College aantekeningen
College notes on Molecular Infection Biology
- Instelling
- Vrije Universiteit Amsterdam (VU)
These notes are taken on the molecular infection biology lectures from Wilbert Bitter in year 20/21.
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MOLECULAR INFECTION BIOLOGYOne question about the literature discussions. The articles are supportive, but details of the articles will not be
asked in the exam.
WHAT IS A PATHOGEN?
Viruses, bacteria, protozoa, yeast/fungi and worms. We will focus mostly on viruses and bacteria.
Normal microflora are endogenous and pathogens are exogenous.
Gnotobiotic animals are germ free.
They need 30% more calories because microflora
degrade and ferment indigestible
plant material. They have less
vascularisation and poor developed
villi, and an underdeveloped
mucosal immune response.
Gut microflora induces immune
responses, including production of
antimicrobial peptides. Gut
anaerobes also release small
simplified carbohydrates (butyric
acid) which is taken up the
bloodstream and used by the host.
Endogenous infection
Diseases by normal microflora are caused by normal microflora at the wrong place or abnormalities in host
defence.
Normal microflora at the wrong place
can be damage to the epithelium, new sites for normal microflora, foreign bodies or wrong host.
-Damage to the colon epithelium (spontaneous or after surgery) results in the infiltration of gut
microflora in the peritoneum. Some pathogens are synergistic and can cause abscess formation by
coinfection of for example E.coli and B.fragilis.
-New sites for normal microflora like urinary tract infections (cystitis) can result in bladder and kidney
infections. Urinary tract infections are mostly caused by E.coli. Cystitis is mainly in woman because of
the close proximity of the urethra and anus.
-Foreign bodies like surgical implants.
-Wrong host, different mammals have similar composition of gut flora, however, with strain-specific
bacteria. Infection with these strain specific bacterial in another host can have serious effects.
E.coli O157:H7 nomenclature is the antigens they are recognised by. O antigen (LPS) and H antigen (flagella).
Abnormalities in host defence
Can be a genetic defect, suppression of the immune response, other infections or antibiotics.
, Genetic defects like herpesviruses, which keeps coming back because it is persistent. 50%-100% of the
population is infected with one or more herpesviruses. It infects the endothelial cells and resides in
the nerve cells, and on reactivation moves back to the endothelial cells, so it is not in CNS. But herpes
simplex encephalitis (HSE) is a rare complication of HSV-1 infection in the brain. The cause has to do
with TLR signalling and INFY. HSE susceptibility is genetic because it is caused by TLR3 pathway defect.
TLR3 binds dsDNA and starts production of Type 1 interferon, which are effective against viral
infection.
A similar case could be true for SARS-CoV2 severity and defects in X-chromosomal TLR7 pathways.
Antibiotics kill sensitive species and can lead to massive outgrowth of endemic species or colonisation
by antibiotic-resistant new species.
The opportunity of microflora is that they are always present. They have factors for colonization which can also
be used for virulence, are adapted to the metabolism in the host and some virulence factors are needed to
withstand other organisms, such as grazing protozoa.
(Pathogenic) bacteria are not only interacting with humans but also with unicellular eukaryotes present in your
microflora.
Vertebrates are ideal breeding ground for bacteria (temperature, high number of nutrients, transport of
metabolites and waste). For example, Vibrio cholerae species colonizing the gut utilize sialic acid released from
cell glucans.
Exogenous infection
All (fairly) recent pathogens are still in progress to fully adapt to their new host (Influenza A). There are also
pathogens adapted to humans already (Malaria, mycobacterium tuberculosis, Herpes, Helicobacter pylori).
Infecting by exogenous pathogens doesn’t always induce disease. Like with TB 90% of infected people do not
get sick.
Tuberculosis infection cycle
bacteria phagocytosed by alveolar macrophages > localized proinflammatory response that leads to a
granuloma > granulomas ‘containment’ phase: no overt signs of disease but also no eradication > caseation of
the centre of the granuloma > viable, infectious bacilli into the airways.
Granuloma of TB is good for the host because it confines the bacteria to one place. But it is also good for the
bacteria because the T-cells can’t reach the centre of the granuloma. Caseation of granulomas is essential for
transmission to a new host.
M. marinum is closely related to M. tuberculosis and is used in experiments on tuberculosis in zebrafish.
ESX-5 protein secretion system is important in virulence and attenuated in macrophage cell death. Some ESX-5
substrates are anti-virulence proteins.
Epstein-Barr virus is a DNA virus and you are infected for life (reside in immortalized B-cells) and the causative
agent of Pfeiffer. The infection process of EBV is switching cell types.
Is EBV an harmonious pathogen?
Herpesvirus (mouse version of EBV) latency confers
symbiotic protection from bacterial infection.
The protection mechanism can be heterologous
immunity or trained immunity (most likely).
Trained immunity is a mechanism independent of
, cross-reactivity. Trained immunity, which is related to enhanced IFNy production, through epigenetic changes,
which puts macrophages and progenitor cells in a higher state of activation.
Life TB vaccine (BCG) protects against other pathogens (such as malaria, candida and even is now tested against
SARS-CoV2). Is the same also true for latent TB infection?
CLONAL NATURE OF MICROBIAL PATOHGENS AND SPECIES/STRAINS CONCEPT
What strain do you use for your study?
In Cystic Fibrosis (CF) mucus clogs the lungs and leads to chronic respiratory infections. It can be caused by
infection with Pseudomonas aeruginosa.
Are you going for a sequenced strain or a clinical isolate?
The sequenced strain is known so the genetics and proteomics is easier, and we can exchange data/materials
with other labs. You have to be careful for attenuation by in vitro growth, most ‘workhorses’ have been around
for a long time and have been frequently subcultured. This could induce mutations. (This is an argument to use
the clinical isolate).
Subculturing selects against different virulence factors (like energetically costly structures as capsule, flagella,
or bacterial clumping and biofilm formation).
Attenuated strains can be used for vaccines (because they can be less virulent after attenuation). Attenuation
can be caused by continuous culturing.
Genome plasticity
Bacterial line of descent is clonal, so all chromosomal mutations are continued in the sub lineage. But it is
diversified by horizontal gene transfer (never mixing but exchanging).
Bacterial species have to have 98% 16S rDNA identity.
Caused of horizontal gene transfer are transformation (extremely efficient but not all bacteria do it),
transduction(transfer of phage DNA is extremely efficient, transfer of chromosomal DNA is not very efficient)
and conjugation (plasmid dependent, transfer of chromosomal DNA possible, extremely efficient).
Recombination is required after transformation/transduction.
The amount and impact of gene transfer is dependent on pathogen species (?).
M.tuberculosis there is no horizontal gene transfer.
Omnipresent HZG (a lot). H. pylori and N. meningitiids show natural transformation. Take up DNA with pilus
ssDNA recombined with the genome.
How to determine horizontal gene tranfer:
GC (nucleotides) content
codon usage
gene order / syntheny :
Horizontal gene transfer is more frequent between closely related strains / species because of high homology
(?).
HGT is important for virulence.
Plasmids can contain virulence…
Virulence of mycobacterium ulcerans dependent on production of mycolactone, both cytotoxic and
immunosuppressive. Enzymes for mycolactone production are on plasmid.
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