Summary of lectures of the course Molecular Infection Biology. The summary consist of notes from the given lectures during this course and also contains supporting images from the powerpoint of the lectures
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Molecular infection biology
Lecture 1:
What is a pathogen?
- A pathogen is a biological agent that causes disease or illness to its host
Normal microflora → endogenous, beneficial for the host
Real pathogens → pathogenic or host?
Gut microflora
- More than 500 species →
o Firmicutes: mostly gram-positive bacteria → Clostridium species
o Bacteroidites: Bacteroides fragilis, bacteroides thetaiotaomicron
- Gnotobiotic animals are germ-free animals
o Need 305 more calories than normal mice with microbiome → you need the
microbiome for the break down of some foods, this does not happen in the
germ-free mice
o Less vascularization and poor development villi
o Underdeveloped mucosal immune response
Gut microflora
- Gut anaerobes degrade and ferment indigestible plant material
o Release of small simplified carbohydrates
o The B. thetaiotaomicron interacts with the carbohydrates and these
carbohydrates become simple sugars → this simple sugars can be taken up bij
the villi
- Induce immune responses, including the production of antibacterial peptides
o The antimicrobial peptides are a-defensins, subset of a-defensins and REG3y
o Mediated by MYD88, which is an adapter-protein of TLRs
o Mediated by NOD2
,Diseases by normal microflora
A Normal microflora at the wrong place
1. Damage to the epithelium → B. fragilis
2. New sites for normal microflora
3. Foreign bodies (surgical implants)
4. Wrong host
B. Abnormalities in host defence
Damage to epithelium
- Damage/rapture of the colon results in infiltration of microflow in peritoneum
- Co-infection E.coli and B. fragilis → synergistic effect: together they orodyce
something that is toxic
o Abscess formation, high morbidity and mortality
New sites for normal microflora
- Urinary tract infection by E.coli → results in bladder infections (cystitis) and kidney
infections (pyelonephritis)
- Mainly women
- Close proximity urethra and anus
Wrong host
- Different mammals have similar composition of gut flora → with strain specific
bacteria
- An bacteria that is non-pathogenic in one host
Outbreak of E.coli o157:H7
- Look for the contamination of the apple juice
- Outbreak traced to unpasteurized apple juice → molecular strain identification: PFGE
- The apples were not pasteurized → probably apples that fell on the ground were also
used for the apple juice
- The E. coli came from deers that were also present at the apple farm → this was the
E.coli strain that was pathogenic for humans
Wrong/host place
- Humans sometimes get infected by bites from dog and cats
- 5-10% of bites become infection
- Capnocytophaga canimorsus belongs to the normal oral flora (of dogs and cats)
- Infection with C. canimorsus → sepsis in humams
Abnormalities in host genome: genetic defect
BCG vaccination
- Live-attenuated virus against M. tuberculosis
- Osteomyelitis was due to BCG vaccination at birth
- 48 hours after a inguinal abscess developed → acid-fast bactili, culture was positive
for BCG → osteomyelitis was due to BCG
BCG post-vaccination disease
- Post-vaccination disease → Median susceptibility to mycobacterial diseases (MSMD)
- Also more sensitive to Candida and Salmonella
- In MSDM there is an disrupted IFNy pathway
,Disrupted IFNy pathway
- interferon (IFN)-γ circuit necessary for an effective immune response to intra-
macrophagic pathogens by inducing apoptosis
- Against pathogenic macrophages → infections which ‘live’ intracellular macrophages
Herpes Simplex Encephalitis
- HSE is a rare compilation of HSV-1 infection
- Most common type of sporadic encephalitis → high mortality/morbidity rate
- Persistence and reactivation of HSV → it reinfects the peripheral tissue
TLR signaling
- Toll-like receptors: mediators of innate immune system
- Antiviral response of TLR3 and TLR7/8/9 → all intracellular receptors
- Inborn errors of TLR3 and IFN-mediated pathway
- TLR3 is located in the endosome and recognizes dsRNA
, Antivital response
- Interferon stimulated genes (>100) → stimulatedby type 1 interferons
- When a pathogen binds to TLR3 this activates the cascade of MyD88 and TRIF → This
results in the production of type I interferons
Antiviral response – genetic defect
- 2 unrelated patietns born to first-cousin parents had recessive TLR3 mutations and
two had UNC-93B deficiency (role in TLR3 signaling through aberrant route)
TLR3 pathway and herpes encephalitis
- Inborn errors of TLR3-mediated and IFN-mediated immunity underlying herpes
simplex virus 1 encephalitis
Antibiotics
- Killing of antibiotic-sensitive species in the gut → this can also cause the killing of
other bacteria that live in the gut → this happens when you use broad-spectrum
antibiotics
- Massive outgrowth of endemic species or colonization by antibiotic-resistant new
species → this results I the growth of pathogenic bacteria:
o Clostridioides difficile
o Enterococcus faecalis
Why are some of the normal microflora good pathogen
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