Escolar Documentos
Profissional Documentos
Cultura Documentos
m. leprae
M. tuberculosis
M. bovis (BCG
strain used as
vaccine)
M. africanum
M. microti
NTM:
Nontuberculous
Mycobacteria
Slow growers
Rapid growers
Nontuberculous Mycobacteria
Photochromogens
o M. kansasii
o M. marinum
Scotochromogens
o M. scrofulaceum (Kings Evil)
o (Also M. gordonae)
Nonchromogens
o M. avium complex
o (Also M. terrae, M. xenopi, m. ulcerans)
Methylene Blue
Zhiel-Neelson Stain (Acid Fast Stain)
Patient sample taken, often sputum
Red carbol-fuchsin stain, decolorize w/ acid-alcohol, methylene blue counterstain
You get red staining bacteria against a blue counterstaining background
Can also stain with Auramine-Rhodamine (fluoresce)
Pathophysiology
Transmission of M. tuberculosis
M. tb spread via airborne particles called droplet nuclei (5um)
Transmission occurs when droplet nuclei inhaled and reach the alveoli of the lungs, via nasal passages,
respiratory tract, and bronchi
Phase I: Infection or Not?
Hardiness of the bacterium
o How well survived transmission to alveoli through droplet nuclei
o Intrinsic virulence
Nontuberculous Mycobacteria
Johnston Lecture (Biofilms): Mycobacterium leprae/ leprosy cannot grow at 37oC; requires lower
T so it forms lesions on skin, esp. extremities (nose, fingers). Bacteria not found in warmer areas
of body (core).
Never grown in culture, but grows in tissues of the armadillo which has a core body temperature of
34C
Transmission of M. leprae
Definitive route never identified
May be aerosols from respiratory tract since nasal secretions of patients with lepromatous leprosy
contain large
numbers of bacilli
Direct contact with ulcerated skin lesions may be important
Pathophysiology
Inhaled bacteria taken up by alveolar macrophages or dendritic (antigen-presenting) cells in the nasal
mucosa or skin
Disseminates hematogenously, but replicates only in relatively cool parts of the body. Preferred cells
are macrophages and Schwann cells.
Incubation period: 3 months to 40 years (average 2 to 7 years)
Subsequent cytokine/chemokine production directs adaptive CMI into a Th1 or Th2 response to M.
leprae.
Cytokine Gene Expression in Leprosy
T-cell type 1 (Th1) like response
Predominance of IL-2, lymphotoxin, and INF- which promotes host resistance
(Kaplan) Tuberculoid T cells are Th1and T cells respond to IL-12
T-cell type 2 (Th2) like response
Predominance of IL-4, IL-5, IL-10, and much less IFN leading to little host resistance
(Kaplan) Lepromatous T cells are Th2, and T cells do not respond to IL-12
M. leprae Clinical Classification reflects progression of disease based on host immune response
Tuberculoid (TT)
Borderline Tuberculoid (BT)
Mid Borderline (BB)
Borderline Lepromatous (BL)
Lepromatous (LL)
BL
>
LL
Lepromatous
Th2
o Low resistance to M.
leprae
o Many bacilli
(multibacillary
form)
o IL-4, IL-5, IL-10
produced
o High antibody
(ineffective)
Foam cell lesions
Marked increase in pro-inflammatory cytokines (TNF-, IL-1, and interferon-) within and
around the nerve
Immune mediated injury can occur before diagnosis, and during and after treatment
Direct Invasion (lepromatous)
Bacillus interacts with specific protein (lamina 2) found in basal lamina of the Schwann cell
and binds to it
Bacteria binding to 2 chain of Laminin produces Schwann cell tropism (Kaplan)
Binding mediates invasion followed by rapid demyelination independent of cellular immunity.
Genetic Factors Affecting Host Response
95% of the worlds population is immune to leprosy
Some persons cannot mount a response to lepromin, a bacterial extract
Occurrence of leprosy more common in identical twins
Susceptibility linked to polymorphisms in the NRAMP1 gene (a transmembrane protein to pump Fe++
out of lysosome)
HLA type important
HLA-DR3 tuberculoid
HLA-DQ1 or HLA-MT1 lepromatous
(Kaplan)Mutations in promoter region of PARK2 is a risk factor for leprosy
PARK2 codes for a ligase in the ubiquitin-proteosome pathway
regulates antigen processing within M and may influence antigen presentation
(Kaplan) NOD2 mutations are risk factor for LL
NOD2 responds to muramyl dipeptide, and helps limit spread of M. leprae
Distribution of clinical forms
In India and Africa, 90% of patients are tuberculoid
In Southeast Asia, 50% are lepromatous and 50% are tuberculoid
In Mexico, 90% are lepromatous
Tuberculoid Leprosy
Anesthetic lesions: cannot feel pinprick/touch within the lesion. Hypopigmented lesion w/ pigmented
border.
Can involve great auricular nerve
Burns due to anesthetic infection (no sensation thru nerves)
Claw hand as result of ulnar nerve involvement
Lepromatous Leprosy
Loss of eyebrows
Involves cool areas (face, nose, earlobe, extremities, can include testicular involvement)
Clinical Features of Leprosy
Nerve involvement
Sensory or motor loss
Fingers/toesresorption of tips
Ulnar/median nerve = claw hand
Peroneal nerve = foot drop
Posterior tibial nerve = claw foot/ulcer
Loss of eyebrows/lashes
Perforated nasal septum ("leonine appearance")
Hoarseness due to laryngeal involvement
Diagnosis of Leprosy
Kaplan: Fernandez reaction is Delayed Type Hypersensitivity-bases skin test for Leprosy
Lepromin injected under skin
History of travel to or residence in an endemic area (ingestion of armadillos?)
Anesthetic skin or mucous membrane lesions
Thickened peripheral nerves
Detection of AFB in slit-skin smears or skin biopsies that include sub-epidermal tissue confirms the
diagnosis
Fite stain of tissue biopsy red snapper appearance with stain
Leprosy: Infection Prevention and Control 2012 AD
Tuberculoid patients are generally not contagious because of the small numbers of bacteria
When a patient with either tuberculoid or lepromatous leprosy is placed on medication, most of
bacteria are killed within a few days.
Within two weeks of starting the treatment, there is no risk of transmission.
It is not necessary to isolate a patient at anytime.
It is not transmitted through sexual contact or pregnancy.
M. tuberculosis
M. leprae
Summary
Global control of leprosy has been successful with only 3 countries currently reporting annual
rates of >1 new case/10,000 persons at risk.
The sine qua non of leprosy is its ability to infect peripheral nerves.
The organism still eludes culture in artificial media.
New knowledge of leprosy has delineated the impact of leprosy on the immune responses by the host
but much remains to be understood.
Effective treatment is available and is most successful when begun early in the course of the illness
Exam #1 (Murphy)
Caseous necrosis - Tissue grossly appears "cheesy". Microscopically, necrotic focus of fragmented
cells and granular cellular debris surrounded by border of granulomatous inflammation. (See
"Chronic Inflammation" lecture.) Characteristic of tuberculosis (TB).
Granulomatous Inflammation - A distinctive pattern of chronic inflammation characterized by focal
aggregates of granulomas within the tissue. At its most basic, a granuloma is a focal aggregate
of macrophages. There are 2 types of granulomas, which differ in their pathogenesis.
A. Immune granuloma.
1. Forms under 2 conditions:
a. Macrophages phagocytose a substance that they are unable to degrade. Usually a
microorganism, such as Mycobacterium tuberculosis or Treponema pallidum (syphilis).
b. The indigestible substance is immunogenic, in that it induces a cell-mediated immune
response by T-lymphocytes. This results in transformation of the macrophages into
epithelioid cells (see below).
2. Morphologically, the immune granuloma consists of:
a. Epithelioid cells - i.e. macrophages that are transformed to resemble epithelial cells.
b. Langhans-type giant cells - Huge cells formed by the fusion of many epithelioid
macrophages. Voluminous cytoplasm with up to 50 macrophage nuclei within. Nuclei are
arranged around the periphery of the cell.
c. Other cell types - Surrounding the mixture of epithelioid and giant cells is a collar of
lymphocytes, plasma cells and fibroblasts, which may produce collagen.
d. Necrosis - Depending on the specific disease, the granuloma may have a necrotic center
(caseous, or cheesy, necrosis). Classic feature of TB granulomas, as well as some fungi.
3. Diseases that can cause immune granulomas:
Disease
Tuberculosis
Leprosy (tuberculoid type)
Histoplasmosis
Coccidioidomycosis
Q fever
Brucellosis
Syphilis
Sarcoidosis
Crohns disease
Antigen
Mycobacterium tuberculosis
Mycobacterium leprae
Histoplasma capsulatum
Coccidioides immitis
Coxiella burnetii (rickettsial organism)
Brucella species
Treponema pallidum
Unknown
Unknown
Note: Common name of TB granuloma is the tubercle. Syphilis granuloma is called the
gumma (rubbery).
Exam #4 (Stevenson)
Isoniazid (INH)
Inhibits mycolic acid synthesis
Highly specific for Mycobacterium tuberculosis
Bactericidal
1st line drug in combination therapy of tuberculosis infections
Ethambutol (EMB)
Inhibits synthesis of arabinogalactan and lipoarabinomannan
Bacteriostatic within macrophages
1st line drug in combination therapy of tuberculosis infections
Pyrazinamide (PZA)
Appears to inhibit lipid metabolism
Bactericidal
Active in acidic environment
Activated by bacterial enzyme
1st line drug in combination therapy of tuberculosis
Exam #4 (Various)
Problems with Anti-TB drugs due to:
1.Very slow growth (antibiotics target metabolically active/dividing cells)
2.The thick, waxy outer covering of mycobacterium excludes many drugs
3.Mycobacterium Tb is an obligate intracellular parasite-drugs have to get into eukaryotic
cells, too.
Exam #4 (Straley)
Pyrazinamide
p-Aminosalicylic acid
Isoniazid (INH)
Ethionamide
= isonicotinyl hydrazine
Cycloserine
Ethambutol
Fluoroquinolones
Rifamycins
Aminoglycosides
Mutations in promoter region of PARK2 is a risk factors for leprosy. PARK2 codes for a
ligase in the ubiquitin-proteosome pathway which regulates ag processing within M and
may influence ag presentation.