HCs molecular infection biology (MIB)
-You can use google scholar better when looking for a certain molecule
-ISI -> useful for having an article, but to see whether there is something published with similar subject
later (more recent).
HC 1: what is a pathogen? – Symbiosis versus Pathogen (31/10/22)
Normal microflora at the wrong place
-What is a normal microflora and a real pathogen?
• Normal microflora -> Endogenous microorganism
o Beneficial for the host?
• ‘Real’ pathogen -> A microbiological agent that causes disease or illness to its host.
o Exogenous
o Pathogenic for the host?
o The term pathogen is derived from the Greek παθογένεια, "that which produces
pain/suffering“.
o Pathogens:
▪ Viruses
▪ Bacteria
▪ Protozoa
▪ Yeasts / Fungi
▪ Worms
-Normal human microflora:
• Stomach -> Helicobacter pylori
• Gut microflora:
o More than 500 species, mainly:
▪ Firmicutes -> Clostridium
species
▪ Bacteroidetes:
• Bacteroides fragilis
• Bacteroides
thetaiotaomicron
o Importance -> Depends on what
animal you are!
▪ Cows, for example, cannot live without
▪ Studying gnotobiotic animals -> animals that are
completely germ-free
• Need 30% more calories to live (because
without microbiome, there is less breaking
down of nutrients (which we need to digest
it)).
• Less vascularisation and poor developed villi
• Underdeveloped mucosal immune response
o Molecules of the bacteria (-> gut anaerobes -> Bacteroides
thetaiotaomicron) (on the surface) break down and ferment
the indigestible plant material, then we take it up (so
happens at the outside of the guts (in the lumen)).
▪ Because we aren’t able to do it ourself.
, ▪ The molecules -> small simplified carbohydrates (butyric acid).
o Also important for immune response -> Gut microflora induce immune response, including
production of antimicrobial peptides.
-Diseases by normal microflora:
• Can happen because:
o Normal flora on the wrong place
o Abnormalities in host defence
• Pathogens who can become opportunistic:
o So, normal microflora are pathogens, BUT there not always pathogenic.
• Diseases caused by normal microflora at the wrong place:
o Damage to the epithelium -> B. fragilis
o New sites for normal microflora -> E. coli
, o Foreign bodies (surgical implants) -> Staphylococcus epidermidis
o Wrong host -> E. coli O157
• Damage the colon epithelium (spontaneous or after surgery) -> infiltration of the body cavity with
microfloral bacteria who shouldn’t belong there.
o Like, coinfection with E. coli and B. fragilis ->
synergistic (samenwerkend) -> Causes abscess
formation, high morbidity and mortality
• New sites for normal gut microflora:
o E. coli -> urinary tract infectious -> Can result in
bladder infections (cystitis) and kidney infections
(pyelonephritis)
▪ Incidence cystitis per 1,000 a year:
▪ Mainly in woman -> Close proximity urethra
and anus
• Entering up in the wrong host -> Because there are different strains of
microflora between different mammals.
▪ Although they seem familiar -> Similar composition of
gut flora, but different strains!
-Example infection normal microflora in wrong host: Outbreak of E. coli O157:H7 -> In western united
states (1996)
• Situation:
o 70 persons were infected
o 25 persons hospitalized
o 14 developed hemolytic uremic syndrome
o 1 person (toddler) died
• Was because of apple juice -> They did not pasteurize it
• Water for washing apples were only changed once a day (not hygienic), but not the same E. coli
strain!
• Also, not the apples at the farm
• One farm was hosted by a deer population -> These deer had the same e. coli strain.
o So, droplets of deer poop (with E. coli) were on the apples.
• So, a friend bacterium in one mammal can be pathogenic in another mammal.
-Another example in wrong host -> bite from a dog or cat
• Bacterium, Capnocytophaga canimorsus, is in the saliva of the dog → sepsis
o 5-10% of bites become an infection
, Abnormalities in host defence (causing disease by normal microflora)
Genetic defect (like with SCID)
-Jean-Laurent Casanova -> “A child (and young adult) with a life-threatening infectious disease is not just
unlucky. A fault in one gene can leave our immune system unarmed against that one infection.”
-BCG -> Vaccine most widely used (against tuberculosis)
• Live-attenuated vaccine, protects on average 50% against TB
• Case report (example of when it can go wrong with live-attenuated)
o 30 -year-old woman with chronic osteomyelitis (bone infection)
o She was vaccinated at birth with BCG
o 48 hours after vaccination a left inguinal abscess developed. Lymph node biopsy showed
acid–fast bacilli, culture was positive for BCG. She was treated for 4 years with antibiotics.
o When she was 8 years, she had recurrent lung infections and antibiotic treatment and left
pneumonectomy was required in combination with antibiotics.
o At the age of 12, the patient developed left mammary masses and a lacrimal gland
infiltration. Rifabutin treatment for 2 years
o Osteomyelitis was again due to BCG….
o Treating did not help
o A case where the person probably had an immune deficient defect
o Term we now use for this -> Mendelian susceptibility to mycobacterial disease (MSMD)
▪ The incidence of disseminated BCG infection is 0.5-2 cases per million vaccinated
children, sometimes fatal.
▪ Also more sensitive for Candida and Salmonella
• What is causing this MSMD? -> disruption of IFN- pathway.
o Interferon (IFN)-γ circuit necessary for an effective immune response to intra-macrophagic
pathogens by inducing apoptosis.
o Mycobacteria can survive the first stages of the macrophages trying to kill it.
▪ BCG can do as well.
o IL-12 is secreted (of the infected cell (the macrophage)) → other immune cells will kill this
infected cell.
o Main genetic defects: IL-12Rβ1, IFN-γR1, STAT1, IL-12p40
-Another example, HSE (herpes simplex encephalitis) -> Diseases because of a defect in the immune
system.
• HSE is a rare complication of HSV-1 infection (one case per million per year)
• Most common type of sporadic viral encephalitis
• High mortality/morbidity rate: before the use of acyclovir: 70% mortality and 3% of survivors with
normal brain function
• Necrosis in the brain due to this virus
-You can use google scholar better when looking for a certain molecule
-ISI -> useful for having an article, but to see whether there is something published with similar subject
later (more recent).
HC 1: what is a pathogen? – Symbiosis versus Pathogen (31/10/22)
Normal microflora at the wrong place
-What is a normal microflora and a real pathogen?
• Normal microflora -> Endogenous microorganism
o Beneficial for the host?
• ‘Real’ pathogen -> A microbiological agent that causes disease or illness to its host.
o Exogenous
o Pathogenic for the host?
o The term pathogen is derived from the Greek παθογένεια, "that which produces
pain/suffering“.
o Pathogens:
▪ Viruses
▪ Bacteria
▪ Protozoa
▪ Yeasts / Fungi
▪ Worms
-Normal human microflora:
• Stomach -> Helicobacter pylori
• Gut microflora:
o More than 500 species, mainly:
▪ Firmicutes -> Clostridium
species
▪ Bacteroidetes:
• Bacteroides fragilis
• Bacteroides
thetaiotaomicron
o Importance -> Depends on what
animal you are!
▪ Cows, for example, cannot live without
▪ Studying gnotobiotic animals -> animals that are
completely germ-free
• Need 30% more calories to live (because
without microbiome, there is less breaking
down of nutrients (which we need to digest
it)).
• Less vascularisation and poor developed villi
• Underdeveloped mucosal immune response
o Molecules of the bacteria (-> gut anaerobes -> Bacteroides
thetaiotaomicron) (on the surface) break down and ferment
the indigestible plant material, then we take it up (so
happens at the outside of the guts (in the lumen)).
▪ Because we aren’t able to do it ourself.
, ▪ The molecules -> small simplified carbohydrates (butyric acid).
o Also important for immune response -> Gut microflora induce immune response, including
production of antimicrobial peptides.
-Diseases by normal microflora:
• Can happen because:
o Normal flora on the wrong place
o Abnormalities in host defence
• Pathogens who can become opportunistic:
o So, normal microflora are pathogens, BUT there not always pathogenic.
• Diseases caused by normal microflora at the wrong place:
o Damage to the epithelium -> B. fragilis
o New sites for normal microflora -> E. coli
, o Foreign bodies (surgical implants) -> Staphylococcus epidermidis
o Wrong host -> E. coli O157
• Damage the colon epithelium (spontaneous or after surgery) -> infiltration of the body cavity with
microfloral bacteria who shouldn’t belong there.
o Like, coinfection with E. coli and B. fragilis ->
synergistic (samenwerkend) -> Causes abscess
formation, high morbidity and mortality
• New sites for normal gut microflora:
o E. coli -> urinary tract infectious -> Can result in
bladder infections (cystitis) and kidney infections
(pyelonephritis)
▪ Incidence cystitis per 1,000 a year:
▪ Mainly in woman -> Close proximity urethra
and anus
• Entering up in the wrong host -> Because there are different strains of
microflora between different mammals.
▪ Although they seem familiar -> Similar composition of
gut flora, but different strains!
-Example infection normal microflora in wrong host: Outbreak of E. coli O157:H7 -> In western united
states (1996)
• Situation:
o 70 persons were infected
o 25 persons hospitalized
o 14 developed hemolytic uremic syndrome
o 1 person (toddler) died
• Was because of apple juice -> They did not pasteurize it
• Water for washing apples were only changed once a day (not hygienic), but not the same E. coli
strain!
• Also, not the apples at the farm
• One farm was hosted by a deer population -> These deer had the same e. coli strain.
o So, droplets of deer poop (with E. coli) were on the apples.
• So, a friend bacterium in one mammal can be pathogenic in another mammal.
-Another example in wrong host -> bite from a dog or cat
• Bacterium, Capnocytophaga canimorsus, is in the saliva of the dog → sepsis
o 5-10% of bites become an infection
, Abnormalities in host defence (causing disease by normal microflora)
Genetic defect (like with SCID)
-Jean-Laurent Casanova -> “A child (and young adult) with a life-threatening infectious disease is not just
unlucky. A fault in one gene can leave our immune system unarmed against that one infection.”
-BCG -> Vaccine most widely used (against tuberculosis)
• Live-attenuated vaccine, protects on average 50% against TB
• Case report (example of when it can go wrong with live-attenuated)
o 30 -year-old woman with chronic osteomyelitis (bone infection)
o She was vaccinated at birth with BCG
o 48 hours after vaccination a left inguinal abscess developed. Lymph node biopsy showed
acid–fast bacilli, culture was positive for BCG. She was treated for 4 years with antibiotics.
o When she was 8 years, she had recurrent lung infections and antibiotic treatment and left
pneumonectomy was required in combination with antibiotics.
o At the age of 12, the patient developed left mammary masses and a lacrimal gland
infiltration. Rifabutin treatment for 2 years
o Osteomyelitis was again due to BCG….
o Treating did not help
o A case where the person probably had an immune deficient defect
o Term we now use for this -> Mendelian susceptibility to mycobacterial disease (MSMD)
▪ The incidence of disseminated BCG infection is 0.5-2 cases per million vaccinated
children, sometimes fatal.
▪ Also more sensitive for Candida and Salmonella
• What is causing this MSMD? -> disruption of IFN- pathway.
o Interferon (IFN)-γ circuit necessary for an effective immune response to intra-macrophagic
pathogens by inducing apoptosis.
o Mycobacteria can survive the first stages of the macrophages trying to kill it.
▪ BCG can do as well.
o IL-12 is secreted (of the infected cell (the macrophage)) → other immune cells will kill this
infected cell.
o Main genetic defects: IL-12Rβ1, IFN-γR1, STAT1, IL-12p40
-Another example, HSE (herpes simplex encephalitis) -> Diseases because of a defect in the immune
system.
• HSE is a rare complication of HSV-1 infection (one case per million per year)
• Most common type of sporadic viral encephalitis
• High mortality/morbidity rate: before the use of acyclovir: 70% mortality and 3% of survivors with
normal brain function
• Necrosis in the brain due to this virus
