mycobacteria Flashcards

1
Q

tb history

A

About 1/4 of the world’s population is estimated to be infected with
Mycobacterium tuberculosis, but are not ill with it.
According to the WHO, in 2022 tuberculosis infected an estimated
10.6 million people and killed about 1.3 million people, including
167,000 people with HIV/AIDS. Incidence is highest in India,
China, Indonesia, the Phillippines Nigeria, Bangladesh, and
Pakistan
In 2019, there were 206,000 new cases of multidrug- or rifampin-
resistance

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2
Q

tb risk

A

HIV infection: 18 times more likely to develop active TB
Undernutrition: 3 times more risk
Alcohol use disorder: 3.3 times more likely
Tobacco use: 1.6 times more likely
Poverty
Poor housing

May proceed to
a generalized
Infection: “miliary”
tuberculosis

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3
Q

Tb and HIV

A

TB is a leading killer of HIV-positive people causing ¼ of all HIV-
related deaths
People living with HIV are 26 to 31 times more likely to develop
active TB disease than people without HIV
Up to 13 million people in the US are infected with M. tuberculosis
without displaying symptoms
1 in 10 of these individuals will develop active TB at some time in
their lives

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4
Q

tb stain

A

Mycobacteria stained with the Ziehl-Neelsen stain

Mycobacteria are termed “Acid-fast bacteria”

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5
Q

Physiology
and structure

A

Complex cell
wall
Are
Mycobacteria
Gram-
negative or
Gram-
positive?

The phylogenetic position of Mycobacterium
tuberculosis relative to other bacteria is controversial. Its cell
wall has characteristics of both Gram-positive and Gram-
negative bacteria. In the standard reference of bacterial
phylogeny based on 16S ribosomal RNA sequence
comparison, M. tuberculosis belongs to the high G+C Gram-
positive bacteria.
In the genome tree constructed based on conserved gene
content, M. tuberculosis is more related to Gram-negative
than to Gram-positive bacteria as reflected by the
evolutionary distance between nearest ancestral units.
This conclusion may be supported by another analysis
showing that M. tuberculosis shares relatively more
orthologous genes for energy production and conversion

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6
Q

peptidoglycan layer

A

Peptidoglycan layer linked with arabinose-galactose-mycolic acid
(arabinogalactan mycolate)
Mycolic acids
Major lipids
Long chain (C78-C90)
How long are the acyl
chains of lipids in human
cells?
In lung surfactant?

Free lipids
Waxes: wax D (Freund’s adjuvant)
Helps withstand drying and thus
increases survival
Mycosides: complex saturated
glycolipids
Cord factor: 6,6’-dimycolate of
trehalose
Inhibits neutrophil migration
Thought to mediate granuloma
formation

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7
Q

polypeptides

A

Act as antigens
Purified protein derivative (PPD)
is used in skin testing

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8
Q

Pathogenesis

A

Infection via inhalation
of infectious aerosols
No exotoxin or endotoxin

replicates in alveolar
macrophages and can
destroy the cells
“Exported repetitive
protein” prevents the
phagosome from
fusing with the
lysosome
What is the
consequence of this?

nfected macrophages migrate to the local
(tracheobronchial) lymph nodes, the bloodstream and
other tissues

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9
Q

two types of lesion

A

Exudative: Acute inflammatory response at the initial site of
infection (usually lungs)
Granulomatous: A central area of infected giant cells
(Langhans’cells) surrounded by epithelioid cells (tubercles)

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10
Q

types of lesions

A

Tubercles may heal spontaneously or may become fibrotic or
calcified
Caseous (cheesy) necrosis and cavitation in the center of the
granuloma, resulting from:
Cellular immune response
Enzymes and reactive oxygen intermediates from dying
macrophages

The exudative lesion and the draining lymph nodes fibrose, and
sometimes calcify, to produce the
Ghon focus seen in X-rays
with associated lymphadenopathy (Ghon complex)

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11
Q

Pulmonary tuberculosis

A

Latent bacilli can be re-activated when the patient’s immune system
is weakened because of:
malnutrition
alcoholism
diabetes
old age
emotional stress

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12
Q

Pathogenesis and immunity

A

Intracellular replication stimulates helper and cytotoxic
lymphocytes
T-cells release interferon- and other cytokines
-> Macrophage activation -> MTB killing
Tuberculin skin test: purified protein derivative (PPD)
Positive 4-6 weeks after infection

Localized activated macrophages can penetrate into small
granulomas (< 3 mm) and kill all bacilli
Larger necrotic or caseous granulomas become encapsulated with
fibrin that protects the bacilli
> It is not known how MTB can reside in tissues for years or
decades

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13
Q

four fates

A
  1. The initial host response is completely effective and kills all
    bacilli; the patient will not develop tuberculosis in the future
  2. The organisms multiply immediately after infection and cause
    clinical disease known as primary tuberculosis
    Schluger & Rom
    Am. J. Respir. Crit. Care Med. 157, 679-691 (1998)
  3. The bacilli may become dormant and never cause disease; the
    patient has “latent infection,” evident only by a positive tuberculin
    skin test
  4. The latent organisms can eventually grow, with resultant clinical
    disease, described as reactivation tuberculosis
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14
Q

epidemiology

A

Transmitted by aerosols
More common among
The urban poor
Patients with suppressed immune systems
Immigrants from high-incidence areas
> Health care workers are at risk for infection!

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15
Q

clinical syndromes

A

Primary tuberculosis
mild and asymptomatic
in 90% of cases does not proceed further
In the remaining 10%
Persistent cough, usually for > 3 weeks
Night sweats for weeks or months
Weight loss, malaise, shortness of breath
Elevated temperature
Bloody and purulent sputum

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16
Q

reactivation

A

Old age
Immunosuppressive disease or therapy
Malnutrition
Alcoholism
Diabetes
Stress
Necrosis may erode blood vessels -> hemorrhage
Most infections in the lungs

17
Q

what can happen

A

Can disseminate to the lymph nodes, pleura, the liver,
genitourinary tract, bone marrow, spleen, kidneys, central nervous
system
“miliary TB”; Each tubercle resembles a millet seed; Latin: milium,
millet seed
M. tuberculosis can also cause meningitis
Can infect oral tissues and lymph
nodes. Lesions can occur in soft
tissues and supporting bone
and at tooth extraction sites

18
Q

lab diagnosis

A

Skin test: “purified protein derivative” injected
into the intradermal layer of the skin.
Induration of 10 mm or more 48 hours later
indicates exposure to MTB
Microscopy: Clinical specimen
stained with carbolfuchsin
(Ziehl-Neelsen and Kinyoun stains)
Fluorochrome dyes (Truant auramine-
rhodamine), de-colorized with acid-
alcohol solution, and counterstained

19
Q

culture vs rapid test

A

medicineCulture: After treatment of specimen with 2% NaOH
(to kill rapidly growing bacteria) MTB is grown on Lowenstein-
Jensen (egg-based) medium, or Middlebrook (agar-based) medium
BACTEC measures the metabolism of 14C-palmitic acid to 14CO2
Rapid test Xpert MTB/RIF® simultaneously detects TB and
resistance to rifampicin, the most important TB medicine

20
Q

treatment and control

A

Pyrazinamide (active at low pH; mechanism unknown)
Lamont et al. Microbial Molecular Biology Reviews (2020)
May be a protonophore (What does this mean?)
Inhibits fatty acid synthase
Inhibits “ribosome rescue”
Indirectly inhibits coenzyme A
Ethambutol (inhibits arabinogalactan synthesis)

American Thoracic Society recommendations:
Initial treatment with these 4 drugs for 2 months, followed by INH/
RIF for 4-6 months
Noncompliance -> emergence of MDR strains
Directly observed therapy (DOT) to ensure treatment

21
Q

drug resistance

A

Multiple-drug-resistant (MDR) strains
Mutations in genes for
mycolic acid synthesis
catalase-peroxidase
required to activate isoniazid
Need in vitro susceptibility testing
Extensively drug-resistant (XDR) TB
Detected in 84 countrie

22
Q

novel therapy regimen for extensively drug-resistant (XDR) TB

A

Nix-TB: Clinical trial in South Africa -> 84–93% favorable outcome
Three antibiotics that have never been used against TB
Bedaquiline: Inhibits mycobacterial ATP synthase
Pretomanid: Cell wall inhibitor; Nitric oxide stimulant;
Protein synthesis inhibitor
Linezolid

23
Q

vaccination

A

Vaccination: Bacille Calmette-Guérin (BCG; attenuated M. bovis)
is used in most developing countries to reduce the severe
consequences in infants and children
Why is BCG not used in the United States?

24
Q

pathogenesis of avium intracellulare

A

Pathogenesis
Asymptomatic colonization in
immunocompetent patients
Disseminated disease in
immunocompromised individuals
Organ dysfunction due to abundance of
bacteria and host response to infection

25
avium intracellulare epidemiology
Ingestion of contaminated food or water Found in soil and water, and infected poultry and swine Inhalation of infectious aerosols: minor role Immunocompromised patients (especially AIDS) and those with long-standing pulmonary disease are at greatest risk Incidence decreasing due to antiretroviral therapy of AIDS patients
26
avium intracellare syndromes
Disseminated disease: Tissues filled with MAC Bacteremia: 100-1000/ml in blood Weight loss, night-sweats, abdominal pain, diarrhea, fatigue, and anemia
27
avium intracellare treatment
Resistant to most antimycobacterial drugs Combination therapy Clarithromycin (or azithromycin) + Ethambutol + Rifabutin For prophylaxis in AIDS patients with low CD4 counts: Clarithromycin or Azithromycin experimental treatment: antibiotics in liposomes
28
Mycobacterium leprae
Pathogenesis and clinical syndromes Causes leprosy or Hansen's disease Leprosy was renamed Hansen's disease after Norwegian scientist Gerhard Hansen, who in 1873 discovered the slow-growing bacterium now known as Mycobacterium leprae as the cause of the illness Tuberculoid leprosy Strong cellular immune reaction Lymphocytes and granulomas, but relatively few bacteria Production of interferon- and IL-2 -> macrophage activation, phagocytosis and bacterial clearance
29
Lepromatous leprosy
Specific defect in the cellular immune response to M. leprae antigens Bacilli populate dermal macrophages and Schwann cells of peripheral nerves The most infectious form of leprosy Ziehl-Neelsen staining of Mycobacterium leprae
30
epidemiology of leprosy
A Neglected Tropical Disease (WHO) 200,000 new cases of leprosy worldwide 2-3 million people living with Hansen’s disease disabilities 10,000 new cases in 2019 in Brazil, India & Indonesia In the U.S. 185 new cases in 2018 were reported from Arkansas, California, Florida, Hawaii, Louisiana, New York, and Texas Spread by person-to-person contact Inhalation of infectious aerosols, skin contact with respiratory secretions or wound exudates Arthropod vectors? Armadillos?
31
leprosy treatment
Tuberculoid leprosy Dapsone (antifolate) + Rifampin (minimum of 6 months) Lepromatous leprosy Clofazimine in addition to Dapsone and Rifampin (therapy extended to 12 months) How does clofazimine act? Controlled by prompt recognition and treatment of infected people
32
others
Mycobacterium kansasii Causes chronic pulmonary disease Disseminated disease in immunocompromised patients Mycobacterium marinum Causes "swimming pool granulomas” nodular lesions along the lymphatics -> ulceration Fish tank granuloma caused by Mycobacterium marinum infection of a lesion acquired while cleaning out a fish tank Mycobacterium abscessus Causes disease in people with cystic fibrosis, COPD and other lung diseases Survives in cells Multi-drug resistant Research on using bacteriophages for therapy