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Summary - Molecular Infection Biology (AM_470657) (Vrije Universiteit Amsterdam)
Summary - Molecular Infection Biology (AM_470657) (Vrije Universiteit Amsterdam)
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Infection biologyLes 1: Microflora and disease
What is a pathogen?
A pathogen is a microbiological agent that causes disease or illness to its host.
Exogenous micro-organisms that are pathogenic to the host
Example:
Influenza A as a viral pathogen
Vibrio cholerae as a bacterial pathogen
Plasmodium vivax (malaria) as a protozoa pathogen
Aspergillus niger as a yeast/fungi pathogen
Hookworm as a worm pathogen
What and where are microflora?
Microflora are endogenous and in normal condition they are not pathogenic. In most cases
microflora have a beneficial function for the host.
Microflora are there in for example the colon, skin, mouth, esophagus, stomach and vagina.
The gut itself has over 500 different species, mainly Firmicutes and Bacteriodites.
Microflora in the gut (bacteroides thetaiotaomicron) are needed for the degradation and
fermentation of indigestible plant material. They degrade with the help of enzymes on their
surface, large carbohydrate structures into smaller sugars that can be taken up by the intestine.
Gut microflora induce immune response, including production of antimicrobial peptides
Research:
What kind of affect has the microbiome on a organism?
Gnotobiotic animals (germ free), they experience:
Need 30% more calories
Less vascularization and poor development of the intestinal villi
Underdeveloped mucosal immune response
How can microflora cause disease?
Microflora have two ways of causing disease:
1. Normal microflora are at the wrong place
2. There are abnormalities in the host defence
Normal microflora at the wrong place
By damage to the epithelium: B. fragilis
Damage of the colon epithelium can arise spontaneously or after surgery and it results in the
infiltration of gut microflora in peritoneum.
Coinfection of E.coli and B. fragilis (synergistic) causes abscess formation and has a high
morbidity and mortality.
By new sites for normal microflora: E. coli
E. coli can cause urinary tract infections and can then further infect the bladder (cystitis) and
kidney (pyelonephritis).
Mainly in women because they have a smaller urinary tract and the urethra and anus are closer
together.
By foreign bodies such as surgical implants: Staphylococcus epidermidis
, By the normal microflora in the wrong host: E. coli O157
Different mammals have similar composition (Firmicutes and Bacteroidetes) of gut flora.
However, with strain-specific bacteria.
Outbreak from a deer E. coli O157 normal microflora caused infections in 70 persons.
Over 50 children in the US were infected with salmonella (normal microbiota on the frog’s skin)
after the movie release ‘The princes and the frog’.
In the saliva of dogs there is Capnocytophaga canimorsus which causes sepsis in humans who
are bitten by dogs.
Abnormalities in host defense
Genetic defect: SCID
BCG vaccination (live-attenuated) against tuberculosis can with a genetic defect cause chronic
infection
Interferon (IFN)-γ circuit necessary for an effective immune response to intra-macrophagic
pathogens by inducing apoptosis. When there is a genetic mutation in this circuit the host is
more susceptible to intra-macrophagic pathogens such as BCG.
Herpes simplex encephalitis (HSE) is a rare complication of HSV-1 infection where the virus
infects multiple neurons. Inborn errors of TLR3-mediated and IFN-mediated immunity
underlying herpes simplex virus 1 encephalitis. TLR3 activation results in the transcription of
IFN against viruses.
Suppression of immune response: transplantation, malnutrition (measles, malaria)
Other infection (HIV, influenza)
Antibiotics
Antibiotics kills the healthy gut flora which are sensitive against this specific kind. Therefore,
pathogenic bacteria have more room to grow. This results in a massive outgrowth of endemic
species of colonization by antibiotic-resistant new species.
Why are (some) bacteria of the normal microflora good pathogens?
They are always present so the opportunity rate is high.
The factors that they use for colonization such as pili for adhesion and capsule to evade the killing
immune response are also used for virulence.
They are adapted to the metabolism of the host which normally makes the environment less
suitable for pathogens. It is also adapted to the immune response that we have.
They use some virulent factors to withstand other organisms, such as grazing protozoa. For
example, the amoebae act like macrophages in the gut.
Why are vertebrates the ideal breeding ground for bacteria?
They have an ambient temperature
They have a high number of nutrients including vitamins etc.
They have a good transport of metabolites and waste
Micro-organisms (microbes) are always looking for new environments to live (niches)
What are exogenous infections and what are the pathogens that cause this?
Exogeneous infections are infections where pathogens enter the body through the environment.
Colonization of mucosal surfaces
Cross anatomical barriers
Tissue invasion
Breach host defenses
Dissemination (spread)
, The pathogens that cause this are pathogens that used to infect other organisms that are now
adapting to the human as their host. Such as influenza, black death, ebola and cholera.
What is tuberculosis and its infection cycle?
Infection of tuberculosis goes through inhalation of an
infectious bacteria.
There is no clear factor (toxin) involved in the disease
symptoms.
Infection cycle:
Bacteria are phagocytosed by alveolar macrophages.
They can not kill the bacteria so they cause a localized
proinflammatory response that attracts other immune cells
and leads to a granuloma forming.
Granulomas: containment phase where there is no sign of
disease but also no eradication. Macrophages are inside the
granulomas and other immune cells on the outside and can
not reach the infected macrophages.
The macrophages caseate (verkazen) and rupture, whereby
the bacteria come free and the person is infectious.
Granuloma formation is good for the host because of the
confinement of the bacteria.
Granuloma formation is good for the bacteria because the T
cells are unable to reach the center of the granuloma and
caseation of granuloma and not systemic spread is essential
for transmission to a new host.
Research:
Problems due to slow growing, no optimal infection model (apart from monkeys), it is a chronic
infection and normally only 5% develop the disease.
Therefore experiments are done with a close relative of M. tuberculosis, M. marinum. It grows
rapid and optimally at 28-32 degrees so they do not grow in humans. The zebrafish is a perfect
infection model for this strain.
Secreted proteins are mostly virulent factors, so researchers thought by blocking the ESX-5 protein
secretion system they could reduce virulence of the pathogen. Indeed the cytotoxicity of
macrophages is less without ESX-5, but the overall survival of the zebrafish goes down drastically.
The blockage of ESX-5 results in the formation of more granuloma in the spleen and liver.
So it is actually possible to isolate variants with increased virulence.
What is Epstein-Barr virus and its life cycle?
The Epstein-Barr virus is a DNA virus and causes a chronic infection inside immortalized B cells. It
is the causative agent of Pfeiffer.
EBV can switch within cell types during the infection process (hos cell tropism) between epithelial
cells and B cells.
Related to enhanced IFNγ production, through epigenetic changes, which puts macrophages and
progenitor cells in a higher state of activation.
The virus just as herpesvirus, protect against bacterial infection.
, Les 2: How to pick a strain?
What is cystic fibrosis?
CF is a genetic disorder caused by point mutations. The mucus in the lung becomes thicker and
this mucus is an ideal breeding environment for pathogens.
Would you go for the sequenced strain?
YES
By taking the sequenced strain you already know the genetics and proteomics of the strain.
It is also easier to exchange data/materials with other labs.
You can order specific isogenic mutants that have a single mutation in its gene. The different
phenotype seen must be caused by this one mutation.
NO
Pathogens can change (attenuate) upon vitro growth. Are you in culture still looking at the
pathogen? Pseudomonas alginate normally secretes a mucus but on the plate it does not need
this so to save energy it will not produce this anymore. You should not passage the strain to much
otherwise you could have an attenuated version of the pathogen that does not produce certain
virulent factors anymore. Subculturing selects against energetically costly structures: capsule,
flagella, protein secretion. It selects against bacterial clumping and biofilm formation.
Genome plasticity. Is it the pathogen you want to study, because you have different strains of the
same bacteria species. The pathogen mutates over time. Each strain is different and has its own
specifications and perhaps different virulence factors.
YES and NO
You can use the standard strain but be aware of differences and check also other clones in your
assays.
Determine the genome sequence of your optimal virulent strain.
What is a bacterial species and what does horizontal gene transfer contribute to this?
Each daughter cell is (in principle) identical to the mother cell.
Chromosomal mutations are continued in the sublineage, but can not be mixed with other
lineages of the same species.
A species have 70% DNA identity and 98% 16S rDNA identity, except for important metabolic and
pathogenic differences. M. tuberculosis and M. bovis are different species, because M. bovis does
not spread from person to person.
If we would apply this rule to humans we would be the same species as lemurs and monkeys.
Horizontal gene transfer diversifies clonal descent.
It causes an exchange of parts of genomes, but never a mixing of genomes.
This is the major cause of genome plasticity.
Transduction: bacteriophages (viruses that infect bacteria) mediate transfer of DNA between
bacteria via transduction whereby DNA from a donor bacterium is packaged into a virus particle
and transferred into a recipient bacterium during infection. For transfer of phage DNA and is
extremely efficient, but not very efficient in the transfer of chromosomal DNA. Bacteriophages will
use the bacteria to produce more phages and then lysate the cell. Filamentous phages are carriers
of virulence plasmids and do not lysate the host cell. These phages help the bacteria to get more
virulent.
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