Transcript Bacteria - frozencrocus.com

Another major cause of human disease is those little
bugs known as bacteria. Even though millions and
millions of bacteria live on us and in us, we rarely get
disease from them. Often this is simply because the
vast majority of the bacteria are harmless. They survive
quite happily on the “refuse” sticking to our eyes, skin,
and mucus epithelia, and wherever else they might live.
Some strains of bacteria, however, do cause problems
because of the toxins they produce or because of the
“toxic” effects of some of the membrane components
in them.
BACTERIA
Procaryote
- single cell
- no nuclear envelope
no discrete organelles
- inclusions (contain CHO, Protein, Lipids)
- cell wall
multiple layers to protect cell
membrane
flagella (movement)
pili (attatchment & exchange
components
- excrete protein toxins (exotoxins)
- LPS (endotoxin)
Bacteria are prokaryotes, which means they have no nucleus nor any other observable organelles.
All their metabolic enzymes and DNA kind of float about in their cytosol.
The metabolic enzymes and DNA are mostly protected from environmental damage from such
things as toxins and radiation by a cell wall made up of many complex proteins and lipids which
closely surrounds the bacterial cell membrane.
Because bacteria are single-celled animals, they simply excrete their waste into their environment.
In some cases, their excretions aren’t waste, but toxic molecules meant to kill other small things in
order to obtain a source of food.
Of the trillions of bacteria that live on our skin and throughout our respiratory and GI tracts, they
rarely grow to such massive populations that can cause harm because they kill and eat each other thereby keeping “everyone in check”.
Bacteria (DNA, propagation - diversity)
Bacteria divide by binary fission, meaning their DNA is duplicated “exactly” and the
resulting 2 cells after division are “identical”... with a division cycle occurring anywhere
from every 15 minutes to one every several hours
Not only can bacteria duplicate their DNA for cell division to produce 2 daughter cells with
the same DNA, they also can pick up plasmid DNA directly from other bacteria through
their pili - effectively increasing the diversity of their DNA before dividing
Bacteria also have an interesting habit of picking up snips of DNA from their environment
and (like us) from viruses. This is another interesting concept because if any DNA pieces
are picked up that actually code for a useful protein, the bacteria immediately gains that
function... High-speed evolution, if you will!
Bacterial DNA also has no introns; unlike human DNA. All the DNA bases code for
something useful. This means that a mutation somewhere will affect a gene. Unlike human
DNA which has many exons & introns and many regions of DNA that do not code for
functional genes; therefor human DNA can afford to mutate many times because the odds
are that most mutations happen in a non-coding part of the DNA strands.
Bacterial DNA and mutation
Because bacteria have no nucleus, their DNA is in somewhat a more dangerous location
than ours. Imagine some bacteria living on your skin while you are sitting in the sun. The
UV radiation is causing the production of oxygen radicals in those cells that it can
penetrate through. The bacteria wall will certainly absorb some of the radiation but any
that gets through will have direct access to damage the DNA.
Compare this to your own more fragile skin cells... The UV radiation must pass through
several layers of dead cells on the surface of your skin and then through a layer of highly
keratinized connective tissue (epidermis) before penetrating through several layers of the
various cells that make up our dermis. Only after penetrating through these layers of cells
can the UV radiation that makes it through actually penetrate into the committed stem
cells in the lowest layer of our skin. And, even though some of the radiation actually
makes it through to these cells, it still must penetrate through the various intervening
membranes of the cell membrane, rER, sER, mitochondria, and nuclear membrane.
There are a lot of targets for UV damage in human skin cells that get in the way long
before the DNA of a dividing stem cell will actually get damaged compared to the
number of targets between a bacterial cell wall and the DNA inside.
This has serious implications for the production of mutations and the evolution of
bacteria.
Bacteria (DNA, propagation & evolution)
So when you put together high duplication rates and high mutation rates and high DNA transfer
rates, you get the end result that bacteria in general can evolve very quickly...
Population density of a typical colony is usually >> 109
With a mutation rate ~ 10-8 mutations / division
AND:
1 x 108 bacteria to 2 x 108 bacteria in a (very small) colony
this would result in ~1 mutant bacteria produced every time the
colony divides once (doubles)
with normally >> 109 bacteria / colony this would result in
> 10 mutants / 15 minutes & doubling every 15 minutes... Means an
awful lot of mutant bacteria being produced every single day.
producing one mutant with a selective advantage (say drug resistance) is
highly likely
and because bacteria exchange DNA a high adaptation rate of resistance for
all bacteria in colony is highly likely
Common Diseases Caused by Bacteria
Food/Water Poisoning
Vibrio cholera
Staphylococcus aureus
Escherichia coli
Clostridium perfringes
Salmonella typhi
Shigella dysenteriae
Skin Lesions (folliculitis, impetego, boils, pimples, carbuncles)
Staphylococcus aureus
Staphylococcus pyogenes
Proprionibacterium acnes
Strep Throat / Tonsillitis
Streptococcus pyogenes
Pneumonia
Escherichia coli
Staphylococcus aureus
Staphylococcus pyogenes
Streptococcus pyogenes
Staphylococcus pneumonia
We get exposed to bacteria that float in the air every time we breathe and to
bacteria in our drinking water every time we drink and to bacteria on our skin
every time we touch something, and then touch our face. Water-borne bacteria
typically live on the tiny bits of sewage, animal feces, and dead things that are in
the water. In most Western countries, water and sewage treatment programs
minimize the incidences of water poisoning. In countries where water-treatment
is minimal or non-existent, water poisoning is common and a serious issue for
small children. When these same bacteria live on food items that have been left
out in the open, and we then eat them, we can suffer food poisoning. Symptoms
of each are dependent on the specific type of bacteria and the effect of their
toxins; reviewed later.
Lyme Disease
Boreelia burgdorferi
Rocky Mountain Spotted Fever
Rickettsia ricketsia
Anthrax
Bacillus anthracis
Meningitis
Haemophilus influenza
Staphylococcus pneumonia
Neisseria meningitidis
Streptococcus pyogenes
Common STD’s
Syphilis
Treponema pallidum
Gonorrhea
Neisseria gonorrhoeae
Chlamydia
Chlamydia trachomatis
Some bacteria produce toxins which create pores in cell membranes, allowing electrolytes and other
compounds to leak out (or in). This can seriously disrupt cell function. If the pores are large enough then
the membrane will rupture and the cell will die. If you kill off enough cells this way you might go along with
them. Another possibility is for bacteria to secrete digestive enzymes. These will digest membranes of
nearby cells and kill them (sometimes extremely quickly).
Some bacteria don’t secrete toxins but rather, simply stimulate an inflammatory response. Very often the
response is stimulated by the lipopolysaccharide (LPS) in the bacteria’s outer cell membrane. The LPS
directly stimulates macrophages to release cytokines (lots of them) and the inflammatory race then gets
started. With a large overgrowth of high LPS bacteria in the intestine it is possible to get such massive
inflammation within the abdominal cavity that blood volume drops, blood pressure drops, and you then die
from it (think ruptured appendix or septicemia).
One other not-very-cute way for bacteria to kill you is to provoke a massive systemic inflammatory response.
Some bacteria proteins act as super-antigens. You already know that antigens stimulate T-cells and B-cells
to proliferate and to release inflammatory cytokines. Normally just a tiny percentage of T-cells are affected
by any antigen. Super-antigens, however, can stimulate as much as 20% of the entire population of T-cells.
This can be disastrous when all of them release inflammatory cytokines at the same time. In essence, the
massive systemic inflammatory response leads to total cardiovascular collapse (imagine what would happen
when the blood-flow changes that typically happen locally, suddenly occur all over your entire body at the
same time - think TSS).
The following slides outline in point form a series of infectious bacteria and the mechanisms of their effects.
Escherichia coli
- lives on skin, intestines
- food poisoning, diarrhea, pneumonia
LabileToxin (LT) – activated by host protease
- Stimulates adenylate cyclase
- Ribosylation of G-proteins
- continual cAMP, cGMP production
- Cl-, Na+, water loss
StableToxin (ST)
- Stimulates guanylate cyclase
- cGMP production
- Cl- loss
No antibiotic treatment recommended due to exacerbation of symptoms.
Escherichia coli 0157:H7
- intestines
- food poisoning, diarrhea, hemorrhagic colitis
Verotoxin / shiga-like toxin
- adhere to intestinal cells
- penetrate cells and inhibit protein
synthesis = no repair of damage
No antibiotic treatment recommended due to exacerbation of symptoms.
Staphylococcus aureus
- skin, nasal mucosa, mouth, throat, vagina
- food poisoning, impetigo, boils, endocarditis,
pneumonia, septic shock, toxic shock
syndrome
A toxin
- membrane damage
- fibrin clot
- release of inflammatory cytokines
Enterotoxins SE-A through SE-G, TSST-1 (Super Antigens)
- stimulate t cells directly (~20% activation
vs usual 0.01%)
- severe diarrhea, vomiting (SE-series)
- cardiovascular collapse
- kidney (and other organs) failure
Penicillin resistant – vancomycin & nefcillin effective
Streptococcus pyogenes
- mouth, throat, urethra, vagina
- strep throat, tonsilitis, meningitis, pneumonia, toxic shock
like syndrome, necrotizing fasciitis
Erythrogenic / pyogenic toxin (Super Antigens – TS like)
- stimulate t cells directly (~20% activation
vs usual 0.01%)
- severe diarrhea, vomiting
- cardiovascular collapse
- kidney (and other organs) failure
Cysteine Protease (necrotizing fasciitis)
- degrades proteins with cysteine
Invasins
lyse RBC’s, phagocytes, & others
Penicillin effective
Chlamydia trachomatis
- mucosal epithelia of urogenital tract but can invade & incubate inside the cells and break
out
- Chlamidia
- inflammation / discharge (mucus / pus)
- Azithromycin, amoxicillin, doxycycline effective
Neisseria gonorrhoeae
- mucosal epithelia of urogenital tract
- gonorrhea
- toxin produces mitochondrial damage - induces apoptosis
- Penicillin partially effective; Ceftriaxone, Spectinomycin effective
Treponema pallidum
- any tissue - route of transmission is sexual – 30% progress
to syphilis (remainder latent) - No adaptive immunity
- toxin inhibits DNA synthesis / protein synthesis
- lipoprotein stimulates macrophages / inflammation
- chancre - rash (flu w/ possible meningitis) - gumma (30%)
- Penicillin effective
This last series of slides illustrates how a bacteria that releases no
toxins can produce disease through an inflammatory response
Mycobacterium tuberculosis
Initial exposure to Mycobacterium
tuberculosis leads to phagocytosis by
alveolar and interstitial macrophages
with release of inflammatory molecules
by the stimulated macrophages
M. tuberculosis do not secrete toxins, they do not have an LPS component to stimulate macrophages to a
“high degree”, and they are very hard to digest; therefore they can live inside macrophages and stimulate a
“weak” adaptive immune response
ROS attack leads to calcium
entry and activation of PLA2
and production of PG’s, TX’s,
& LT’s.
Activated macrophages
migrate to lymph to interact
with t-cells to produce cellmediated immune response.
In response to cytokines
cellular adhesion molecules
are synthesized to attract and
activate circulating neutrophils
and monocytes.
A full-blown inflammatory attack on
M. tuberculosis is initiated with the
recruitment of large numbers of
neutrophils and macrophages.
Collagen production by fibroblasts
and fibrinogen production by
epithelial cells is greatly stimulated
and COX-2 enzymes are induced.
Cellular damage by ROS leads to
cellular necrosis, DNA damage, and
activation of AP-1 while T cell
activation of macrophages leads to
their death by apoptosis (killing the
bacteria as well).
A fibrotic granuloma is formed from
the necrotic cells, apoptotic cells, and
infected macrophages. The
granuloma effectively walls off the
infected macrophages (and
dead/dying cells) from the healthy
tissue and prevents further
inflammatory responses. When the
infected macrophages die, further
inflammatory responses will be
initiated by the released bacteria.
Pulmonary function is progressively
compromised with each subsequent
infection and fibrotic response. Stem
cells in the area proliferate in response
to the cellular necrosis to replace the
destroyed pulmonary cells.
Isoniazid, rifampin, pyrazinamide, ethambutol are partially effective.
Prevention tactics
- Stay clean; wash hands and face frequently
- Wash any cut or abrasion thoroughly with
soap/water & antiseptic and keep covered/clean
- Avoid close contact with infected persons
- If infected: use appropriate antibiotics (as indicated)
& treat symptoms
- Avoid all use of antibiotics unless absolutely
necessary