Microbiology, virulence & treatment strategies Flashcards
What is virulence, and how can microorganisms benefit from it?
Virulence is the degree to which a microorganism is pathogenic.
LD50 (= lethal dose at 50% mortality) is a measure of virulence.
Virulence factors are pathogen products that facilitate colonization, infection or pathogenesis. Ex: toxins, adhesion factors, flagella, molecules that salvage nutrients or counteract host-defence mechanisms. Most virulence factors are either secreted or surface-exposed (proteins mostly, LPS and sugars).
Regulation: The virulence potential of a pathogen is defined genetically but bacteria adjust the expression and activity of virulence factors adaptively. Virulence costs energy, virulence factors should be expressed only when they are required, in order to maximize fitness.
Describe the steps of molecular pathogenesis for an infectious disease discussed in the course.
Stages of molecular pathogenesis:
1: transmission - infect the host!
2: adhesion - adhesion factors
3-5: invasion, infection, and disease - immune evasion: destroy, block, hide!
Passive invasion - through injury of the epithelial cell layer.
Active invasion - require virulence factors!
Evading phagocytosis: prevent phagocytosis utilizing the capsule having a change of patterns; make yourself too large to be phagocytosed (ex: biofilms); kill the phagocyte by secretion of toxins; invade the non-phagocytic cells; survive within the phagosome (prevent acidification, etc..); escape from the inside (triggering lysis or cell death).
Immune evasion strategies by intracellular pathogens: Interference with MHC/antigen presentation; inhibition of cell death pathways; killing of host cell; prevent acidification and effector enzymes.
Enabling infection means adjusting to new niches and accessing nutrients means evading host-immunity.
6: transmission - spread and infect new hosts!
What are antibiotics?
Antibiotics are molecules that in high dilutions can stop the growth of or kill bacteria (or fungi). They can be either natural products from microorganisms or man-made synthetic chemicals. And they can be either bacteriostatic (prevents growth) or bactericidal (kill the bacteria).
Ex: penicillin, carbapenem, vancomycin
What does bacteriostatic mean?
Bacteriostatic means that the drug will not be able to kill the bacteria, but it will prevent the bacteria to grow, and thus suppress the infection to accelerate.
Which molecular targets can antibiotics act on?
Cell wall/membrane: beta-lactam (penicillin), glycopeptide, lipopeptide
Protein synthesis: aminoglycoside, tetracycline, amphenicole
RNA/DNA synthesis: rifamycin, quinolon, nitroamidazole
Folic acid synthesis (metabolic pathway): trimetoprim, sulphonamide
How can bacteria become resistant?
Bacteria can become resistant to antibiotics through several mechanisms:
Ex: through genetic mutations that occur spontaneously during bacterial replication. These mutations may alter the target site of the antibiotic, reduce drug uptake, or increase drug efflux, thereby diminishing the antibiotic’s effectiveness.
Ex: acquire resistance genes from other bacteria via HGT (horizontal gene transfer) mechanisms like conjugation (plasmid), transformation (free uptake), or transduction (phage). These genes often reside on mobile genetic elements (plasmids or transposons), which can spread rapidly between bacteria. This acquisition of new genetic material can provide bacteria with the ability to degrade antibiotics enzymatically, alter their antibiotic’s target, or pump the antibiotic out of the cell.
Overuse and misuse of antibiotics in both healthcare and agriculture further exacerbate the problem by providing selective pressure that favors the survival and proliferation of resistant bacteria, leading to the emergence and spread of antibiotic resistance.
What are the side effects of antibiotic treatment?
Commonly side effects: diarrhea, nausea, vomiting, rash, upset stomach, sensitivity to sunlight (tetracyclines), reduction of the bacterial diversity in the gut (reduced microbiota).
What differences do you have to consider when developing antibacterial and anti-parasitic agents?
The differences to take into consideration:
1: biological differences - bacteria (cell structure, size, and metabolism) vs. parasites (complexity (single/multicellular organism) and life cycle of the vector (eggs, larvae, adults))
2: host interaction - bacteria (infection site and resistance development) vs. parasites (immune evasion (antigenic variation or immune suppression) and tissue specificity (liver, blood cells))
3: drug development and delivery - bacteria (target identification and drug delivery) vs. parasites (safety (host toxicity) and selectivity, and drug formation).
4: epidemiological considerations - bacteria (rapid response) vs. parasites (geographical distribution)
What is parasitism?
Parasitism is generally defined as a relationship between the two living species in which one organism is benefited at the expense of the other (= parasite).
Give an example of a life cycle of a parasite?
Life cycle of Plasmodium (causative agent/parasite of malaria)
1: mosquito bite and sporozoite transmission: the life cycle begins when an infected female mosquito bites a human injecting plasmodium sporozoites into the bloodstream. The sporozoites travel through the bloodstream to the liver.
2: liver stage: in the liver, sporozoites infect hepatocytes and undergo asexual multiplication, producing thousands of merozoites. This liver stage may be asymptomatic and can last from several days to weeks, depending on the plasmodium species.
3: blood stage: merozoites are released back into the bloodstream from the liver and begin to infect red blood cells. Inside the red blood cells; merozoites mature into trophozoites multiply further, and rupture the host cells, releasing more merozoites that continues to infect additional red blood cells. This cyclical process leads to the clinical symptoms of malaria (including fever, chills, and anemia).
4: sexual reproduction and mosquito infection: some of the merozoites develop into sexual forms called gametocytes, which are taken up by a mosquito during a blood meal. In the mosquito’s gut, male and female gametocytes fuse to form zygotes, which develop into motile ookinetes that penetrate the gut wall and form oocysts.
5: sporogony: within the oocysts, sporogony occurs leading to the formation of new sporozoites. The oocysts eventually rupture, releasing sporozoites that migrate to the mosquito’s salivary glands, ready to be transmitted to another human host during the next bite.
Which factor can decide over the outcome of an infection?
It relies on three main factors the pathogen, microbiome, and the host.
The pathogen contribute by its virulence factors, the infecting dosage, and the transmission route (varies between the species).
The host contribute by its integrity of physical defence barrier (injury or no-injury), state of the immune system (co-infections, previous infections, immunosuppression), and genetic predisposition.
What alternatives to antibiotics are emerging to treat antibacterial infections, and what are their advantages and disadvantages?
Some examples:
1: Bacteriophage therapy
* Advantages: Specificity - bacteriophages are viruses that infect specific bacteria, meaning they can target pathogenic bacteria without harming the beneficial microbiota; evolutionary advantages - phages can co-evolve with bacteria, potentially overcome bacterial resistance mechanisms that develop over time.
* Disadvantages: narrow spectrum - the high specificity of phages can also be a disadvantage as it requires precise identification of the bacterial strain causing the infection; immune response - phage can trigger immune responses that neutralize them, reducing their effectiveness.
2: antimicrobial peptides (AMPs)
* Advantages: broad spectrum - AMPs have a broad spectrum of activity and can be effective against a wide range of bacteria, including multi-resistant strains; multiple mechanisms - AMPs can kill bacteria through multiple mechanisms, reducing the likelihood of resistance development.
* Disadvantages: stability and cost - AMPs can be unstable in the body and expensive to produce; toxicity - high doses of AMPs can be toxic to human cells, limiting their therapeutic use.
3: probiotics
* Advantage: restoring microbiota - it can help the natural microbiota, which can outcompete pathogenic bacteria and enhance the immune response; safety - probiotics are generally safe and well-tolerated in most individuals.
* Disadvantages: variable efficacy - the effectiveness of probiotics can vary widely depending on the strains used and the individual’s conditions; regulatory challenges - there are challenges in regulating an standardizing probiotic treatment.
