Molecular Infection Biology
Lecture 1 – 28/10/24
Normal microflora vs. real pathogens
Normal microflora: endogenous, can be beneficial for the host
Real pathogens: exogenous, can be pathogenic for the host
(micro) biological agent that causes harm or illness to its host
it is difficult to distinguish between microbiological agents in our body between microflora
and real pathogens
Normal microflora/microbiome:
5 regions; mouth, skin, oesophagus, colon, vagina. Stomach has helicobacter pylori
Gut microflora has more than 500 species (mainly firmicutes and Bacteroidetes). Induce
immune response including production of antimicrobial peptides.
Gnobiotic animals: germ-free animals.
- Need 30% more calories: microbiome is needed for the breakdown of some foods,
which doesn’t happen in germ free (mice/)animals
- Less vascularization and poor development of the villi
- Underdeveloped mucosal immune response
Gut anaerobes (example: bacteroides thetaoitaomicron), can degrade and ferment indigestible
plant material, allowing release of small, simplified carbohydrates (like butyric acid).
bacteria can help degrade certain materials
this bacterium example interacts with carbohydrates, which become simple sugars.
Sugars can be taken up by the villi.
Gut microflora induce immune responses, including the production of
antibacterial/antimicrobial peptides AMP. Intestinal epithelial cells regulate AMP production
to defend against microbial threats. Three types of expression:
1. Constitutive expression (AMPs like α-defensins are continuously produced to
maintain baseline levels of antimicrobial defense, preventing overgrowth)
2. TLR dependent expression (TLR activation via molecular patterns associated to
microorganisms, leading to downstream signaling through MYD88, inducing RAG3y
production. All enhances bacterial killing)
3. NOD2-dependent expression (NOD2 recognition of muramyl dipeptides, causing
production of α-defensin subset, providing additional defense layer)
Two ways of diseases by normal microflora are A) normal microflora at the wrong place, or
B) abnormalities in host defense
,A) Normal microflora at the wrong place:
1. Damage to the epithelium
Damage to colon epithelium gives infiltration of gut microflora in
peritoneum. Can be spontaneous or after surgery. The bacteria can be quite
harmless in the gut, but cause abscess, morbidity and mortality when in
other regions. Coinfections can be synergistic, increasing abscess
formation, morbidity and mortality rates.
epithelium protects the body from the outside space where the
microflora is. Damaged epithelium causes spread of harmful microflora in
the body
2. New sites for normal microflora
UTI’s can be caused by E.coli, which can result in bladder infections and
kidney infections. (UTIs mostly in women due to close proximity between
urethra and anus, so bacteria moved to new place)
3. Infections after surgical implants/foreign bodies
Skin bacteria can be helpful or harmless, but can cause implant infections
s epidermis produces surface proteins and exopolymers that facilitate
adhesion and biofilm formation on human skin and implanted devices
skin barrier disruption allows entering of the pathogen into
sterile areas
surgical implantation provides surface for bacterial adhesion
and biofilm formation
can exclude bacteria from the skin by blocking autoinduction and
synergizing with AMPs.
Normally, this bacterium is required for skin protection as a key skin
microbiota component. Occupies physical space on the skin, preventing
harmful pathogens (above) from colonizing. It also produces AMPs which
inhibit pathogen growth. It interacts with skin immune cells to promote
balanced immune response.
4. Wrong host
Example: E. coli O157 (O= antigen, part of lipopolysaccharide layer)
Cause possibly: unpasteurized meaning bacteria aren’t killed
Was due to deer poop. This strain is a natural inhabitant of cattle
microbiome, gives no obvious disease. BUT in humans
highly virulent
So: different mammals can have a similar composition of gut flora, but
in different ‘normal’ amounts: wrong bacteria in wrong place can cause
disease/infection. Each host has their own safe strains of bacteria.
different mammals have a similar composition of gut flora, but with
strain-specific bacteria.
, Another example: infection after dog/cat bite, because C. canimorsus is
native to oral flora of them but not of humans, where it can cause sepsis
B) Abnormalities in host defense
1. Genetic defect
Example: SCID (boy in the bubble)
Example: BCG vaccination, a live attenuated vaccine against TB, gives
averagely 50% TB protection
MSMD: Mendelian Susceptibility to Mycobacterial Disease.
Incidental infection of mycobacteria after vaccination in kids, can
become fatal.
disrupted IFNgamma pathway which is a necessary circuit for
effective immune response into intra-macrophage pathogens via apoptosis
induction
Or:
Herpes Simplex Encephalitis (HSE), complication of HSV-1
infection. High mortality/morbidity rate, common type of viral sporadic
encephalitis. Is a genetic defect, TLR3 mutation probably.
Persistence and reactivation of HSV due to reinfection of peripheral
tissue; viral ability to establish lifelong latency in host, and reactivate
under specific conditions. Antiviral treatments reduce reactivation
frequency and symptoms, cannot eliminate virus (so lifelong)
Antiviral response: TLRs are mediators of the innate immune
system, detect microbial components. Antiviral response regulated by
TLR3,7,8,9: intracellular receptors specialized in detecting viral
components (nucleic acids) in the endosome. Inborn errors disrupt
normal TLR3 signaling/downstream pathways, impairing recognition of
dsDNA (genetic defects in TLR3 (related pathways) impair IFN
production, leading to increased susceptibility to viral infections like
HSV encephalitis). Causes inability of IFN pathway activation,
resulting in impaired antiviral defense.
inborn errors of TLR3-mediated and IFN-mediated immunity
underlie HSV1 encephalitis
2. Suppression of immune response
Transplantation, malnutrition (measles, malaria)
3. Other infections
HIV, influenza
4. Antibiotics
You can kill antibiotic-sensitive species, i.e. healthy gut flora, resulting in
massive outgrowth of endemic species or colonization by antibiotic-
resistant new species. Will cause problems when in large amounts
Why are some bacteria of the normal microflora good pathogens?
- They’re already adapted to host’s immune system/metabolism
- They are always present have the opportunity
- Factors important for colonization are also used for virulence:
, o Adhesion (pili) and Evade killing immune response (capsule)
- Some virulence factors are needed to withstand other organisms, like grazing protozoa
o Protozoa look like macrophages and try to kill microorganisms like
macrophages. Survival in protozoa often means (ability to) survive in
macrophages. they don’t only interact with humans
Vertebrates great host for food-searching pathogens:
Ambient temperature, high nutrient number, good transport of metabolites and waste.
Microbes always look for new niches and adapt to them. Older niches then acquire virulence
factors. Viruses acquire new metabolic functionalities in new niches, and specialize to it: loss
of function, metabolic gain
Exogenous infections
From non-microflora microbacteria
Colonization of mucosal surfaces, cross anatomical barriers, tissue invasion, breach host
defenses, tissue invasion
Adapted human pathogens: include malaria, Mtb, herpes viridae, helicobacter pylori
Epstein-Barr virus: DNA virus (herpes viridae), life-long infection, causes
mononucleosis (Pfeiffer). Associated malignancies: (non-)Hodgkin’s lymphomas,
Burkitt’s lymphoma
Infection process host cell type switching during infection (host cell tropism),
between infecting epithelial cells and B lymphocytes and back. Done to manipulate
immune system.
Herpesvirus latency confers symbiotic protection from bacterial infection
HPVs can enhance host’s immune response during latency, providing
protection against certain bacterial infections. Latency-associated viral factors may
stimulate the immune system, keeping bacterial pathogens in check.
Mechanism: independent of cross-reactivity. It is related to IFNy production
through persistent epigenetic changes of macrophages and progenitor cells
infection/vaccination causes epigenetic reprogramming in innate
immune cells (histone modification, DNAme, miRNA modification,
long-noncoding RNA expression etc.), which causes trained immunity
in transcriptional and functional programs
Mtb
Infection via inhalation of infectious bacterium, 5% develop active disease. Can
disseminate extrapulmonary to liver/kidneys/brain
Virulence problems: no clear involved toxin to symptoms, 90% doesn’t get symptoms.
Only when too much tissue damage is caused by the immune response, it causes
disease. Some variants have increased virulence.
