Summary MG: Infectious diseases and oncology
Lecture 1: Introduction
The connection between infections and oncology is that some viruses like the Rous Sarcoma virus (an
oncovirus) or the HPV virus (may cause cervical cancer) can cause problems. There are also bacteria that
might induce cancer, like Helicobacter pylori.
History
In the past it was unknown what caused infections. It was thought
that it could be bad air (during black plague and cholera outbreak).
John Snow traced the source of infection during the cholera
outbreak: all people that drank from the same water pump were
infected. In France the Hausmann renovation was meant to clean
the ‘bad air’ by planting more trees and removing houses. The first
man that really knew how infections occurred was Robert Koch,
who invented Kochs postulates: from a sick patient, samples are
taken, and a suspected pathogen is cultured (that is not present in
healthy individuals). To know whether this is the microorganism
that causes the disease, the isolated organism must cause the
disease in a healthy individual. Also, the pathogen must be plated
again, and the colonies must look the same as the first colonies. Infections can be caused by viruses,
bacteria, and bacteriophages.
Cohabitation and presence of bacteria in the human body
Cohabitation models of organisms are mutualism, in which both organisms profit, commensalism, in which
one benefits and the other has no benefit or harm, and parasitism, in which one organism benefits and the
other is harmed. Bacteria are not evil or bad, because they can help us break down food, decompose,
make food, and fix nitrogen. Natural flora are present in our nose, mouth, throat, skin, vagina, urethra, and
large intestine. We have more bacteria than cells in our body, and the number of bacteria increases when
moving down the GI tract. Most of them are commensal bacteria but they prevent pathogens from
entering and can sometimes stimulate the immune system. There are some bacteria using mutualism: they
get minerals and give vitamins and metabolism in return. Bacteria in the mouth and on the skin vary for
everyone, it can be so unique that it can be traced back to one individual.
Infections
Immune system
The human immune system has different barriers, like the skin, pH
in gut and genital area, flushing of urinary tract, mucus, and
lysozymes. Antimicrobial peptides are present in tears, liver, and
intestine, and because they are amphiphilic, they are very broad
spectrum. Because there are no charged phospholipids in
eukaryotic cell membranes, they do not react to our body’s cells.
Since bacteria have negatively charged phospholipids,
electrostatic interactions take place, causing pore formation,
leading to more entering of antimicrobial peptides or complete
destroyal of the microorganism.
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,Preventing diseases
Good measures to prevent diseases are nutrition (feeding of ‘good’ bacteria), personal hygiene, and
resistance. On top of that, there is vaccination, hygiene protocols in the hospitals (ozone dispersion) and
general antimicrobial compounds (disinfectants and antiseptics). Examples of disinfectants (sterilants) are
alcohol (denature proteins) fenols (denature proteins, disrupt membrane, inactivate enzymes),
chlorhexidine (pore formation), ammonia (denaturation) or aldehydes (alkylation of proteins and nucleic
acids). Disadvantages are that they also act on human proteins and cells.
Enemies
Zoonosis are diseases from animals, either directly via air, saliva, or bites,
or indirect via vectors (viral, bacterial, protozoa, helminths, mycoses,
arthropoda). An example is Q fever (bacterial infection) that enters
macrophages and survives there, which originated in Brabant and is
transmitted via animals. Breathing in air but also eating dairy products
leads to infection. Famous viruses are of course Ebola and the Coronavirus.
Local infection leads to drug intake, but this can lead to distribution of the
drug and it ending up in the intestine, killing beneficial bacteria and
promoting pathogen growth; out of balance.
Opportunistic infections
Infections that only are pathogenic in case of a weakened immune system are called opportunistic
infections. This occurs in people with neutropenia (HIV, chemotherapy), diabetes, and lymphomas. It can
also infect locally, by for example skin damage or a defect in the mucus layer. A very famous opportunistic
pathogenic bacterium is the Pseudomonas aeruginosa which lives everywhere and is resistant to a lot of
antibiotics. It causes pneumonia, burn wound infections, urinary tract infections and gram-negative sepsis
(bloedvergiftiging). It is famous for being green.
Bacterial biofilms
Biofilms are created by bacteria that attach to a surface, form a micro colony, and eventually grow out to a
biofilm. They cause chronic infections, and a lot of treated infections are related to bacteria in biofilms.
They have high tolerance against antibiotics. Biofilms are in catheters, mesh, artificial joints and on more
surfaces. During longer hospital stay, the immune system is already challenged, and because of
contaminated catheters infections may occur. Quorum sensing is a way for bacteria to measure their
population density. Bacteria excrete signals, and when there are other bacteria, there will be a reaction.
With a lot of bacteria, a physiological reaction occurs, like biofilm formation or expression of virulence
vectors.
Antibiotics
Targets
Antibiotics are toxic, but they only target bacteria by using the
differences between human cells and bacteria. These are the cell wall,
protein synthesis, DNA gyrase, RNA elongation, or the membrane. When
the target is protein synthesis, ribosomes are targeted since these differ
in eukaryotes and bacteria. Tetracycline for example blocks the binding of
tRNA to the A site of the bacterial ribosome (lecture 5). Other antibiotics
act on both eukaryotic cells and bacteria, or even only on eukaryotic cells,
dependent on the goal.
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,Gram negative and gram positive
Gram negative bacteria contain two membranes (inner and outer), with
a thin layer of peptidoglycan between them. They show pink staining.
Gram positive bacteria only have one membrane with a thick layer of
peptidoglycan around them. During gram staining, they show purple
color.
Bactericidal and bacteriostatic
Bactericidal drugs (like beta lactams, aminoglycosides) kill bacteria, whereas bacteriostatic drugs (like
tetracyclines, erythromycin) ‘freeze’ the bacteria, clearance must be done by the human immune system.
Removal of the bacteriostatic allow the bacteria to grow again. The choice of antibiotic depends on the
status of the patients, like allergies, age, kidney and liver function, pregnancy, lactation, genetic factors,
and immune response.
Infections treated by GP
Airway infections, urinary tract infections, skin infections, STDs, and intestinal infections are all treated by
the GP, using penicillin, tetracyclines, sulfa’s, trimethoprim, co-trimoxazole, metronidazole, antiviral agents
and antimycotics.
Infections treated in hospitals
Patients with immunity disorders, like neonates, infants and children, elderly, surgery patients, patients
with burn wounds, diabetics, cytostatic and prednisone patients, and innate immune disorders are treated
in the hospital, just like patients that were in traffic accidents. There are special hospital antibiotics
because there is low-defense, special pathogens are present, and resistance occurs. The big difference is as
well that the infection is first cultured before it is treated. Treatment occurs with cephalosporins,
quinolones, aminoglycosides and antimycotics.
Resistance
In hospitals, resistant bacteria quickly arise. Some bacteria get resistant to one or more antibiotics, due to
evolution. Resistant bacteria can spread genetic material and resistance, both over the livestock and over
human healthcare environments. Therefore, antibiotics must only be used when necessary, and for the
prescribed time. A list has been released with priority bacteria for new antibiotics.
ESKAPE pathogens (no drugs available)
Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni,
Pseudomonas aeruginosa, Enterobacter species. These species have almost no possibility of eradication
because they are resistant to almost every antibiotic.
Superbugs
Next to the ESKAPE pathogens, there are some other microorganisms that cause big troubles:
MRSA (methicillin resistant Staphylococcus aureus), ESBL (extended spectrum β-lactamase, in E.coli and
Klebsiella pneumoniae), Iraqibacter (MDRAB, multidrug resistant Acinetobacter baumannii), VRE
(vancomycin resistant Enterococcus), CRE (carbapenem resistant Enterobacteriaceae), and multidrug
resistant Pseudomonas aeruginosa).
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, Gene transfer
There can be vertical gene transfer, which occurs from mother to daughter,
just like evolution occurs in plants and vertebrates, but the bigger problem
is horizontal gene transfer. This is the exchange of DNA, which can occur in
three ways:
- Bacterial transformation: a donor cell releases DNA to a recipient cell
- Bacterial transduction: a bacteriophage takes part of the DNA and infects
another cell
- Bacterial conjugation: active exchange of genetic material by plasmids or
transposons via a channel
Mechanisms of resistance
To gain resistance to a certain antibiotic, the bacteria can change,
overproduce, or bypass the target of an antibiotic. Also the
antibiotic itself can be inactivated by degradation or modification
(beta lactamase cleaves beta lactams in penicillin, carbapenems,
cephalosporinases), or the concentration can be lowered by
lowered uptake or enhanced secretion by increasing pumps that
excrete drugs from the cytoplasm. An estimation is that bacteria
will be the number 1 cause of death in 2050 due to resistance.
Answer of humans to resistance
Humans can do the same as bacteria: change the antibiotics to get new properties and overcome
resistance to old antibiotic. Also new investigations can be done (non-explored biotypes, symbiotic
communitis, unexplored microorganisms, natural products are searched in soil). Streptomycetes: activating
sleeping gene clusters. Lantibiotics are cyclized peptides that make holes in the membrane. Novel
treatment options for biofilm are to interfere with the biofilm so that the immune system can kill the
bacteria. Also the signal of quorum sensing can be destroyed so that the biofilm formation and virulence is
inhibited. This can be done by cleaving the signal molecule, using PvdQ. An ideal idea is the use of viral
therapy, using bacteriophages to give to patients, and letting them kill bacteria. Advantages are that this is
bactericidal, replication occurs, specific, disruption of biofilms and low toxicity. However, there is little
research, neutralizing antibodies occur, it is not for intracellular pathogens, there is exchange of toxins,
and it cannot be patented.
Use and policy
Resistance numbers are monitored, and actions are taken to improve care and reduce infections. Also,
there should be more identification of the organism before treatment, but this takes a lot of time. Quick
diagnosing could be beneficial to get a specific antibiotic and less resistance problems. So, the approach is
good diagnostics, antibiotic and treatment (length and dose). Resistance is partly due to unruly practice:
the GP treats the symptoms and not the specific infection, so there is blind therapy. Also, the patient itself
forms a problem when he or she does not finish the treatment, and antibiotics are overused in agriculture.
In general, there is increased mobility as well.
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