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
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
