1. Pathogenesis of bacteria

2. Original and development of Bacterial Infection

3. Infection：
the invasion of a host organism's bodily tissues by disease-causing organisms, their multiplication, and the reaction of host tissues to these organisms and the toxins they produce.

4. A disease causing microorganism. Nonpathogen:
A microorganism that does not cause disease.
Opportunistic pathogen:
A microorganism does not cause disease in normal conditions,
but is capable of causing disease under contain conditions.

5. A bacterial infectious disease is a multi-factorial event which depends on:
Nature (virulence factors) of bacterial species or strain.
Immune status of bacteria invading hosts.
Environment conditions
Pathogenesis of microbial infection includes:
a) general process of infection
b) mechanisms of microbes causing disease
Number of initial invaded bacteria.
transmissibility, adherence to host cells, invasion of host cells and tissues, toxigenicity, and ability to evade the host's immune system

6. pathogenesis Pathogenicity virulence How a disease develops
Disease-causing ability of microorganisms
virulence
Degree of pathogenicity

7. Pathogen-- Pathogenicity
The ability of a microorganism to cause disease
Factors that determine bacterial pathogenicity:
Virulence: The quantitative ability of a pathogen to cause disease that containing invasiveness and toxigenicity.
The amount of entry
The portal of entry

8. LD50 (Lethal Dose, 50%) : ID50 (Infective Dose, 50%) :
The number of pathogen required to cause lethal disease in half of the exposed hosts.
ID50 (Infective Dose, 50%) :
The number of pathogens required to cause disease or infection in half of the exposed hosts.
Lethal Dose of a microbes toxin that will kill 50% of experimentally inoculated test animal
infectious dose required to cause disease in 50% of inoculated test animals

9. Adhesion (adherence, attachment): the process of microbes sticking to the surfaces of host cells.
Adhesion is a key initial step during infection (then invasion).
Surface molecules on a pathogen, called adhesins or ligands, bind specifically to complementary surface receptors on cells of certain host tissues.
E. Coli bacteria on human bladder cells
Bacteria adhering to human skin

11. Invasiveness: The process of microbes entering host cells or tissues as well as spread in the body.
Toxigenicity: The ability of a microorganism to produce toxins that contributes to the development of disease.

12. intracellular bacteria:
capable of living and reproducing either inside or outside cells
Listeria monocytogenes
Salmonella
Brucella
Mycobacterium
Yersinia
Neisseria meningitidis
Cryptococcus neoformans
extracellular bacteria:
capable of replicating outside of the host cells

13. Source of infections Exogenous infection
Infections caused by infectious agents that are come from the external environment or other hosts (patient, carrier, diseased animal or animal carrier).
“carrier”: individuals infected with infectious agents but no clinical signs or symptoms.
Endogenous infection
Infections caused by normal flora under certain conditions (opportunistic infection)

14. Transmission of bacterial infection
Bacteria can be transmitted in airborne droplets to the respiratory tract, by ingestion of food or water or by sexual contact.
Specific bacterial species are being transmitted by different routes to specific sites in the human body:
Respiratory tract (Mycobacterium tuberculosis)
gastrointestinal tract (pathogenic E. coli)
Genitourinary tract (Neisseria gonorrhoeae)
Closely contact
Insect bite (Rickettsia)
Blood transfusion
Skin and other mucosa (eye)

15. Common Diseases contracted via the Respiratory Tract
Common cold
Flu
Tuberculosis
Whooping cough
Pneumonia
Measles
Strep Throat
Diphtheria

16. Mucus Membranes Gastrointestinal Tract
microbes gain entrance thru contaminated food & water or fingers & hands
most microbes that enter the G.I. Tract are destroyed by HCL & enzymes of stomach or bile & enzymes of small intestine

17. Common diseases contracted via the GastrointestinalTract
Salmonellosis
Salmonella sp.
Shigellosis
Shigella sp.
Cholera
Vibrio cholorea
Ulcers
Helicobacter pylori
Botulism
Clostridium botulinum

18. Fecal - Oral Diseases
These pathogens enter the G.I. Tract at one end and exit at the other end.
Spread by contaminated hands & fingers or contaminated food & water
Poor personal hygiene.

19. Mucus Membranes of the Genitourinary System
Gonorrhea
Neisseria gonorrhoeae
Syphilis
Treponema pallidum
Chlamydia
Chlamydia trachomatis
HIV
Herpes Simplex II

20. Types of bacterial infection

21. According to infectious state:
Inapparent or subclinical infection: The infection with no manifesting clinical signs and symptoms.
Latent infection or Carrier state: The infection is inactive but remains capable of producing clinical signs and symptoms.
Apparent infection: The infection with manifesting clinical signs and symptoms.

22. According to infectious sites:
Local infection: The infection is limited to a small area of the body.
Generalized or systemic infection: The infection is throughout the body, it can present as:
Bacteremia (菌血症): Bacteria enter bloodstream without propagation in
bloodstream (bloodstream only used as a channel tool for bacteria
to spread)
-Salmonella
Toxemia (毒血症): Exotoxins enter bloodstream but no bacteria in the blood.
- corynebacterium diphtheriae, clostridium tetani

23. According to infectious sites:
Endotoxemia (内毒素血症): Endotoxins enter bloodstream but no
bacteria in the blood.
- Shigella
Septicemia (败血症): Bacteria enter bloodstream with propagation and release their virelent substances (e.g., toxins).
- clostridium perfringens, Yersinia pestis
Pyemia (脓毒血症)：Pyogenic bacteria enter bloodstream with propagation and release their virulent substances, and spread through bloodstream into the target organs to form pyogenic foci.
- staphylococcus aureus

24. Normal flora & Opportunistic infections & Hospital acquired infections

25. All humans have bacteria (normal flora) that living on their external surfaces (skin) and their inner surfaces (Respiratory, Gastroenteric and Genitourinary tract mucosa). Normally due to our host defenses, most of these bacteria are harmless.
The infectious diseases that initiated in hospital are referred to as nosocomial infection (Hospital acquired infection ).

26. Normal flora
Microorganisms that live on or in human bodies, and ordinarily do not cause human diseases

27. Distribution of normal flora
Skin Flora:
Various environment of the skin results in locally dense or sparse microbial populations. Usually Gram-positive bacteria (e.g., Staphylococci and Micrococci ) are predominating.
Oral and Upper Respiratory Tract Flora:
Various microbial floras can be found in the oral cavity (e.g., anaerobic bacteria) and upper respiratory tract (e.g., Neisseria, Bordetella and Streptococci ).

28. Gastrointestinal Tract Flora:
In normal hosts, flora in stomach are rare as well as transient, flora in duodenum and jejunum are sparse, and ileum contains moderately mixed flora.
Flora in large bowel is dense ( bacteria/g of the content) and is predominantly composed of anaerobes.

29. Urogenital Flora:
Flora in vaginal (e.g., anaerobes and Lactobacillus) changes with the age of the individual, pH and hormone levels.
Distal urethra contains a sparse mixed flora (e.g., Corynebacterium).
Conjunctival Flora: Conjunctiva (eye) has few or no microorganisms. However, Haemophilus and Staphylococcus are frequently detected.

30. Physiological Role of normal flora
Antagonism: a) Normal flora on skin and mucosa of hosts can form biolfilm (as a biological barrier) that acts as colonization resistance of exogenous pathogenic microbes; b) Normal flora may antagonize exogenous pathogens through the production of antibiotics.
Trophism: Normal flora in the intestinal tract synthesize nutrients that can be absorbed by human (e.g., vitamin K and vitamin B).
Immunoenhancement: Normal flora promotes the development of local lymphatic tissues (e.g., Peyer’s patches in the intestines).

31. Conditions that opportunistic pathogens cause human diseases
Alteration of colonization sites
Declination of the host immunity defense
Dysbacteriosis
-the state in which the proportion of bacterial species and the number of the normal flora colonizing in a certain site of a host present large-scale alteration

32. Opportunistic infections (Infections caused by normal flora)

33. “Opportunity” for opportunistic infection
I. Low immunity of human body: Normal flora that usually don't cause disease in a person with a healthy immune system. If a person with a poor immunity, some of them can cause infection.
II. Translocation of normal flora: Members of normal flora removed from the original inhabitancy into bloodstream or other tissues, these microbes may become pathogenic.
III. Suppression of normal flora: When some numbers of normal flora are killed or inhibited, it creates a partial local void that tends to be filled by exogenous microbes or microbes from other parts of the body. Such microbes behavior as opportunists and some of them may be pathogens.

34. Hospital acquired infections
(Nosocomial infections)

35. Hospital acquired infections specially indicate the opportunistic infections acquired during hospital stays. Formally, they are defined as infections arising after 48 hours of hospital admission.
Hospital acquired infections can be bacterial, viral, fungal or even parasitic. The most common pathogens include Staphylococci, Pseudomonas, Escherichia coli and Saccharomyces (fungus).
Most of microbes causing hospital acquired infections usually have a high resistance to antibiotics.
Prevention of hospital acquired infections includes personal hygiene (patients and hospital staff), a clean and sanitary environment in hospital, and complete sterilization of medical materials and equipments.

36. Generally, infection process caused by a bacterial pathogen involves the four steps as the following:
I. Adhesion
II. Penetration and spread
III. Survival and propagation in the host
IV. Tissue injury
Bacterial virulence is dependent on various virulent factors produced by bacteria.
Any bacterial factors involved in the four steps determine the virulence of bacteria.

37. i. Bacterial virulent factors
(Implying of Nature of bacterial species or strain)
In step I: Adhesion

38. BACTERIAL VIRULENCE FACTORS
Environmental signals often control the expression of the virulence genes.
Common signals include: Temperrature/Iron availability/low ion/ Osmolality/Growth phase/pH/Specific ions

39. The fist step of bacterial infection is the adhesion to a specific epithelial surface of the host.
Adhesion is a specific interaction and then a specific combination between adhesins (virulent factors) of bacteria and their receptors on the surface of host cells.
Adhesins include lipoteichoic acid (for G+), some of outer membrane proteins (for G-), ordinary pilus (for both) and so on.

40. Adhesion E. coli fimbriae receptor adhesin Type 1 Epithelium mannose P
Bacterium
fibronectin
lipoteichoic acid
F-protein
mannose
Type 1
galactose
glycolipids
glycoproteins P
E. coli fimbriae

41. i. Bacterial virulent factors In step II: Penetration and spread

42. After the adherence, the bacteria may entered into host cells.
Invasion is commonly used to describe the entry of bacteria into host cells, implying an active role for the organisms and a passive role for the host cells.
Invasion often occurs in mucosa of intestine, urinary tract and respiratory tract, and much less in skin.

43. 1. reside on epithelial surface for a few of bacteria
(e.g. Vibrio cholerae)
2. penetrate the epithelial barrier and invade host cells but remain in local tissues for a few of bacteria
(e.g. Shigella spp.).
3. pass into the bloodstream and/or from there spread into systemic sites including internal organs for many of bacteria
(e.g. Salmonella typhi spread into spleen and liver through bloodstream).

44. Invasive pathogen reach epithelial surface
pathogen produce hyaluronidase
Pathogens invade deeper tissues

45. Degradative enzymes
Collagenase: to destroy collagen. There are a lot of collagens in soft tissue including connective tissue.
Hyaluronidase: to destroy hyaluronic acid which is a major component in the matrix of connective tissue.
Coagulase: to coagulate fibrinogen in tissue fluid and plasma into fibrin. (to protect bacteria from damage by many agents)
Streptokinase/fibrinolysin: The former activates fibrinogenase to thrombin, which results in the degradation of fibrin. And the latter directly lyse fibrin.
Streptodornase: it is a DNase.
Cytolysins: 1) hemolysins (to dissolve red blood cells)
2) Leukocisins (to kill leukocytes or tissue cells )
In the invasion step, bacteria secrete certain degradative enzymes which can loosen the connective tissue matrix and help bacteria to penetrate the epithelial barriers.

46. i. Bacterial virulent factors
In step III: Survival and propagation in the host

47. After bacteria enter hosts, they must have anti- phagocyte ability for surviving. Surviving is a basis for further propagation of bacteria.
In human body fluids, there are phagocytes, antibody, complement and lysozyme, which can destroy extracellular bacteria.
Some of bacteria can produce anti-phagocyte factors.
Propagation: is the aim of bacteria entering hosts. On the other hand, only certain number for a bacterium can cause disease!!!

48. Antiphagocytic Substances
1. Polysaccharide capsules of S. pneumoniae, Haemophilus influenzae, Treponema pallidum ; B. anthracis and Klebsiella pneumoniae.
2. M protein and fimbriae of Group A streptococci
3. Surface slime (polysaccharide) produced as a biofilm by Pseudomonas aeruginosa
4. O polysaccharide associated with LPS of E. coli

49. Antiphagocytic Substances
5. K antigen (acidic polysaccharides) of E. coli or the analogous Vi antigen of Salmonella typhi
6. Cell-bound or soluble Protein A produced by Staphylococcus aureus. Protein A attaches to the Fc region of IgG and blocks the cytophilic (cell-binding) domain of the Ab. Thus, the ability of IgG to act as an opsonic factor is inhibited, and opsonin-mediated ingestion of the bacteria is blocked.

50. Protein A inhibits phagocytosis
Fc receptor
BACTERIUM
PHAGOCYTE
immunoglobulin
M protein inhibits phagocytosis
Complement
fibrinogen
M protein r
peptidoglycan

51. i. Bacterial virulent factors
In step IV: Tissue injury

52. Bacteria cause tissue injury by many factors or some special mechanisms involving:
Exotoxin
b) Endotoxin
c) Inducement of Immunopathological reaction

53. a) Exotoxin
Definition: Exotoxin is a toxic protein or polypeptide that is usually secreted by living bacteria.
Produced by many Gram+ and a few of Gram- bacteria.
Most of exotoxins have strong and specific toxicity and frequently cause acute infection and serious effects (e.g. death).
Antibody against exotoxin can neutralize the toxicity.
Exotoxins become toxoids after treatment with formaldehyde. Toxoids lose toxic properties but retains antigenicity, which can be used as vaccines to prevent the exotoxin-mediated disease.

54. Enterotoxin: cause food poisoning:
According to the differences of the target cells and acting mechanisms, exotoxins can be divided into three types:
Enterotoxin: cause food poisoning:
botulin, staphylococcal enterotoxin.
Nuerotoxin: Systematic toxic effects :
diphtheria, tetanus, and streptococcal erythrogenic toxins.
Cytotoxin: Local toxic effects :
cholera, and toxigenic E. coli enterotoxins.
These exotoxins will be discussed in detail in the sections of related bacteria
Antibodies (anti-toxins) neutralize
Vaccination

55. This child has diphtheria resulting in a thick gray coating over back of throat. This coating can eventually expand down through airway and, if not treated, the child could die from suffocation

56. neonatal tetanus patient displays sardonic smile, lockjaw and dyspnea
Severe case of adult tetanus. The muscles in the back and legs are very tight.
neonatal tetanus. It is completely rigid. Tetanus kills most of the babies who get it when newly cut umbilical cord is exposed to dirt. 56

57. ◆ Many exotoxins are called as A-B type toxins because they consist of A and B subunits.
A subunit provides the toxic activity.
B subunit generally mediates the toxin complex molecule to adhere and then enter the host cell.
Toxic
Binding A
Cell surface B

58. b) Endotoxins (LPS)
Endotoxin usually released by damaged G- bacteria because it is a structural component of the cell wall.
Endotoxin is general poisonous to all mammal cells but its toxicity is much lower than most of exotoxins.
The toxicity of LPS from different G- bacteria is similar.
Endotoxin can not become toxoids after treatment with formaldehyde.
Antibody against endotoxin can not neutralize the toxicity.

59. Pathophysiologic effects of LPS
LPS (endotoxin) has many pathophysiologic effects.
One of the effects is to cause inflammation by many different ways including:
Non-specific inflammation
cytokine release
complement activation
B cell mitogen, polyclonal B cell activator and adjuvant
Stimulation of marrow and blood vessels

60. Cytokine release
LPS are able to induce macrophage and neutrophilic leukocyte to synthesize and release cytokines such as interleukin 1 (IL-1), tumor necrosis factor (TNF), interferon (IFN) and so on.
These cytokines results in inflammation reaction

61. Complement activation
LPS is an activator of the complement cascade.
Certain complement by-products are the attractants for neutrophilic leukocyte.
On the other hand, in the absence of specific antibody, complement binding bacteria will encourage phagocytes to kill the target bacterial cells.

62. B cell mitogen, polyclonal B cell activator, & adjuvant
LPS is also a B cell mitogen, polyclonal B cell activator and adjuvant, which plays a role in the development of a suitable chronic immune response in handling the microbes if they are not eliminated acutely.

63. Stimulation of marrow and blood vessels
LPS acts on small blood vessels to increase the expression of adhering proteins to bind leukocytes in bloodstream.
LPS is a powerful activator to stimulate marrow to release leukocytes.
LPS has an effect to dilate small blood vessels.
LPS can also activate blood coagulation system to cause thrombus forming in small blood vessels.

64. Due to those pathophysiologic effects of LPS, the following major phenomenon can be observed clinically or experimentally:
a) Fever (LPS is a typical pyrogen)
b) Firstly leukopenia (binding to small blood vessels) and Secondly leukocytosis (marrow stimulation)
c) Shock (dilatation of small blood vessels)
d) DIC Disseminated intravascular coagulation (thrombus forming )
e) Death from massive organ dysfunction.

65. Major difference between endotoxin and exotoxin
Properties
Exotoxin
endotoxin
Origin
G+ and G- G-
Release
Secreted from living cells or released upon bacterial lysis
Released upon bacterial lysis
Composition
protein
LPS
Heat-resistance
Sensitive
resistance
Immunity
High, antitoxin, toxoid
Low, no toxoid
toxicity
High, tissue specificity
Low, no tissue specificity

66. c) Inducement of Immunopathological reaction
Human immune responses to bacteria may cause tissue injury by:
Over-stimulation of cytokine production and complement activation by endotoxin can cause tissue injury.
Continuously generated bacterial antigens will subsequently elicit humoral antibodies and cell mediated immunity, which resulting in chronic immunopathological injury.
Some of bacterial antigens (e.g., M protein of Streptococcus pyogenes) can cross-react with host tissue antigens. This bacterial antigens will cause the development of autoimmunity.

67. virulence invasiveness Virulence factors Adherence factor
Capsule and slime layer
Invasive enzyme
exotoxin
endotoxin

68. ii. Number of invaded bacteria iii. Route of bacteria invading hosts

69. Invaded number and invading route of bacteria
Number of invaded bacteria: 1)The more number of invaded bacteria, the stronger for pathogenecity; 2) diversity of different bacteria in number for pathogenicity (e.g., 50~100 cells of Vibro cholerae but 30,000~50,000 cells of Staphylococcus aureus can cause infectious diseases).
Route of bacteria invading host: For most of bacteria, they have specific invading routes (e.g. Clostridum tetani infects human through wounds and Mycobacterium tuberculosis has multiple invading routes to cause diseases).
As mentioned above, bacterial infectious disease is a multi factorial event which depends on Nature (virulence) of bacterial species and strain, Number of invaded bacteria and Route of bacteria invading host.

70. Summary
Concepts of virulence, normal flora, hospital acquired infection, latent infection, toxemia, septicemia, endotoxemia and pyemia.
The physiologic role of normal flora.
The conditions for generation of opportunistic infection.
The steps relative to bacterial infection.
The difference between exotoxin and endotoxin.
Virulence of bacteria.
Clinical characteristics of bacterial infections.