chlortetracyclin)
FIGURE 33-8 Pathogenesis of nocardiosis.
Medmicro
Fig. 2.69 Pulmonary nocardiasis. Nocardia asteriodes in sputum. Left: acidfast stain. Right: Gram’s stain. By courtesy of Dr. T.F. Sellers and Dr. H.P.
Holley
Fig. 3.86 Nocardia. In this pus
smear the organisms appear
mainly as irregularly staining
filaments, but a variety of forms is
often seen, including rods cocci
and even spiral forms. By courtesy
of A.E. Prevost.
Fig. 3.87
Nocardiosis.
Brain abscess
revealing
filamentous
gram-positive
bacilli of
Nocardia
asteroides
Brown and
Brenn stain.
By courtesy of
Dr. P. Garen.
ENDE
Samos, 2007