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Summary of all the lectures of MG infectious diseases and oncology
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MG: Infectious diseases and oncologyLecture 1 Introduction
04/01/2020 Prof. Quax
Infectious diseases deal with pathogens that penetrate our body e.g. bacteria, parasites
which all try to infect our body. In tumours, cells divide uncontrolled resulting in lesions. This
is very different, but if you look more carefully there is an interaction. Medicines focus on
targets that are unique to infectious or cancer cells. So if you want to treat an infectious
particle or a cancer cell you should have a drug that will target that particle and that will not
affect healthy human cells.
- Example 1: the Rous sarcoma virus. This is a virus that is causing sarcomas
(tumours). The Rous sarcoma virus produces Src kinase which is a regulatory protein
that stimulates cell growth when activated. So the infection will stimulate cell division
resulting in a sarcoma.
- Example 2: human papillomavirus. This infects the skin and mucous membranes and
thereby disturb the cell division. Most HPV cell divisions are benign but in some cases
it can develop into cancers. This depends on the type of HPV. Many species are
known and especially 16 and 18 are known to cause cervical cancers. They take
away the break on cell division.
- Example 3: helicobacter pylori. Infects the stomach and gut and is also involved in
stomach cancer. The bacteria has long tentacles and is able to survive the stomach.
The enzyme urease, will convert urea to ammonia and thereby create a small
environment around itself which is neutralised. Ulcers are often caused by this
bacteria which can later develop into cancer. Such infection can also induce the
formation of a MALT lymphoma. This bacterium can be treated with antibiotics.
COVID-19: the virus binds to the ACE2 receptor that will internalise the virus via endocytosis.
Then the RNA is released and translated in the ribosome resulting in polymerase production
that will replicate the RNA resulting in mRNA. These mRNA are encoding the spike protein
and several other proteins. They are then assembled on the ER and then viral particles are
reassembled and excreted resulting in replication of the virus. During endocytosis, the virus
has to fuse with the membrane which could be inhibited. And there is looked at inhibition of
glycosylation. And you can interfere with the mRNA molecule of the spike protein which is
the current vaccine. The spike protein will enter the cell resulting in antibodies being
produced against it resulting in resistance to COVID-19.
Miasma (contamination, staining) is caused by bad air. So plagues and infections are spread
as a consequence of rotting organic material resulting in e.g. polluted water, poisoned air and
bad hygiene. For example malaria is a disease caused by bad air.
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,Antonie van Leeuwenhoek discovered the first microscope. Then Louis Pasteur and Robert
Koch found out that microbes/germs cause human diseases. Robert Koch postulates:
whenever there is an infectious disease, you should be able to purify the pathogen from a
diseased animal. Then if you have a purified pathogen and bring it into a healthy animal, the
animal should be diseased again. And you should be able to isolate that suspected pathogen
from the diseased animal again. In a healthy animal, you expect to not observe any of those
pathogens. However, viruses are much smaller than bacteria and therefore discovered later
than bacteria. The viruses also do not comply with the theory of Robert Koch. This is
because a virus needs a host that will replicate that virus. You also have non-culturable
infections and prions which also are not visible using the theory of Robert Koch.
The human body has a number of anatomic barriers to keep out infections.
- Skin → dry and full of proteins that are not nice for infectious particles to grow on.
There are viruses, bacteria, fungi and mites. These can be commensal and help to
keep out pathogens. There is quite some variation from person to person in the
microbiome of the skin flora. These differences are very big and can therefore be
used for forensic research. People can be discriminated using this microbiome. This
differentiation has to do with lifestyle, food, etc.
- Saliva → enzymes e.g. lysozymes, peroxidase, etc. can kill bacteria. There are over
600 species in the mouth. There are quite a lot of streptococci. Also pathogenic
bacteria are present in the mouth of many people without making them ill e.g.
Yersinia and porphyromonas. There are bacteria that only become pathogenic when
the person is in bad conditions. These are opportunistic bacteria.
- Eyes → lysozymes. Lysozymes are enzymes that will cut the sugars of the cell wall of
bacteria resulting in collapsing.
- Lungs → cilia will move the infectious particles upwards.
- Stomach → acidic so infectious particles will not survive.
- Gut → commensals (bacteria living in our gut) will protect and keep out pathogenic
organisms. Especially in the gut there are different numbers of bacteria in the
different parts of the GI tract: stomach (10-100), duodenum (1000), jejunum (104),
ileum (104-107) and colon (1010-1012). These commensals can be protective: displace
pathogens, compete for nutrients that are required for the pathogen to survive,
compete for receptors to which the pathogens bind, and produce antimicrobial factors
like bacteriocins and lactic acids. They also have structural functions: production of
IgA which defend pathogens, etc. They also have metabolic functions: production of
short-chain fatty acids, vitamin K, biotin, folate, ions.
- Urine tract → commensals and flushing.
Microbiome: natural protection that we have of bacteria that live inside us. E.g. in the nose,
mouth, throat, skin, vagina, urethra, large intestine. These are not pathogenic. We have
about 4*1013 bacteria in our body. This is more than we have cells (3*1013). In total these
bacteria have a weight of 200 grams. This natural protection can be stratified:
- Mutualism → the bacteria and human benefit from this. E.g. degradation of food by
bacteria when the human is not able to degrade it by itself.
- Commensalism → there is no interaction but we are also not bothered by each
other. There is no specific benefit.
- Parasitism → no benefit which is not wanted. Whenever we fight pathogenic
organism, we must take care to not attack the bacteria that we need.
Viruses can also infect bacteria. These viruses are called phages. These viruses are very
stable and very distinct. The viruses also shape the microbiome. The bacteria in the
microbiome also produce vitamins.
2
,Antimicrobial peptides: peptides are being produced either by the human body or by
bacteria. These peptides act antimicrobial against pathogenic particles. These peptides have
a big hydrophobic and a big hydrophilic part, so they are amphipathic. So they tend to move
in between a membrane. These peptides are present in tears, liver and intestine. They are
broad-spectrum, so they can kill a variety of bacteria (G+ and G-). They also play a role as
immunomodulators and there is little resistance occurring in pathogens against these
antimicrobial peptides. A number of these peptides have been reengineered to function as
antibiotics.
- Mechanism of action: the bacterial cytoplasmic membrane has quite some charge
residues on the outside. So there is charge and it is hydrophobic. So these peptides
move to this bacterial membrane and interact strongly. Eukaryotic membranes are
uncharged, so the peptides will not interfere with this membrane since this is a weak
interaction. When the peptides bind to the bacterial membrane, they will cluster and
flip to the inside. By doing so, they make a gate and disrupt the membrane. Or the
peptides can bring themselves inside where they will target intracellular targets in the
pathogen which leads to death. So this is an innate defence system.
The microflora are the first line of defence, then the innate defence (e.g. peptides,
macrophages), then the ideotype defence (general mechanisms e.g. IgA) and the adaptive
defence system (this takes days/weeks since specific antibodies must be developed to kill
the pathogens). The adaptive defence is the one that is targeted whenever you vaccinate.
The majority of the infections are already stopped at the level of the microflora. In addition,
there is neuro-endocrine control which is connected to the defence system. Memory cells will
help to activate defence systems once there is an infection.
Prevention is better than curing → take care of nutrition, personal hygiene and try to prevent
the development of resistance. Vaccination is preferred over getting the disease. In hospitals
you have hygiene protocols and use disinfectants.
Sterilants (H50): the most used disinfectant is 75% alcohol which will kill vegetative bacteria
by denaturation of proteins. This is a very effective method. If you have spore forming
bacteria, they will survive and you have to use other compounds e.g. phenols. Phenols will
denature proteins, disrupt membranes and inactivate enzymes. However, phenols are very
toxic for the human being. You can only clean surfaces with this. Chlorhexidine is another
one, which will kill G+ bacteria and their spores. Ammonia is also very effective for
denaturation of enzymes. And aldehydes can alkylate proteins and nucleic acids. However,
none of these should be used at the skin as they are aggressive compounds.
3
, Hospital hygiene: household bleach (5% NaOCl). This normally is sufficient to kill all
pathogenic organisms that you might expect in the hospital. Sometimes higher
concentrations of hypochlorite are needed. The newest hospital hygiene method is using
Ozon. Ozon together with water and peroxide will lyse the cells. Ozon may only be used
when nobody is in the room. Also UV is used a lot and also very effective against viruses.
Rooms where COVID patients have been treated, are illuminated with UV to disinfect the
room within a few hours.
Zoonosis: quite some diseases come to humans via animals. This can be via air, saliva or a
bite. Or indirect via a vector e.g. Ebola (primates), COVID-19, Q-fever (goat), anthrax,
typhus, pest, MRSA, toxoplasmosis (cats), helminths, mycoses and mites. Large scale
culturing of animals can be quite dangerous and can be the start of a pandemic e.g. large
scale pig or goat.
- Q-fever is a bacterium that escapes from the immune system. It penetrates human
cells and induces cell division. The bacteria is not seen by immune cells.
Our microbiome can get out of balance. This gives an opportunity for some pathogens to
enter. The pathogens might then overgrow. These pathogens are named opportunistic
pathogens, so they are only pathogenic in case of a weakened immune system. For
example people that are treated for cancer or HIV can easily develop secondary infections.
Also diabetic people and certain lymphomas can increase the risk of an infection by an
opportunistic pathogen. This can also occur locally e.g. a skin wound can give an
opportunistic pathogen a chance to infect the body.
- Pseudomonas aeruginosa → present everywhere and most people do not have any
symptoms. However, it is resistant against antibiotics so when it does induce an
infection, there is hardly anything to use against it. In the hospital this infection is very
abundant (11% of all hospital infections). This bacterium is the main cause of
nosocomial (hospital originated) pneumonia. It is the second cause of burn wound
infections, the third cause of UTIs and the third cause of G- sepsis (bloedvergiftiging).
Opportunistic pathogens use biofilms to grow. So they form a film that plays a role in 80% of
the infections. Pseudomonas aeruginosa is very good in forming biofilms. So the bacterium
grows and matures on a surface and are very harsh and difficult to penetrate. Antibiotics
usually cannot penetrate into biofilms as they are 3D. One of the control mechanisms that we
are looking at is the mechanisms by which these biofilms are being controlled at a genetic
level. Quorum sensing is used by these bacteria, meaning that they are feeling other
bacteria around them. At low density, the bacteria do not make any virulence factors as they
do not feel like they are with sufficient bacteria together. However, when they go to a surface,
they will start dividing leading to secretion of quorum sensing molecules. So as the density of
bacteria increases, the concentration of these molecules increases which will induce a signal
to produce virulence factors.
Biofilms can easily develop on contact lenses,
catheters, cardiac valves, implants, tissue fillers. Also
patients that are suffering from cystic fibrosis can have
a lung infection caused by biofilms.
Antimicrobial agents can target: cell wall synthesis, DNA gyrase (make use of the difference
in DNA replication in prokaryotes and eukaryotes), RNA elongation, DNA-directed RNA
polymerase, protein synthesis (50s and 30s inhibitors), protein synthesis (rRNA), cytoplasmic
membrane structure (bacteria have a negatively charged membrane) and folic acid
metabolism.
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