1. I. Normal Human-Microbial Interactions
23.1 Beneficial Human–Microbial Interactions
23.2 Microflora of the Skin

2. 23.1 Beneficial Human–Microbial Interactions
Most microorganisms are benign
Few contribute to health, and fewer pose direct threats to health
Normal microbial flora (“microflora” or “microbiome”)
Microorganisms usually found associated with human body tissue

3. 23.1 Beneficial Human–Microbial Interactions
Humans are colonized by microorganisms at birth
Acquire microbes via birth canal-lactobacillus
Trends Mol Med. Author manuscript; available in PMC 2015 Jun 13.
Published in final edited form as:
Trends Mol Med Feb; 21(2): 109–117.
Published online 2014 Dec 11. doi:   /j.molmed
PMCID: PMC
NIHMSID: NIHMS695563
The infant microbiome development: mom matters
Noel T. Mueller,1,2 Elizabeth Bakacs,3 Joan Combellick,4 Zoya Grigoryan,3 and Maria G. Dominguez-Bello3
Author information ► Copyright and License information ►
Scientists swab C-section babies with mothers' microbes
Newborns were exposed experimentally to vaginal microbes to restore the microbiomes they missed.

4. 23.1 Beneficial Human–Microbial Interactions
Continued exposure throughout life
Evolutionary perspective???
Clin Exp Immunol Apr; 160(1): 1–9.
The ‘hygiene hypothesis’ for autoimmune and allergic
diseases: an update
H Okada, C Kuhn, H Feillet, and J-F Bach
Gut Mar; 54(3): 317–320.
Microbes, immunoregulation, and the gut
G A W Rook and L R Brunet
‘old friends hypothesis’

5. 23.2 Microflora of the Skin-a sample habitat
The skin surface varies greatly in chemical composition and moisture content
Three microenvironments
Dry skin
Moist skin
Sebaceous skin
Skin microflora examined by genomic methods
19 phyla detected
Each microenvironment shows a unique microbiota (Figure 23.2)

6. Figure 23.2 Figure 23.2 Normal skin microflora. Others 1%
Bacteroidetes
6.3%
Gram
negative
Proteobacteria
16.5%
Actinobacteria
51.8%
Other
Firmicutes
24.4%
Flavobacteriales
Betaproteobacteria
Gram
positive
Corynebacteria
Figure 23.2 Normal skin microflora.
Staphylococci
Propionibacteria
Figure 23.2

7. Distribution of microflora on surface of human body

8. II. Pathogenesis 23.6 Pathogenicity and Virulence 23.7 Adherence
23.8 Invasion, Infection, and Virulence Factors
23.9 Exotoxins
23.10 Endotoxins

9. 23.6 Pathogenicity and Virulence
Pathogen-a disease-causing microbe
Pathogenicity-the ability of a pathogen to inflict damage on the host
Virulence is the relative ability of a pathogen to cause disease
Measure of pathogenicity
variable
Pathogens use various strategies to establish virulence (Figure 23.9)
Opportunistic pathogen-causes disease only in the absence of normal host resistance

10. 23.6 Pathogenicity and Virulence
Measuring virulence
Virulence can be estimated from experimental studies of the LD50 (lethal dose50)
The amount of an agent that kills 50% of the animals in a test group (Figure 23.10)
Highly virulent pathogens show little difference in the number of cells required to kill 100% of the population as compared to 50% of the population

11. 23.6 Pathogenicity and Virulence
Attenuation
The decrease or loss of virulence
Toxicity
Organism causes disease by means of a toxin that inhibits host cell function or kills host cells
Toxins can travel to sites within host not inhabited by pathogen
Exo-, endo-, entero- toxins

12. 23.6 Pathogenicity and Virulence
Invasiveness
Ability of a pathogen to grow in host tissue at densities that inhibit host function
Can cause damage without producing a toxin
Many pathogens use a cocktail of adherence, toxins, invasiveness, and other virulence factors to enhance pathogenicity

13. 23.7 Adherence First step in disease
Adherence is ability of microbe to stick to a surface
Pathogenic bacteria that initiate infection must adhere to epithelial cells through interactions between molecules on the surfaces of the pathogen and the host cell (Figure 23.12)

14. 23.7 Adherence Bacterial adherence can be facilitated by
Extracellular macromolecules that are not covalently attached to the bacterial cell surface
Examples: slime layer, capsule (Figure 23.13)
Fimbriae and pili (Figure 23.14)
Examples: pathogenic strains of E. coli, Neisseria gonorrheae, Shigella spp. “adherence factors” or “adhesins”

15. Figure 23.12 Adherence of pathogens to tissues.

16. 23.8 Invasion, Infection, and Virulence Factors
The initial inoculum of a pathogen is insufficient to cause host damage
The pathogen must multiply and colonize the tissue
The availability of nutrients is most important in affecting pathogen growth
Pathogens may grow locally at the original site or invade throughout the body

17. 23.8 Invasion, Infection, and Virulence Factors
Infection: any situation in which a microorganism (not a member of the local flora) is established and growing in a host
Bacteremia: the presence of bacteria in the bloodstream
Septicemia: bloodborne systemic infection
May lead to massive inflammation, septic shock, and death

18. 23.8 Invasion, Infection, and Virulence Factors
Virulence factor: any microbial substance that enhances pathogenicity
Virulence factors may be:
Antibiotic resistance compounds
Enzymes that enhance virulence by breaking down or altering host tissue to provide access to nutrients
Example: hyaluronidase
Enzymes that protect the pathogen by interfering with normal host defense mechanisms
Example: coagulase
Toxic substances released outside the pathogen: exotoxins
Example: neurotoxins

19. 23.8 Invasion, Infection, and Virulence Factors
Example of enzyme as virulence factor: streptokinase
Produced by Streptococcus pyogenes
Strep throat, scarlet fever, impetigo, others
Streptokinase is an enzyme released by the pathogen
It initiates a cascade that leads to the breakdown of fibrin in blood clots
Enhances invasiveness of pathogen
Was used as medication to help dissolve blood clots

20. 23.9 Exotoxins
Exotoxins
Proteins released from the pathogen cell as it grows
Three categories based on mechanism of action
Cytotoxins
AB toxins
Superantigen toxins

21. 23.9 Exotoxins Cytotoxins (cytolytic toxins)
Work by degrading cytoplasmic membrane integrity, causing cell lysis and death
Toxins that lyse red blood cells are called hemolysins (Figure 23.18)
Staphylococcal α-toxin induces apoptosis and lyses erythrocytes (Figure 23.19)

22. Efflux of cytoplasmic components Out Cytoplasmic In membrane
RCSB PDB 3ANZ
Efflux of
cytoplasmic
components
Out
Figure Staphylococcal α-toxin.
Cytoplasmic
membrane In
α-Toxin pore
Influx of
extracellular
components

23. Clostridium perfringens alpha toxin
Degrades plasma membrane
Leads to cell and tissue death
“gas gangrene”
Zone of hemolysis

24. 23.9 Exotoxins AB toxins Consist of two subunits, A and B
Work by binding to host cell receptor (B subunit) and transferring damaging agent (A subunit) across the cell membrane (Figure 23.20)
Examples: diphtheria toxin, tetanus toxin, botulinum toxin

25. 23.9 Exotoxins
Clostridium tetani and Clostridium botulinum produce potent AB exotoxins that affect nervous tissue
“botulism” food poisoning due to anaerobic production of toxin-often in home canned foods
Botulinum toxin or Botox consists of several related AB toxins that are the most potent biological toxins known (Figure 23.21); tetanus toxin is also an AB protein neurotoxin (Figure 23.22)

26. BTX is the most lethal toxin known
Excitation signals
from the central
nervous system A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A
Muscle A A
Figure The activity of botulinum toxin from Clostridium botulinum.
Normal
Acetylcholine (A) induces contraction
of muscle fibers
Botulism
Botulinum toxin, , blocks release of A,
inhibiting contraction
Figure 23.21

27. 23.9 Exotoxins Enterotoxins
Exotoxins whose activity affects the small intestine
Generally cause massive secretion of fluid into the intestinal lumen, resulting in vomiting and diarrhea
Example: cholera toxin (Figure 23.23)
Causative agent-Vibrio cholera in contaminated food or
water

28. Figure 23.23 Figure 23.23 The activity of cholera enterotoxin.
1. Normal ion movement, Na+ from lumen to blood,
no net Cl– movement
4. Na+ movement blocked, net Cl– movement to lumen
Blood
Intestinal
epithelial
cells
Lumen of
small intestine
GM1
5. Massive water movement to the lumen; cholera symptoms
2. Infection and toxin production by V. cholerae
Cholera
toxin
AB form
GM1
Vibrio
cholerae
cell B A
3. Activation of epithelial adenylate cyclase by cholera toxin
Figure The activity of cholera enterotoxin.
A subunits
Cholera
toxin B
subunit
Adenylate cyclase
ATP
Cyclic
AMP
Figure 23.23

29. 23.9 Exotoxins Superantigens
An antigen is a substance that can provoke a response by by the immune system
Act by hyperstimulation of immune system
Promiscuous binding to immune cell receptors
Staphylococcus, Streptococcus
S. aureus food poisoning - more than just GI tract

30. 23.10 Endotoxins
Endotoxin
The lipopolysaccharide portion of the cell envelope of certain gram-negative Bacteria, which is a toxin when solubilized
Not secreted but released upon cell breakdown
Generally less toxic than exotoxins
Neisseria gonorrheae lipo-oligo-saccharides

31. 23.8 Invasion, Infection, and Virulence Factors
Salmonella species encode a large number of virulence factors of many types (Figure 23.17)
Several genes that direct invasion are clustered together on the chromosome as pathogenicity islands
Another Salmonella pathogenicity island contains genes that promote a more systemic disease
Salmonella also contains resistance plasmids (R plasmids)

32. Figure 23.17 Enterotoxin (diarrhea) Siderophores (iron uptake)
Injectisome
(inv and prg
products form
complex)
Type Ι fimbriae
(adherence)
Endotoxin in
LPS layer
(fever)
Virulence
plasmid
SPΙ2
SPΙ1
Anti-
phagocytic
proteins
induced
by oxyR
Cytotoxin
(inhibits host cell protein
synthesis; Ca2+ efflux
from host cell; adherence)
Figure Virulence factors in Salmonella.
O antigen
(inhibits
phagocyte
killing)
Vi capsule antigen;
inhibits complement binding
Pathogenicity
islands on
chromosome
Flagellum (motility)
H antigen (adherence;
inhibits phagocyte killing)
Figure 23.17