Download Bacterial Disease in Humans

Bacterial Disease in Humans
What are pathogens?
They are disease-causing agents.
Bacterial Disease in Humans
• What are the two general ways that bacteria
cause disease?
– Some damage the tissues of the infected
organism directly by breaking them down for
food.
– Others release toxins that harm the body.
Bacterial Disease in Humans
• What kind of tissue do the bacteria
that cause tuberculosis break down?
–They break down lung tissue.
Mycobacterium tuberculosis
World TB Day March 24th
• Acid fast aerobic rod Gram +ve
• Multi- lobate colony morphology
• Doubling time 24-30 h
History
• TB has been known as
Pthisis, King’s Evil,
Pott’s disease,
consumption, and the
White Plague.
• Egyptian mummies
from 3500 BCE have
the presence of
Mycobacterium
tuberculosis
• 460 BC: Hippocrates identifies “consumption”
as “most widespread disease of the
time” and “is always fatal”
• 1679: Physician Sylvius describes TB lung
pathology
• 1702: First reference to infectious nature of
disease and first description of
disinfection to stop transmission
• 1720: Physician Marten conjectures about
“wonderfully minute living
creatures” as cause of consumption
• 1854:
Brehmer opened first sanitorium,
Isolated the infected in sanitariums, which served as
waiting rooms for death
• 1865: Villemin demonstrated human to cow to rabbit transmission
• 1882:
Koch isolated agent, Mycobacterium tuberculosis, in pure
culture
• 1895:
Calmette and Guerin developed BCG vaccine
• 1943:
Streptomycin discovered
Disease progression- Stage 1
•
Stage 1
– Droplet nuclei are inhaled, and
are generated by talking, coughing
and sneezing.
– Once nuclei are inhaled, the
bacteria are non-specifically taken
up by alveolar macrophages.
– The macrophages will not be
activated, therefore unable to
destroy the intracellular organism.
– The large droplet nuclei reaches
upper respiratory tract, and the
small droplet nuclei reaches air
sacs of the lung (alveoli) where
infection begins.
– Disease onset when droplet nuclei
reaches the alveoli.
Disease Progression- Stage 2
• Begins after 7-21 days after initial infection.
• TB multiplies within the inactivated
macrophages until macrophages burst.
• Other macrophages diffuse from peripheral
blood, phagocytose TB and are inactivated,
rendering them unable to destroy TB.
Disease Progression- Stage 3
• Lymphocytes, specifically T-cells recognize TB antigen. This
results in T-cell activation and the release of Cytokines,
including interferon (IFN).
• The release of IFN causes the activation of macrophages,
which can release lytic enzymes and reactive intermediates
that facilitates immune pathology.
• Tubercle forms, which contains a semi-solid or “cheesy”
consistency. TB cannot multiply within tubercles due to low
PH and anoxic environment, but TB can persist within these
tubercles for extended periods.
Disease Progression- Stage 4
•
Although many activated macrophages surround the tubercles,
many other macrophages are inactivated or poorly activated.
•
TB uses these macrophages to replicate causing the tubercle to
grow.
• The growing tubercle may invade a bronchus, causing an infection
which may spread to other parts of the lungs. Tubercle may also
invade artery or other blood supply.
• Spreading of TB may cause milliary tuberculosis, which can cause
secondary lesions.
• Secondary lesions occur in bones, joints, lymph nodes, genitourinary
system and peritoneum.
Disease Progression- Stage 5
• The caseous centers of the tubercles liquefy.
• This liquid is very crucial for the growth of TB, and
therefore it multiplies rapidly (extracellularly).
• This later becomes a large antigen load, causing the
walls of nearby bronchi to become necrotic and rupture.
• This results in cavity formation and allows TB to spread
rapidly into other airways and to other parts of the lung.
Virulent Mechanisms of TB
TB mechanism for cell entry
–
The tubercle bacillus can bind directly to mannose
receptors on macrophages via the cell wallassociated mannosylated glycolipid (LAM)
TB can grow intracellularly
–
–
–
Effective means of evading the immune system
Once TB is phagocytosed, it can inhibit phagosomelysosome fusion
TB can remain in the phagosome or escape from the
phagosome ( Either case is a protected environment
for growth in macrophages)
Antibiotic Mechanisms
• Inhibition of mRNA translation and
translational accuracy (Streptomycin and
derivatives)
• RNA polymerase inhibition (rifampicin) –
inhibition of transcript elongation
• Gyrase inhibition in DNA synthesis
(fluoroquinolone)
Antibiotic Mechanism II
• Inhibition of mycolic acid synthesis for
cellular wall (isoniazid)
• Inhibition of arabinogalactan synthesis for
cellular wall synthesis (ethambutol)
• Sterilization – by lowering pH
(pyrazinamide)
Resistance Mechanisms of TB
• TB inactivates drug by acetylation – effective on
aminoglycoside antibiotics (streptomycin)
• Also, through attenuation of catalase activity, in
this way TB has developed resistance against
certain drugs (asonizid)
• TB microbe has accumulated mutations that
resist antibiotic binding (rifampicin and
derivatives)
“The co-epidemic”
HIV & TB
• HIV is the most powerful
factor known to increase the
risk of TB
• HIV promotes both the
progression of latent TB
infection to active disease and
relapse of the disease in
previously treated patients.
• TB is one of the leading
causes of death in HIVinfected people.
TB/HIV Facts
• Individual infected with HIV has a 10 x
increased risk in developing TB
• By 2000 nearly 11.5 million HIV-infected
people worldwide were co-infected with M.
tuberculosis
- 70% of these 11.5
million co-infection cases
were in sub-Saharan
Africa
Reasons for Fear
• Drug resistant strains of Mycobacterium
tuberculosis have developed
• Underdeveloped countries are the most
affected by TB
• 95% of reported cases come from
underdeveloped countries
• High HIV rates in those areas contribute to
the contraction of TB
What is MDR-TB ?
•
It is a mutated form of the TB microbe that is extremely resistant to
at least the two most powerful anti-TB drugs - isoniazid and
rifampicin.
• People infected with TB that is resistant to first-line TB drugs will
confer this resistant form of TB to people they infect.
• MDR-TB is treatable but requires treatment for up to 2 years.
• MDR-TB is rapidly becoming a problem in Russia, Central Asia,
China, and India.
MDR-TB in the news:
Man with tuberculosis jailed as
threat to health
- USA Today 4-11-2007
• Russian-born man with extensively drugresistant strain of TB, has been locked in a
Phoenix hospital jail ward since July for not
wearing face mask
Case 1 – miliary tuberculosis
Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
What will happen if treatment delayed? – gibbus
formation (acute angulation of spine with or
without neurological damage)
The physical appearance – Potts
disease of spine - gibbus
Diagnosis
Mycobacterium tuberculosis (stained red)
in sputum
Microscopic examination
Tuberculin skin test : which yields a delayed hypersensitivity
type response to an extract made from
M. tuberculosis
Interferon-γ release assays : from blood sample
QuantiFERON-TB Gold (licensed in US, Europe and Japan); and
T-SPOT.TB, a form of ELISPOT (licensed in Europe).
Chest photofluorography has been used in the past for mass screening
for tuberculosis (x-ray fluoroscopy of the thorax)
Molecular dignostic polymerase chain reaction assays for the detection of bacterial DNA
Amplified mycobacterium tuberculosis direct test :is highly sensitive and specific
when used to test smears positive for acid-fast bacilli (AFB), which was approved by the
FDA in 1996
Prevention
•Bacillus Calmette-Guérin (BCG) vaccine
• An experimental vaccine, with positive results in mouse models, may
be effective in not only preventing infection, but also in eradicating the
infection once established. A tuberculosis vaccine aimed at
sterile Mtb eradication should be able to target latent Mtb as well
as Mtb that causes early-stage tuberculosis. The vaccine is a
combination of antigens Ag85B and ESAT-6 as well as the protein
Rv2660c. Ag85B and ESAT-6 together form the vaccine Hybrid-1, while
Rv2660c is a protein that is expressed even in late-stage infections,
when protein transcription is generally reduced. The novel combination
of Ag85B, ESAT-6, and Rv2660c allows for both short- and long-term
protection as a result of the continued expression of target proteins. The
new vaccine, currently referred to as H56, works by promoting a
polyfunctional CD4+ T cell response against tuberculosis protein
components. Phase I clinical trials are scheduled to begin in Cape Town,
South Africa
Treatment
•Antibiotics to kill the bacteria- Isoniazid and Rifampicin or
-Combination of several antibiotics
•The DOTS (Directly Observed Treatment Short-course) strategy
of tuberculosis treatment recommended by WHO was based on
clinical trials done in the 1970s by Tuberculosis Research Centre,
Chennai, India
•Is for MDR-TB
•Technical strategy develop by Dr. Karel Styblo in 1980
This contributed to a steady global uptake of DOTS TB control servies over the
subsequent decade. Whereas less than 2% of infectious TB patients were
being detected and cured from TB with DOTS treatment services in 1990,
approximately 60% are now benefiting from this care. Since 1995, 41 million
people have been successfully treated and up to 6 million lives saved through
DOTS and the Stop TB Strategy. 5.8 million TB cases were notified through
DOTS programmes in 2009
TB requires much longer periods of treatment (around 6 to 24 months) to
entirely eliminate mycobacteria from the body