bug parade part 2 Flashcards
1
Q
C. Diff characteristics All clostridial species are Gram-______!
A
positive
2
Q
C. Diff characteristics poisened by oxygen they are ________ _____?
A
obligate anaerobe
3
Q
C. Diff characteristics _______ _______ and produces 2 _____?
A
Spore former toxins
4
Q
C. Diff characteristics What are the two toxins produces by the Gram positive, Spore- Forming, clostridial species?
A
A-entrotoxin BAB cytotoxin
5
Q
C. Diff characteristics Many strains are still susceptible to ________ but are quickly becoming a major problem in ______, many countries now recognize it as a __________?
A
antibiotics hospitals Superbug
6
Q
C. Diff Disease and Ecology Clostridium difficile was first isolated in ______ from _____ _______?
A
1935 infant stool
7
Q
C. Diff Disease and Ecology Clostridium difficile was first recognized as a pathogen in the year _______ when it was isolated from ______, ______,______, and _______ ____ of patients with a variety of illnesses, However it was still not a problem.
A
1960 wounds abscesses blood
8
Q
C. Diff Disease and Ecology Clostridium difficile was first associated with causing ________ ________ or _ _ _?
A
pseudomembranous colitis PMC
9
Q
C. Diff Disease and Ecology The first association between C. difficile and PMC was in the year _____? the same year C. difficile was isolated from patients with the illness or experiencing ________ ________?
A
1978 Postoperative diarrhea
10
Q
C. Diff Disease and Ecology Clostridium difficile was recognized as ______ _____ in the 1960’s-70’s but was not taken seriousley till the ________?
A
antibiotic resistance 1980’s
11
Q
C. Diff Disease and Ecology one of the side effects of antibiotic use is the Disruption of normal protective ______ _____. so while antibiotics are successfully treating one cabterial infection could cause antoher infection in the same patient.
A
resident flora
12
Q
C. Diff Disease process 1. After ingestion _____ _____ are killed by stomach acid but _____ survive.
A
vegetative cells spores
13
Q
C. Diff Disease process 2. ________ germinate in the ____ _____ upon exposure to _______ acids?
A
Spores small bowel bile
14
Q
C. Diff Disease process 3. Movement is made from the Small bowel to the _____ by the use of _____. The ______ _____ protects the organisum from _______?
A
Colon Flagella Polysaccharide capsule phagocytosis
15
Q
C. Diff Disease process 4. Organisms ________ in the colon and adhere to ______ ____?
A
multiply epithelial cells
16
Q
C. Diff Disease process 4. After adherence to the epithelial cells of the colon the organisum creats a local producation of ________ ____ and _____, production of ______, _____, ______ ____ _____ , ____ and _____ _____.
A
toxins A B a-TNF Inflammation Increased vascular permeability neutrophile monocyte recruitment.
17
Q
C. Diff Disease process 5. After production of toxins and adherence Opening of the _____ ____ ____ and cell _____?
A
epithelial cell junctions apoptosis
18
Q
C. Diff Disease process 6. After opening of the epithelial cell junctions and cell apoptosis local production of ____ _____ cause ______ _____ _______?
A
hydrolytic enzymes connective tissue degradation
19
Q
C. Diff Disease process 7. connective tissue degradation leads to ______ , _______ _____ ( dead tissue, fibrin, mucus phagocytes, DNA) and watery ______?
A
Colitis pseudomembrane formation diarrhea
20
Q
C diff
Disease process
Breakdown of the epithelium mainly by the action of ____ _ allows entry of ____ _ to underlying tissue causing yet more damage?
A
toxin A
toxin B
21
Q
C diff
Disease process
With extensive damage ____ _____ or other _______ form the colon can pass into the blood ( and in addition to strong inflammatory response due to tissue dmage) cause ____ _____
A
LPS (gr-ve)
bacteria
septic shock
22
Q
C diff
Disease process
Strain variations include _____ and ______ _____ strains?
A
toxogenic
non toxogenic
23
Q
C diff
Disease process
1-5% normal population harbor this organisum this raises to 20% in ____ _____. and has now spread to the community.
A
hospital enviroment
24
Q
CDAD is also know as _______?
transmission is spread from ____ to ____- via ______ ____ route
A
c. difficile associated Disease
person
person
fecal oral
25
\_\_\_\_\_ ________ is a severe ulceration of the colon, described 100 yrs ago and still rare until 1970.
fatal within a few days
-
pseudomembranous colitis
26
pseudomembranous colitis
accumulation of \_\_\_\_, ____ , ___ \_\_\_ ___ -yellow layer on surface of mucosa.
fibrin
mucin
dead host cells
27
Pseudomembranous colitis
Separate ________ become more widespread becoming the \_\_\_\_\_\_\_\_. fatel within a few days is not treated.
leasions
pseudomembrane
28
Pseudomembranous colitis
\_\_\_\_\_\_ may be so sever that the ____ \_\_\_\_\_ becomes distended and the ____ \_\_\_\_\_ \_\_\_\_\_?
inflammation
large bowel
bowel wall thins
29
Pseudomembranous colitis
when the bowel becomes distended and the bowel wall thins ____ \_\_\_\_\_ can occure this carries a risk of ____ \_\_\_ and _____ ?
toxic megacolon
bowel perforation
peritonitis
30
Virulence factors of C. diff
1. A and B toxins
toxins A and B are the _______ \_\_\_\_ ___ toxins known.
largest single molecule
31
Virulence Factors
Toxins A-B
Toxins A-B Modeify membrane ____ \_\_\_\_\_\_ that control many cellular activities?
G protein
32
Virulence Factors
Toxins A-B
Unlike many toxins these types were difficult to work on ( tend to aggregate, elude purification) untillgenes cloned and characterized _____ and \_\_\_\_\_?
tcdA
tcdB
33
Virulence factors
Toxin A-B
This Activates enteric _______ affecting _______ of _______ contents thus contributing to \_\_\_\_\_\_\_\_?
nerons
motility
intertinal
diarrha
34
Virulance factors
Toxin A-B
Attract/activates PMN's by __________ - this causes an ________ response that leads to ______ \_\_\_\_\_ \_\_\_\_\_\_?
cytokines
inflammatory
mucosal cell destruction
35
Virulance factors
Toxin A-B
Effects motility of intestinal contents causing ________ of _________ into ______ \_\_\_\_\_\_\_\_\_?
leakage
water
lumen diarrhea
36
Virulance Factors
Toxin B
Toxin B Collapses ____ \_\_\_\_\_\_, so the shape of the cells lost?
actin cytoskeleton
37
Virulence Factors
Toxin B
Toxin B damages underlaying tissue of the ____ \_\_\_\_\_ and ____ \_\_\_\_?
mucosal membrane
intersinal wall
38
39
Lethal hospital bug cases rocket, United Kingdom
-Potentially lethal cases of C.diff rocketed from 1990- \_\_\_\_\_\_?
Cases had increased from 1,000 in 1990 to over 35,000 in \_\_\_\_\_\_?
-45,000 cases of ___ \_\_\_ in ___ year olds in 2004?
2004
2003
C. difficil
\>=65
40
C. difficil Outbreaks
2007- United Kingdom
-the number of deaths linked to the hospital infection ____ \_\_\_\_ more than doubled in the previous two years.
Clostridium difficil
41
2007- United Kingdom
England and Wales 8,324 people died from either _ \_\_\_\_\_ or were infected with it when they died from other causes - a rise of ____ percent in just one year.
C. Diff
28
42
2007 -United Kingdom
The infection which particularly affects ____ people increases _____ times over 2001 when 1,804 deaths where linked to the \_\_\_\_\_\_\_?
elderly
4
superbug
43
The general public are now more aware of ___ \_\_\_\_\_\_- but ____ is the key to prevention?
C. difficile
education
44
2007 -United Kingdom
The third major outbreak in 2007 occured in ____ \_\_\_\_\_ ?
maidstone hospital
45
C. diff
Prevention and treatment
- Early diagnosis- ________ associated diarrhea- routine monitoring for __ &\_\_\_\_\_ _________ in feces?
antibiotic
A
B
Toxins
46
C. Diff
Prevention and Treatment
Replace antibiotic causing problem with _______ or ______ this kills c. difficil but does not adversely affect ______ \_\_\_\_\_\_?
vancomycin
metronidazole
normal flora
47
C. Diff
Prevention & treatment
-Relaspes (multiple) in _____ \_\_\_\_ % of patients?
10-20
48
C. Diff
Prevention & treatment
Failure to clear C. difficile and restore stable, _____ \_\_\_\_\_\_\_ leads to _____ \_\_\_\_\_?
nonpathogenic flora
resistant spores
49
C. Diff
Prevention & treatment
Treatment is best when coupled with improved _____ \_\_\_\_ within \_\_\_\_\_\_?
cleaning practices
hospitals
50
C. Diff
Alternative therapy
One of the Alternative therapies for C. diff treatment is to _______ \_\_\_\_ \_\_\_- using an enema containing dilute feces from a family member?
Replace resident flora
51
Alternative therapies
C. diff
Replacement of resident flora using an enema containg dilute feces is referred to as ____ \_\_\_\_ or ____ \_\_\_\_\_ \_\_\_\_\_\_\_?
Fecal Bacteriotherapy
Fecal Microbiota transplantation (FMT)
52
An _________ is the procedure of introducing liquids into the rectum and colon via the anus?
enema
53
Fecal bacteriotherapy/ Fecal microbiota transplantation (FMT)/
replacemant of resident flora using an enema containing dilute feces from a family member Previously used in health clinical for so called _______ \_\_\_\_ but now is accepted and widely used treatment for C. diff infections?
detox Therapy
54
what is Pulse Net
detection of Foodborn Diseases by Pulsed field Electrophoresis (PFGE)
55
Potential reasons for increased CDAD, incidence and severity
Historical
changes in underlying ____ \_\_\_\_\_\_\_\_?
and changes in ____ \_\_\_\_\_\_\_?
host susceptibility
antimicrobial prescribing
56
potential reasons for increased CDAD, incidence and severity
Recent
- New strain with increased \_\_\_\_\_
- \_ _ \_ -binary toxin
- variations in _ \_ _ \_ activity
- changes in ____ \_\_\_\_ \_\_\_\_\_\_
virulence
CDT
TcdB
infection control prctices
57
58
treponema pallidum
Is A ________ bacterium with subspecies that cause treponemal diseases such as \_\_\_\_\_\_\_\_\_\_
spirochaete
syphilis
59
spirochetes
are gram ________ , they are _____ \_\_\_\_\_\_\_ shaped with a Motile , ______ style of movement?
negative
Thin helical
corkscrew
60
internal flagella
what two spirochete organisums where listed with internall flagella and what do they cause.
Borrelia burgdorferi -Lyme Disease
Treponema pallidum- Syphilis
61
TTreponema pallidum
Treponema pallidum is never cultured in the laboratory on ____ \_\_\_\_\_
Insted it isw cultured on tissue culture cells of ____ \_\_\_\_ \_\_\_\_\_?
artificial media
cottontail rabbit epithelium
62
Treponema pallidum is known to cause _______ and is only found in ____ \_\_\_\_ ?
syphillis
human host
63
Syphillis is caused by ____ \_\_\_\_ is Extremly sensitive to ____ \_\_\_\_, and is transfered ______ to ______ by _____ \_\_\_\_\_\_?
Treponema pallidum
enviromental stress
person
person
sexual contact
64
Syphillis is often transferred with ____ \_\_\_\_\_\_\_ but potentially is much more serious.
N. gonorrhoeae
65
Shypillis is most prevalent among\_\_\_\_ and _____ \_\_\_\_\_?
minority
ethnic populations
66
Syphilis is 60X higher in ___ \_\_\_\_ than in \_\_\_\_\_\_\_\_?
African american
caucasins
67
80% of syphilis is in the ______ United states?
southern
68
Morphology, physiology and motility:
even though Treponema pallidum is gram negative it still has a small amount of _____ \_\_\_\_ between _ \_\_\_\_\_?
Peptidoglycan
2 membranes
69
70
Morphology, physiology and motility:
Treponema Pallidum has a ______ \_\_\_\_\_\_\_ that makes up the cell body it is ______ and generally \_\_\_\_\_\_\_\_?
protoplasmic cylinder
rigid
generally helical
71
Morphology, physiology and motility:
72
Morphology, physiology and motility:
Spirochetes such as Treponema pallidum has 1 to many ______ \_\_\_\_\_\_ that emerge from poles called \_\_\_\_\_\_\_\_\_?
internal flagella
Endoflagella
73
Morphology, physiology and motility:
Spirochetes are covered by a multilayered, flexible membrane called an _____ \_\_\_\_\_\_\_?
Outer sheath
this is important to avoid the immune system. most bacteria have many things attached to thier outer membrane( sugars ect. )
Treponema pallidum Has a smooth outer membrane with not many sugars or receptors ..... not many targets for the immune system
74
75
Morphology, physiology and motility:
Endoflagella ___________ the _____ \_\_\_\_\_\_\_\_ is rigid and the _____ \_\_\_\_\_\_\_\_ is flexible. When flagella rotate in the same direction, the protoplasmic cylinder rotates in the _____ \_\_\_\_\_\_\_?
rotate
protoplasmic cylinder
outer sheath
opposite direction
76
Morphology, physiology and motility:
tension placed on the cell causes \_\_\_\_\_\_\_\_, _____ ,\_\_\_\_ _____ movement?
flexing
twisting
jerky corkscrew
77
Morphology, physiology and motility:
The twisting , jerky corkscrew movement is effective in _____ \_\_\_\_, _____ and \_\_\_\_\_?
viscous solution
blood
tissues
78
diagnosticaly how are Ricketts and shypillis diffrent?
ricketss rash all over but not on palms and feet
shypillis rash primarily on hands and feet
79
in 2008 the CDC estimates Total infections at _____ million with _____ million new annual infections costing the United states a total of _______ \_\_\_\_ in medical cost?
20
110
$16 billion
80
History
Syhillis is considered an ____ \_\_\_ for the _____ centery with the surge of mankind, but became a even bigger problem in \_\_\_\_\_\_\_?
Old disease
15th
1960's
81
History
shypillis infections increased in the 1960's because of the _____ \_\_\_\_\_ and the invention of the _____ \_\_\_\_?
sexual revolution
contraceptive pill
82
History
The 1960 caused a sexual revolution with the invention of the ____ \_\_\_\_ which led to ______ \_\_\_\_ ____ (control when /if to have kids)
and it also led to an increase in \_\_\_\_\_\_\_\_?
contraceptive pill
increased sexual activity
prostitution
83
disease progression
Disease progression of shypillis has similarties to ____ \_\_\_\_\_\_\_, Both caused by \_\_\_\_\_\_, however they are diffrent \_\_\_\_\_\_\_\_?
Lyme disease
spirochetes
genera
84
Disease progression
Both ______ \_\_\_\_\_ and ______ have ______ \_\_\_\_\_ in thier life cycles?
lyme disease
syphilis
multiple stages
85
History
shypllis
first outbreak was in _______ on the year ______ also called the ______ \_\_\_\_ due to it causeing large sores compared to \_\_\_\_\_\_\_\_?
london
1748
great Pox
Smallpox
86
History
During the Great Pox outbreak in London in 1748 the causes , of this along with many other illness whas not understood. many belived the causes to be ?
hand of God
Astrological events
Curses
Gaseous emmissions, miasms- noxious bad air
87
An infamous experiment– John Hunter, Physician
Hunter hypothesized that two diseases could not exist simultaneously in the same
organ. Therefore syphilis and gonorrhea were believed to be different symptoms
of the same sexual illness.
Dry –chancre or Wet –discharge?
Had a theory that is was one disease that was transferred by the
discharges observed. So, he needed a healthy penis….!
He took some discharge from a male patient and transferred it to
the glands of his own penis…
He then stabbed himself with a lancet, several times !! and then
squeezed the cut open with the liquid discharge could enter !!
In a few day he reported a “tingling” in his penis followed a few
days later by two chancres
Treated himself with mercury.
3 mths later he got a skin rash, treated again with massive dose of
mercury
-he reported that the symptoms had disappeared for good ?..
Approx. 25yrs later – he died of syphillis and possible mercury
poisoning!!
88
virulence factors
ability to _______ \_\_\_\_\_ to invade the body
- Ends of the bacteria attach to the _____ \_\_\_\_ containing ______ \_\_\_\_ that joins capilillary _____ \_\_\_\_\_?
transit epithelia
hyaluronic acid
extracellular matrix
endothelial cells
89
Virulence factors
the ______ \_\_\_\_\_\_ allows the organisum to cross tissue layers and enter and exit bloodstream.
-it also has the ability to cross the \_\_\_\_\_\_\_
corkscrew motility
placenta
90
Primary syphillis
T, pallidum ________ pass through unbroken skin. infection probably occurs via small tiny breaks in the ______ \_\_\_\_ caused during sexual activity?
for males this is the \_\_\_\_\_\_\_?
Females\_\_\_\_ , _____ and surrounding regions
\_\_\_\_% of cases extra \_\_\_\_\_\_\_, usally _____ and _____ regions
cannot
epidermal layer
penis
vagina
cervix
10
genital
oral
anal
91
Sypillis has the ability to cross the placenta and infect the fetus- this is called ____ \_\_\_\_\_\_
first noticed symptoms as \_\_\_\_\_( irritation and inflammation of the _____ )and then \_\_\_\_?
congenital syphilis
rhinitis
nose
rash
92
untreated infants who survive syphillis show signs of ____ \_\_\_\_\_, \_\_\_\_\_\_and ________ malformations, \_\_\_\_\_\_\_\_, \_\_\_\_\_\_\_, and ___________ syphilis
cronic infection
teeth
bone
blindness
deafness
cardiovascular syphilis
93
T. Pallidum _______ at the sire of entry and a characteristic _______ (\_\_\_\_\_\_ ) is formed within \_\_\_\_weeks to ____ months?
multiplies
lesion
chancre
2
2
94
The lesion(chancre) maybe hidden on _____ under the \_\_\_\_\_\_, \_\_\_\_, ____ or \_\_\_\_\_?
scapl
hair
vagina
anus
mouth
95
a false sense of relief for the patent when the ______ disapperears after a few ______ and heals spontaneously during this time _____ are migrating away from the site of infection.
patient is infectious
chancre
weeks
bacteria
96
Secondary syphilis
1-3 months
-Bacteria penetrate _____ \_\_\_\_\_\_ and enter \_\_\_\_\_\_\_\_\_?
\_Bacteria spread to mucous membranes ,\_\_\_\_, \_\_\_\_\_\_, ____ or _ \_ \_?
mucosal membranes
bloodstream
eyes
joints
bones
CNS
97
Secondary syphilis
- Body mounts an _____ \_\_\_\_\_ causing ____ like symptoms- _____ \_\_\_\_, \_\_\_\_\_\_, \_\_\_\_\_,\_\_\_\_ ____ \_\_\_\_?
immune response
Flu
sore throat
headache
fever
swollen lymph glands
98
Secondary syphilis
Key features include ?
hypersensitivity reaction
rash that covers entire body (puss filled marks) larger than smallpox
highly contagious
99
The rash and symptoms from shyphillis resolve sponataneously and the patient enters the clinically ____ or ___ \_\_\_\_ where they belive they are cured?
inactive
latent phase
100
\_\_\_\_\_\_\_\_\_\_\_ (Late ) Syphilis ______ years?
A small number of cases progress to this stage. Range of symptoms from mild to fatal infections
during this stage there is a relatively ____ number of bacteria?
Tertiary
3-30
low
101
Tertiary Syphilis
in late stage syphilis the immune response is ____ \_\_\_\_\_ causing destruction of virtually any organ or tissue. Disabling fatigue, disfiguring skin leasions, bone malformation ( archeological information)
\_
chronic inflammation
102
fatal infectionsif vital systems/organs are affected cardiovascular and CNS.?
Complexes tht consist of ___ \_\_\_\_\_\_, _____ and host \_\_\_\_\_\_?
Depositied on various body sites and elicit and _____ \_\_\_\_\_ - ______ disease?
treponemal proteins
antibodies
inflammatory response
autoimmune
103
Diagnosis and treatment of sypilis?
reliable _____ \_\_\_\_\_ have been available for decades?
bloods tests
104
Diagnosis and treatment of syphilis
the _______ test is based on ____ produced by host not the bacterium!!!
\_\_\_\_\_\_ is released from ______ \_\_\_\_ from lysing cells. not normally seeen by the immune system and processed as foreign (non-specific)
Wassermann Test
antigen
Cardiolipin
mitochondria membranes
105
in the Wassermann Test a sample of _______ or ______ \_\_\_\_\_ is taken and introduced to the antigen.
But can be produced in response to other conditions, viral, protozoan, autoimmune diseases resulting in _______ \_\_\_\_\_\_\_\_?.
blood
cerebrospinal fluid
false positive
106
there are now more sensitive test avaliable for T. Pallidum such as ____ test- _______ \_\_\_\_\_\_\_ test -(anti treponemal antibodies)
- Based on the fact that the organisms lose _______ when incubated with serum containing anti-treponemal antibodies.
- Both test require _____ \_\_\_\_ and _____ \_\_\_\_\_ (problem with sampling)
inactivation
Flurescent antibody test
motility
live organisms
sophisticated microscopes
107
Because of expense, physicians use non-specific test such as _____ \_\_\_\_\_.
depending on the clinic or hospital
- \_\_\_\_\_\_ ______ is used as preferred confirmatory test ( also resolves ____ \_\_\_\_\_)
- but this is more sophisticated and problematic for ______ communities /contries?
Wassermann test
Western Blot
false positives
poorer
108
Treatment
Syphilis is teated by \_\_\_\_\_\_\_\_, t. pallidum is one of the few bacterial species where _____ has not been observed?
But treatment must be administrated early to avoid damage caused by ______ disease triggered by the bacterial infection?
currently there is no _____ for syphilis?
Penicillin
resistance
autoimmune
vaccine
109
Tuskegee Experiment
-one of the most outrageous abuses in medical history undertaken in \_\_\_\_\_\_, ______ by the ______ \_\_\_\_\_ ______ \_\_\_\_\_\_?
Tuskegee
Alabama
U.S. Public Health service
110
Tuskegee Experiment
in ______ -\_\_\_\_ poor rural black men who thought they were receiving free health care from the U.S. government.
INvestigators enrolled in the study of _____ improverished African American _______ from _____ \_\_\_\_\_\_\_, Alabama.
1930-1972
600
sharecroppers
Macon County Alabama
111
Tuskegee Experiment
For participating in the study the men where given free ____ \_\_\_,\_\_\_\_, and ____ \_\_\_\_\_\_?
of the 600 men ____ had previously contracted syphilis and ______ without the disease.
They were _____ \_\_\_\_\_ they had \_\_\_\_\_\_, nor were they ______ for it?
medical care
meals
free burial insurance
399
201
never
told
shyphilis
treated
112
Tuskegee Experiment
The Experiment was a _____ year study that was controversial for reasons related to _______ \_\_\_\_; primarily because reasearchers ________ failed to _____ patients appropriately after the ______ validation of ______ as an effective cure for the disease they were studying?
40
ethical standards
knowingly
treat
1940's
penicillin
113
Tuskegee Experiment
By the year \_\_\_\_\_, penicillin had become the standard treatment for syphilis but the study continued.
The study continued under numerous Us public Health Service Supervisors until _______ when a leak to the press eventually resulted in its termination.
1947
1972
114
Tuskegee Experiment
The victims of the study included numerous _____ who dies of syhillis, _____ who contracted the disease and ____ born with _____ \_\_\_\_\_\_?
men
women
children
congenital syphilis
115
Tuskegee Experiment
cited as "arguably the most infamous biomedical research study in U.s. history, led to _____ \_\_\_ ____ for the protection of human subjects. Now studies require ____ \_\_\_\_( with exceptions possible for U.S. Federal agencies which can be kept secret by Execuctive ORder, Communication of diagnosis and accurate reporting of test results.
institional Review Boards
informed consent
116
prevention of Syphilis
- Some parts of the world have eradicated or almost eradicated this disease.
- Controlled by ____ \_\_\_\_, contact of sexual parteners for _____ ( test used to be used to obtain a marrige liscens in the US.)
-
safe sex
treatment
117
- Although at one time couples needed to have a certified blood test for (VDRL) syphilis " Pursuant to the Marriage Amendment Act of 2008, DC Law.
Effective September 11, _______ a ___ \_\_\_\_ is no longer a requirment to obtain a marriage license in the District of Columbia.
-Problem with prostitution among drug uses that causes a viscous cycle of infection.
\_Legalizedbrotheles ect have improved this situation - robust debate.
2008
blood test
118
famouse people with syphlis?
119
94
Legalized brothel etc have improved this situation- robust debate
1. Safety of the men and women involved in the sex industry
- State licensed and controlled.
- Safe working environment rather than on the street where abuse can take place
2. Increased control of diseases
- the workers are use safe sex and screened on a regular basis for STDs
- and clients are also screened, at least on a visual basis
- But certain groups in society are vehemently opposed to this but these measures have
been shown to have positive outcomes in Europe.
120
Syphilis
\_\_\_\_\_\_ of the organisum on the site of ____ triggers massive ____ \_\_\_\_, blood vessle _____ , tissue ______ or \_\_\_\_\_\_?
Replication
entry
leukocyte infiltration
damage
necrosis
Chancre
121
Syphilis
Most cases of primary and _______ syphilis are spontaneously resolved by the _______ \_\_\_\_\_\_\_\_?
secondary
adaptive system
122
Syphlils
primary and Secondary shyplilis are spontaneously resolved by the adaptive system involving?
- CD8+ cytotoxic T lymphocytes
- cytokine production ( a-interferon, interleukins) as demonstrated by degraded treponemes are found in phagolysosome.
123
in some cases the adaptive system cannot cleare the organisum and can produce to the ______ \_\_\_\_\_ that may last for years or\_\_\_\_\_?
tertiary stage
decades
124
\_\_\_\_\_\_\_\_ studies have shown that _ \_\_\_\_\_\_ is largely devoid of ______ -\_\_\_\_\_\_\_\_\_\_ proteins?
Ultrastructure
T. Pallidum
membrane
associated
125
\_\_\_\_\_\_\_\_\_ -\_\_\_\_\_\_\_\_\_ proteins that are present may be involved in ______ and _____ of the host and may be the target of the _____ \_\_\_\_ response?
Membrane
associated
attachment
invasion
adaptive immune
126
\_\_\_\_\_\_\_ ____ harvested from ______ that are less susceptible to \_\_\_\_\_\_\_?
This Suggested that subpopulations of _____ \_\_\_\_\_ account for these \_\_\_\_\_\_\_\_\_\_\_?
Persistent treponems
rabbits
macrophages
antigenic variants
persisters
127
orgins of Syphilis
many blame _________ and his crew for bringing syphilis to ____ in \_\_\_\_\_\_?
skeletons from archaeological sites in the United states and Ecuador ranging in age from ______ to ____ years?
Columbus ( europen sailors not used to seeing beautiful women half naked .... led to sexual liaison)
Europe
1492
400
6,000
128
Syphilis orgins
Europe constantly at War _______ in particular could spread disease because of ________ \_\_\_\_\_\_ to diffrent countries?
Small cities of people often accompanied \_\_\_\_\_\_\_\_, ______ , _____ and brothels were prominet - rampant ______ rate?
soldiers
constant movements
armies
Taverns
Prostitutes
infection
french -blames naples
italians - the french
russians- polish
english -spanish
129
Syphlils
orgins
European evidence, especially syphilitic lesions in skeletons from a _____ centery _____ \_\_\_\_\_\_\_?
Now many new findings in England and Europe show tell tale signs of syphilis _____ years before the ________ of \_\_\_\_\_?
14
english monastery
70
voyage
Columbus
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What is PBP's called Tp47
recently discovered PBPs called Tp47
The binding of the beta lactam component of Penicillin to Tp47 results in
hydrolysis of the beta-lactam bond of the antibiotic resulting in the
production of several byproducts.
The thought is that these byproducts have a higher affinity for Tp47 than the
beta lactam itself. Thus as a consequence of Penicillin being broken
down, products are released which make it more difficult for the betalactamase
to bind the antibiotic and deactivate it.
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Treatment of syphlis
Penicillin is the treatment of choice for treating syphilis. According to the
Centers for Disease Control and Prevention (CDC).
Patients with known penicillin allergies should undergo penicillin allergy skin
testing and penicillin desensitization, if necessary.
The 2010 CDC STD treatment guidelines recommend desensitization in
penicillin-allergic pregnant women, followed by treatment with penicillin.
Treatment
Many pathogens are resistant to Penicillin- so why not T. pallidum?
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Genome sequencing of T. pallidum: 1998
1.138 Mbp, one of the smallest genomes identified.
• 1000 genes
• Does not have genes for making nucleotides, fatty acids, most amino acids and
enzyme cofactors
- no wonder it cannot be grown in the lab.
\*Now this is known these compounds can now be added to
artificial media in new attempts to grow this organism. –to
date not very successful.
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genome sequincing 1998
Over 20 genes encoding outer surface lipoproteins.
- proteins to punch holes in host cells
- or attachment proteins to stick to mucous membranes
But these surface proteins may be subject to antigenic variation
and adopt a “stealth” strategy leading to “persistence”
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134
syphlis reviw
• syphilis ancient disease that as mutated to take advantage of human
behavior
• no animal reservoir
• however modern treatment (antibiotics) is relatively simple
•Therefore could, in theory be eradicated but……
.... Human behavior cannot be controlled but through
safe sex practices we may be able to reduce the incidence?
135
case study
1996, Georgia. Initial outbreak.
However, from a few individuals, investigations led to over 200 infected young
adults.
1 yr before the outbreak
• 18 young white girls with two groups of young men
- One group white, second was African-American
- met for drug, alcohol and sexual activities
- met in public areas, back seat of cars etc
- sequential and simultaneous partners
• limited or no safe sex practices -16 pregnancies and 200 infected individuals.
136
Mycobacterium tuberculosis and Tuberculosis
is also called?
the peoples plague
one of histories most feared killers
Tuberculosis or consumption- because it seemend to consume people from within.
137
Mycobacterium tuberculosis
## Footnote
* **Aerobic, very slow growth 6-8 wks** to form colonies
* Gr. +ve type cell wall but Gram stain not useful
- High content of **mycolic acids** (lipids 10% cell weight) –leads to term
**“acid-fast**” as a robust method of staining is used
**Highly contagious,** aerosol spread (talking, sneezing, coughing etc)
138
• Multiplicity of infection
**Salmonella:** 10 million,
**E.coli 0157**:- \>10,
**M. tuberculosis** - 3
divides itself every 16 to 20 hours
E. Coli -20 mins
139
TB shap and morphology
Acid-fast staining produces
diagnostic \_\_\_\_\_\_\_\_?
red bacilli
140
TB
Described in \_\_\_\_\_\_\_\_\_by \_\_\_\_\_\_\_\_\_.
-Aggressive surveillance and antibiotic treatment
But today ….. Asylums dismantled, care in the community?!
• Still one of the most infectious curable diseases –\_\_\_\_\_\_\_\_% of adult
deaths
• Top\_\_\_\_\_\_\_ killer along with\_\_\_\_\_\_ and \_\_\_\_\_
-synergistic with HIC x800 chance of contracting TB
1882
Koch
20
3
HIV
Malaria
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• Tuberculosis (TB) is one of the top 10 causes of death worldwide.
• 2016, 10.4 million people fell ill with TB, and 1.7 million died from the disease
• Seven countries account for 64% of the total, with India leading the count, followed by
Indonesia, China, Philippines, Pakistan, Nigeria, and South Africa.
• TB is a leading killer of HIV-positive people: in 2016, 40% of HIV deaths were due
to TB.
• Multidrug-resistant TB (MDR-TB) remains a public health crisis and a health
security threat. WHO estimates that there were 600 000 new cases with resistance
to rifampicin – the most effective first-line drug,
• An estimated 53 million lives were saved through TB diagnosis and treatment
between 2000 and 2016.
• Ending the TB epidemic by 2030 is among the health targets of the Sustainable
Development Goals.
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Orgian of TB
Evolved from a disease of _____ in \_\_\_\_\_\_-\_\_\_\_ BC in \_\_\_\_\_\_
- probably from the soil organism _ \_\_\_\_\_\_
Early Egyptian mummies (1000 BC), found with characteristic _______ \_\_\_\_\_\_\_\_\_but not evidence of ______ \_\_\_\_\_\_\_ but this was found
in more recent mummies (Ramses II) (400-1000BC)
cattle
8000
4000
herdsmen
M. bovis
bone malformations
lung damage
143
Earliest Known Human TB Found In 9,000 Year-old Skeletons
submerged off the coast of Israel
Characteristic bone malformations
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TB
Symptoms:
-highly contagious, 3 organisms can cause
disease!
Fever, coughing, bloody sputum, weight loss, and malaise
• Progressive, irreversible lung destruction
• Bones, joints, liver, spleen, GI tract and brain.
• Fatal, progresses slowly (yrs), more rapid in AIDS, fatality is 80%
145
Chlamydia trachomatis
- Small Gr-ve short rods
- **no** **detactable** **peptidoglycan**
- **Obligate intracellular pathogen**
- **Many serovars ( strains) associated with specific disease**
- **Reduced genome** - size 1000 kbp (E. colie 4600)
- Unusual 2 stage life cyle
• Chlamydia is an organism that has very **specific requirements** that allow
it to **exist in the cervix, urethra, and fallopian tubes.**
You can get chlamydia by having **vaginal, anal, or oral sex with someone**
who has chlamydia.
• Because of these specific requirements**, chlamydia cannot live
outside the body,**
146
147
• Cervical infection is the **most common STD**
• US -4 million cases –cost $2 billion
• Little public perception of this organism and the diseases it causes
• **Trachoma** –chronic disease (North and sub-Sahara Africa, Middle
East, Asia and South America).
* *- Causes blindness to 6 million
- 150 million in need of treatment
- Leading cause of preventable blindness**
148
Stigma
- STD-gonorrhea and syphilis associated with
underprivileged etc, but
chlamydial diseases found on college campuses and rich
neighborhoods -doesn't differentiate!!
149
chlamydia in women
* Cervicitis - inflammation of the tissues of the cervix
* Pelvic inflammatory disease (PID)
Endometritis -inflammation of the endometrium, the inner lining
of the uterus
• Ectopic pregnancy /Premature birth
190
150
* in some cases Pelvic pain, chronic or acute
* Newborn eye or lung infection
Makes women much more susceptible to HIV,
-macrophages, and T-cells travel to genital area and are the target of
the HIV
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chlamidia
men
• Prostatitis - inflammation of the prostate gland.
Epididymitis (covering of the testis) -the epididymis becomes
inflamed
• Fluid discharge?
152
chlamdia
both sexes
* Urethritis
* Infertility
* Proctitis (rectal disease and bleeding)
* Long term can lead arthritis
153
Life cycle of Chlamydia:
**transition** **between two distinct developmental forms**
**Elementary Body (EB)** -a small, dense cell that is resistant to drying
and means of dispersal.
**Non multiplying, infectious agent (outside host cell).**
**Reticulate Body (RB)** –larger, less dense cell, vegetative form -
multiplies (2-3hrs).
**Non-infectious, multiply inside host cells** to form a large inoculum for
transmission.
**Whole** **cycle takes only about 48hrs**.
154
Avoidance of cell lysis.
No PG that normally provides strength to the bacterium – but
**high osmolarity of the interior of a human cell prevents cell lysis of
reticulate body**
- **modified membrane structure to** **strength** **the cell**
results in the large number of **Serovars** that refers to distinct variations
within a species of bacteria
155
chlamydia
**Membranes with proteins containin**g multiple disulfide cross-links
•Major outer membrane protein (MOMP)
•Polymorphic outer membrane protein (POMP)
•**Large and smal**l Cysteine-rich proteins (CRP)
156
Reduced Genome size:
**Minimum genome** is the smallest number of genes needed to
encode functions of a free-living microbe
But still has a complex life-cycle.
•Energy parasite as it uses host ATP
•Lacks genes for amino acid biosynthesis but
•But contains genes for several energy-generating pathways –
glycolysis, pentose phosphate pathway and a partial TCA cycle
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157
Virulence Factors:
Problem – we can’t grow C. trachomatis in cell-free culture. 10
litres gives \>200mg (E.coli, many grams)
Genetic manipulation models- held back
• Mice- different mice show different levels of infection
158
Adherence and Invasion by EBs
EBs have a number of ways of entering the cell:
-normal phagocytosis
• endocytosis,
• pinocytosis
159
1. **Phagocytosis** (literally, cell-eating) is the process by which cells
ingest large objects, such as bacteria.
**The membrane folds around the object (Pseudopodia), and
the object is sealed off into a large vacuole known as a
phagosome.**
160
Pinocytosis- (liThis process is concerned with the uptake of solutes and single
molecules such as proteins?
**Formation of small vacuoles.**
161
Endocytosis (receptor-mediated)
--material absorbed from the outside by engulfing it with their cell membrane.
It is used by all cells of the body because most substances important to them are
polar and consist of big molecules, and thus cannot pass through the
hydrophobic plasma membrane.
Substances absorbed across the membrane via association with
**specific receptors and requires energy**
162
•EBs enter and form vesicles known as **Endosomes** (near neutral
pH) Endosomes containing one EB may fuse with other endosomes –
know as an **Inclusion.**
**Endosome membrane lipids may come from Golgi membranes in
addition to RB proteins (Inc proteins)**.
Hence this **membrane is a hybrid of host and bacterial lipids and
proteins and is important in the non-fusion with****lysosome****.**
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• EBs are covered with projections which appear to penetrate the
endosomal membrane to reach into the cytoplasm.
• These projections appear to be hollow, transport of nutrients from cell
or introduce bacterial proteins into cytoplasm.
• EBs transformed into RB and begin to replicate (2-3 hrs-relatively rapid).
• As the number of RBs increase the **endosome membrane** expands to
accommodate these.
• For the **endosome** **membrane lipids may come from Golgi
membranes in addition to RB proteins**(Inc proteins).
• Hence this **membrane is a hybrid of host and bacterial lipids and
proteins and is important in the non-fusion with****lysosome****.**
• RBs stay attached to endosome membrane, but at some point
**migrate to the internal part of the vacuole and differentiate into EBs.**
212
164
• During RB replication stage, even though the cells can take up a large
proportion of the host cell, little damage or adverse functionality
appears ?
Organism totally dependent on cell for nutrients and energy
214
•After about 40hr EB are release from cells
Actual mechanism is unknown and may be the result of 2 events:-
1. **lysis of cells and release EBs into cytoplasm** that can infect adjacent
cells.\
2. **endosomal membrane can fuse with cell membrane releasing EBs and
RBs into****cytoplasm** **or extracellular space** to infect adjacent host cells.
165
Active discussions / research on this on how damage is caused to host cells
Some scientists think, **some host cells are killed during the process of EB escaping
the cell causing tissue damage**
some think it is the **immune response to EB that is thought to be the main cause
of cellular damage.**
Inflammatory response could be to EB and other proteins prior to the EBs
entering the host cells or when released from the cell causing collateral damage.
Could be strain specific
166
Lymphogranuloma venereum
**• Caused by distinct serovars (strains) of C.trachomatis, and is the only
chlamydial infection that invades beyond the epithelial cell layer.**
Affect both men and women,
1st stage**1-4wks, primary lesion** -penis, urethra, scrotum, vaginal wall,
cervix, vulva.
Absence of pain, but fever, chills, anorexia.
2nd stage –**inflammation and swelling of lymph nodes- buboes**
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Buboes -rupture- infection becomes systemic -fever, chills,
anorexia, headache.
• Bacteria spread to other regions, eg.rectum
**Reifer’s syndrome** (urethritis, conjunctivitis) or reactive arthritis
3 seemingly unrelated symptoms: arthritis, redness of the eyes, and
urinary tract signs….
….Although most chlamydia infection remains localized. When the
i**nfection becomes systemic the bacteria can travel** **to** **joints and
other body parts** –inflammation leads to pain.
168
Prevention and Treatment:
In studying infection rates of chlamdyia among 800 army recruits, UK researchers
found that nearly 90% of those who tested positive for chlamydia showed no obvious
symptoms.
**most men with chlamydia have no symptoms**"Many studies have shown about one in 10 women are infected,
**Both can be carriers but males tend not to be as quickly diagnosed and spread the
disease from partner to partner.**
recommended **screening for chlamydia** in all sexually active females aged
24 years or younger and in older women who are at increased risk for
infection.
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Screening /treatment
• Historically, detection was a problem- invasive methods
- **Women** –cervical cell sample•
**Men –** urethral cells needed to be collected
–”urethral stripping” –small brush inserted in penile opening –
painful –locker room talk- discouraged men seeking medical aid!
170
• Gram stain to eliminate **N.** **gonorrhoeae** from diagnosis –culturing is
time-consuming and expensive (Chlamydia is too small to view via a
microscope)
• Now **rapid diagnostic tests
- DNA probes, PCR and other DNA amplification methods.
- –specific monoclonal fluorescent antibody tests**
**Non** **invasive** **/ rapid** **tests** used with urine sample
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chlamidia
no vaccine avalaoble
•Treatable with antibiotics, **Chlamydia and N.** **gonorrhoeae****.**
- **Doxycycline (a tetracycline) and azithromycin** (macrolide) (inhibit
protein synthesis) +
- **Cephalosporin (**cell wall –PG) for gonorrhea.
•Resistance not a problem -yet?
Probably due to the organisms lifestyle, not in contact with other
bacteria or antibiotics when compared with gut microorganisms. (
reduced risk of Lateral gene transfer)
224
172
The Chlamydial peptidoglycan paradox
Why is C. trachomatis **susceptible to penicillin** whose main mode of
action is to inhibit PG synthesis?
Small amounts produced that cannot be detected with current
methods?
173
**Development of EBs from RBs is affected**
-division of RB is affected by Penicillin
- a number of Penicillin Binding Proteins are specifically affected
- these appear to be less accessible to penicillins in the Ebs and therefore
resistant to the antibiotic.
**Pathogenomics** - genomic studies have provided recent
information and confirmed the small genome..?
226
174
**Genome contains genes that appear to encode a near complete
pathway for synthesis of PG**
Found in 5 species of Chlamydia confirming the conservation of this
pathway
Microarray analyses of transcription revealed a marked increase in
expression of PG synthesis genes at later developmental stage including
RB division.
1.8 % of genome composed of genes for PG and its been suggested
that PG plays an important, yet atypical role in chlamydial cell biology
so **susceptible to Penicillin**
175
Final Thoughts:
• Very unusual organisms –once thought to be viruses due to very small size
• 6 species from many animals, specific strains may cause different symptoms
within the host
• Many interactions with host cells
• **Much to be learned form these interactions
- Drug delivery systems
- other ways of destroying bacteria**
•Developing countries -still causes blindness
• The most prevalent STD and in the US (4 M = 5%).
•Asymptomatic infections- Screening with new cheaper DNA methods
may facilitate early detection.
• Need to increase treatment of men who are the main carriers.
•Safe sex practices
230
176
**Case study: Outbreak of Lymphogranuloma** **vernerium** **in
Homosexual Men**
2003 –Rotterdam the Netherlands, men aged 26-48.
• cluster of ulcerative STD, tests showed the same pathogen
•13 were HIV positive, 8 had additional STDs
•All reported unprotected sex !!
•Many anonymous relations -contact tracing difficult but traced to
individuals in Germany, Belgium, UK and France.
177
Infectious Disease: The Future
• Need for alternative antimicrobial compounds (and appropriate
use of these?!)
• Genome sequencing will lead to:
- better, more rapid diagnostic tests
- the ability to grow bacteria that so far have eluded culture?
• Molecular tests will take precedence in the laboratory, but rapid diagnosis
through MALDI-TOF-MS is changeling molecular methods
• Globalization, transmission of microbial agents can be extremely rapid
• Gene therapy, and other new treatments –Bacteriophage therapy/ Viral
drug delivery systems, pre and pro-biotics will have a major impact on
future……
….will paralysis, blindness etc be treatable and eliminated !!!!
178
• Will society become two-tiered?
- The rich and the poor, the have and have-nots
- Those that can afford health care and those that
cannot.
• will we squander the Earths’ resources? -oil?
- water and food sources could /are become limited!
- could be a potential target for terrorists
- limited resources could be the spark that ignites local
and global conflict
179
The immune system in infants requires stimulating, lets not all use
disinfectant / antimicrobial compounds in wipes to try and sanitize all
things
- We should not try and raise children in a sterile environment
- Antibiotics should be cherished as a weapon against pathogens but
must be used appropriately we may be in the twilight of there
usefulness!
180
TB.
Progression of the Disease:
1. **Entry of host – aerosol**s in airway.
2. **Invasion of unactivated alveolar macrophages**: key factor
-stage process
**M. tuberculosis binds directly to a macrophage surface proteins CR3
and CR4 (complement receptors).**
Unactivated macrophages have fewer CR3 than CR4 but PMNs rushing
to infection site have more CR3. Inflammation also increases CR3
receptors.
181
TB.
• **T-helper (CD4+)** stimulate antibodies against M.
tuberculosis but cannot act on intracellular organisms (serum
resistant).
but -**M. tuberculosis** also:-
• interferes with produce IFN-g that stimulates macrophage
activation
• Interferes with production of **Cytotoxic Lymphocytes (T cells)** cells
that kill infected phagocytes
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• Internalization of bacteria in a vesicle (not normal
phagocytosis) that appears to have a reduced ability to fuse
with lysosome by preventing acidification.
• Reduced oxidative / respirative burst
• Reduced ability to produce IL-12 (cytokine) that stimulates Th-
1 response – reduced antibody response?
• **reducing antibodies may give the bacteria an advantage and
time for more to invade macrophages.**
183
TB
II. Some of the bacteria are killed, those that survive appear to bud-off
from the vesicle but still have a membrane encasing them.
Evidence:
MHC-I cytotoxic T cell response (antigens processed from an internal
source)……
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TB
MHC-I antigen presentation pathway –
All cells have MHC complexes for host recognition.
• Protein antigens degraded by the proteasome in the cytoplasm
are transported across the endoplamic reticulum membrane
formed by the TAP (transporters associated with antigen
processing).
• MHC-I protein is held in place by a chaperone until the peptide
is bound
• Chaperone is released and the protein complex is transported
to the cell surface and interacts with the T-cell receptors
(TCRs).
185
TB
In addition other cells of the immune system are involved
B cells have antibodies that recognize a foreign antigens
The antigen is internalized and in turn presented to a T helper
cell that stimulated the B cell to differentiate into plasma cells
that produce more antibodies to search out mycobacteria.
Mycobacterium tuberculosis is able to overcome these
mechanisms ii that they actively infect macrophages and survive
the destructive activates normally found in the phagolysosome.
**The T cell response is not initiated and so cytokines, IFN,
gamma TNF are not produced.**
These normally recruit more macrophages to the site of
infection and increase phagocytosis and inflammation
186
• if the phagocytes fail to kill the bacteria, T cells and
macrophages wall off growing bacteria with a thick fibrin coattubercle
**- Granulomatous response.**
• **Calcification,** visible on chest X-rays
• Phagocytes trying to kill bacteria cause considerable damage
to lung tissue –lysosomal enzymes, TNF-a.
• Lesions initially have a thick (cheeselike) consistency
**(caseous necrosis)**
• as phagocytes continue to enter site the necrotic region
becomes more liquid- easier to become aerosols
-more contagious
• Bacteria spread to other parts of the body
187
TB
Latency and Persistence: TB can be a chronic infection
• bacteria in lungs (and other organs?) can persist for decades. If later in life
suppression of the immune system may allow these to break out and
multiply. Latency.
- Reactivation TB
• **Persistence factors** – allow bacteria to survive for long periods.
- genes found that are related to sporulation (spores) mechanisms
- Metabolic shutdown
Evidence for latency -Animal models:
• Mice develops TB similar to humans.
• Treated with anti-TB drugs, bacteria are cleared, but **DNA is still
detected by****PCR ?**
• Gene coding for **a-crystallin, a chaperone protein**, expressed
during stationary phase. Disruption of this gene reduces
persistence.
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TB
Virulence Factors:
No toxins or hydrolytic enzymes !
• Research hindered by low generation time 18-24 hr. Takes weeks to form
a colony on agar.
• Molecular techniques were impeded, difficulty in extracting DNA
• Culture mammalian cell lines (macrophage like) now used to investigate
virulence factors.
So if no toxins or degradative enzymes how does the organism cause disease?
151
189
TB
Induction of destructive Inflammatory response
Even though some M. tuberculosis cells escape the immune response
enough appear to persist and do initiate an immune response.
Experimental evidence…….
**Cell wall components:**
•Mycobacterium mycolic acids injected into animals elicit an
inflammatory response.
•PG-trigger production of
-Cytokine, TNF-a /macrophage toxic lysosomal components
**Result - destructive lung tissue damage.**
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190
Factors that affect host susceptibility and severity of
symptoms…
Different individuals in a population exposed to TB respond very
differently from:-
no infection --- latent infection --- active /chronic infection.
•Size of inoculum, length and number of exposures all have an
affect but…….
Are there genetic predispositions that render some
people more susceptible to infection?
Mouse models
**Bcg** - genetic locus involved in susceptibility of different strains of
mice to TB
Codes for **natural resistance-associated macrophage protein**
191
TB
**Diagnosis, Treatment** **and** **Control:**
1800s Sanitariums, fresh-air: wide-open windows, outside
balconies (hot summers/freezing winters.
USA:
1900 – 34 Sanitaria
1925- 356 sanitaria
Not a cure -death rate still 69%
156
• Highly contagious
• Isolation in negative-pressure hepa-filtered room
• face masks with high efficiency filters.
But first you have to identify the disease and
individuals infected….
192
TB
Early diagnosis difficult, asymptomatic patients, slow gradual progression
and symptoms may be slow to show themselves…..
Fever, chills, and night sweats.
Fatigue and weakness.
Loss of appetite and unexplained weight loss.
Shortness of breath and chest pain.
These can be general symptoms associated with a number of diseases
but…
158
….. **not for more than 2 weeks** becomes a cause for concern
A cough with thick, cloudy, and sometimes **bloody mucus from the lungs (sputum).**
Test for **presence of “acid-fast” bacillus in sputum** (but must be present in
larger numbers)
193
Tuberculin test.
Tuberculin, protein extracted from M. tuberculosis is injected and a
localized immune reaction is seen.
Pre-primed TH CD4 cells at the site of injection secrete cytokines.
Poly Mono Nucleocytes (PMNs), monocytes and macrophages are
recruited to the injection site leading to the immune reaction…
**Positive test: Redness and swelling** -48-72 hrs
Demonstrates prior exposure to the bacterium 159
194
**Problems:**
**with TB skin test**
Takes 4 wks after exposure, so **recent infections are missed.**
Many people show this trait showing past exposure (low level as
soil organism) or vaccination by BCG.
**False** **positives / cross-reactivity** to other species of
Mycobacterium.
195
Search for better tests:
Bypass the need to culture this slow growing organism.
• PCR and sequencing - Extremely rapid (hrs):-
-**16S rRNA genes but low copy number** **therefore** **other targets
favored**
• Probes to **Insertion elements (in other regions of the chromosome)**
that are specific to M.tuberculosis strains.
**• Interferon Gamma Release Assay (IGRA)**
**Interferon Gamma Release Assay (IGRA)**
Prior BCG (bacille Calmette-Guérin) vaccination
does not cause a false-positive IGRA test result.
White blood cells from most persons infected with M.
tuberculosis will release interferon-gamma (IFN-g) when mixed with
antigens (substances that can produce an immune response) derived
from M. tuberculosis.
196
TB
Antibiotics and the1939-Selman Waksman and his graduate students (Albert Schatz)
started screening soil organisms for anti infectious disease
properties.
1945 -clinical use of Streptomycin derived from actinobacterium
Streptomyces griseus
1952, Waksman received Noble Prize but not Schatz who did most of
the work and development. problem of resistance
Inhibits the synthesis of the waxy cell-wall and so
susceptible to macrophages and the phagolysosome process
-• Special antibiotics used- Isoniazid (inhibits mycolic acid synthesis)
• Rifampin (inhibits processing of RNA and shuts down protein
synthesis)
Basic lack of knowledge on how anti-TB drugs work
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TB
Drug cocktail developed –MDT (Multiple-drug-therapy)
Rifampin and Isoniazid
Used for 9mths but shown that patients were not completing
the course of drugs
Late 1980s: CDC –Direct Observation of therapy (DOT)
Drug cocktail developed –MDT (Multiple-drug-therapy)
198
Resistance:
• Isoniazid-rifampin –most effective combination 90%
• But resistance occurs at high frequency – 50% mortality
• If so effective (ideal conditions), why resistance so high?
• Slow growing, long treatment times -9-12mths, patients didn’t finish the drug
program 10% (early programs had officials to ensure compliance) –DOTS helping
this.
Is the worst yet to come?
1. MDR-TB –Multiple Drug Resistant TB.
• Resistant to 2 or more of anti-TB drugs (isoniazid and rifampin)
• 1990s W strain emerged in New York, resistant to almost all of the
antibiotics used.
• Highly virulent and infectious
• Could have gone out of control- drastic measures
-isolation
-surgical removal of lung tissue
-use of experimental drugs
74% mortality
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199
2. XDR-TB –Extremely Drug Resistant TB.
• defined as resistant to isonizid and rifampin and at least 3
second line drugs
These strains are a major problem and are predicted to kill millions
3. Extensively Drug Resistant tuberculosis (EDR-TB), !!
New deadly strain discovered
in India
Totally Drug Resistance
200
Immunity and TB:
• Major killer worldwide- vaccine is a high priority
1930s work began
• Avirulent M. bovis strain BCG (Bacillus Calmette–Guérin) used as
vaccine. French scientists transferred for 231 generations over 13
yrs to produce this “Attenuated “ (weaken strain).
• Enters macrophages, breaks down eliciting an immune response
but does not cause disease
• Easily administered -orally and can be given to infants
201
TB
• first used on Germany, 1930 but not a good start
- 249 babies, 79 died!
- not from BCG vaccine but from contamination from live
M. tuberculosis stored in the same incubator!!
- restricted the use for decades because of public
concerns.
173
Not all plain sailing:
• Does not prevent reactivation
• Protective range - 0 to 80% - so extremely variable between
populations!
- Genetic predisposition of human populations
- make all patients skin test positive ?
• BCG elicits different immunogenic properties to
M. tuberculosis.
• **Recent discovery of bacteriophages that convert avirulent
vaccine strains to****potential** **deadly pathogen!**
202
Future vaccines
• Introduce M. tuberculosis genes into BCG vaccine.
- Introduce genes for effective antigens from a number of
bacterial species for a multipurpose vaccine effective against a
number of diseases.
Requires a live vaccine that replicates briefly in the body to establish
immunity.
Use of psoralen and UV treatment, cross-links DNA and prevents
DNA synthesis while allowing protein synthesis and
metabolism. Organisms do not multiply but remain alive and
produce antigens to illicit an immune response 175
176
Tuberculosis vaccine development
To reach the new End TB goals of a 95% reduction in TB deaths and a 90%
reduction in TB cases by 2035, a comprehensive approach is needed that
includes new and more effective vaccines
Bacille Calmette-Guérin (BCG) vaccine was developed in 1921 and remains
the only available vaccine against TB. Unfortunately, BCG is only partially
effective
Sixteen different TB vaccine candidates are currently in clinical trials.
These vaccine candidates include five which are based on whole cell
mycobacteria, and the remainder are various sub-unit based approaches in
which Mtb antigens are expressed as recombinant proteins recombinant
viral vectors.
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The Future: TB
Trials for “booster” vaccines -?
Problem with accessing success –many decades
Infant vaccines, shorter time period but still accessed in years
Discovery of new antigens not expressed in BCG
Latency –post-exposure multiphase vaccine would be important
to reduce incidence –not yet available
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A return to old therapies?!
DOTS: Direct Observational Therapy Short course.
• adopted by WHO in 1992 to combat noncompliance
and complacency.
• health care workers physically watch patients swallow
their daily dose of anti-TB drugs. –back to the old days!
- within first 2- 4 wks patients become
noninfectious.
VERY EFFECTIVE:
Bangladesh, 85% cure rate, Peru, 90% cure rate.
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Mycobacterium and TB: Final thoughts
TB as killed million in the past and is the leading cause of death
from a curable infectious disease (30 million deaths over the next
decade)
In resource-poor countries and those blighted with HIV TB is on the
rise (1 person infected every second!!)
Largely forgotten in the USA
Almost 125 years after the discovery of the cause of TB it is still
“The Peoples Plague” and a scourge of mankind
