Pathogenesis

*If a microorganism is capable of causing disease, it is called a pathogen. *Some organisms are highly virulent and cause disease (even with a small inoculums). *Opportunistic organisms caused disease only in compromised individual (when their defences are weak) ( normal flora)

*Virulence can be measured by the no. of organisms required to case disease. LD50 {50%lethal dose} no. of M.O. needed to kill half the hostsID50 {50% infectious dose} no. of M.O. needed to cause infection in half the hosts.

Microbes and humans

Very few microbes are
always pathogenic
Many microbes are
potentially pathogenic
Most microbes are
never pathogenic


Some tissues, organs are dense with normal flora, others are normally sterile a. colonized sites i. Alimentary /intestinal tract ii. upper respiratory tract iii. distal genitourinary tract iv. skin b. normally sterile sites i. blood ii. CSF iii. interstitial fluid and spaces iv. lymph

Communicable disease:-

If the infections are spread from the host to host. Note:- Many but not all infections are communicableex: tuberculosis is communicable while staphylococcal food poisoning is not((exotoxin produced by staphylococcus affect only those eating that food while tuberculosis is spread by air born droplets produce by coughing))- Contagious disease:- if the disease is highly communicable e.g. ((chicken pox)).



Classification of infection according to the degree of incidence and prevalence of an infectious disease in a community:-
1. An endemic infection:- present at low level in a specific population e.g. endemic malaria in some African countries. 2. An epidemic infection:- if it occurs much more frequently than usual e.g. epidemic of influenza in the winter. 3. A pandemic if it has world wide distribution e.g. (HIV infection).


1. The incubation period {time between the acquisition of the m.o. or toxin and the commencement of the symptoms} (may vary from hrs. to days to weeks). 2. The prodormal period:- non-specific symptoms fever, malaise and loss of appetite appear during this periods  3. The acute specific illness:- the characteristic sign and symptoms of disease are evident during this period. 4. The recovery period:- the illness subsides and the patient return to health during this final phase.
Stages of an acute infection:-

Transmission

1- Exogenous:- transmission from external sources. 2- Endogenous:- caused by members of N.F. (opportunist pathogen)

Transmission can be by:-

Inhalation- the air born route Ingestion- fecal contamination of food and water. Inculcation-by sexual contact, contaminated needles, skin contact, blood transmission or biting insects .

There are four important portals of entery of pathogens:-

#Skin # Respiratory # Gastrointestinal tract # Genitourinary tract



Adherence to host surface

Invasiveness:

Play a critical role in pathogenesis, this property is upon secreted bacteria enzymes:- 1- Collagenase and hyaluronidase:- allowing easy spread of bacteria through tissues. e.g. Str. pyogenes caused skin infections. 2- Coagulase:- produced by Staph. aureus fibrinogen fibrin clot (it helps protect the organisms from phagocytosis by walling off infected area and by coating the organisms with a fibrin layer.


3- Immunogloblulin A(IgA) protease:- Degrades protective IgA on mucosal surface allowing organisms to adhere to mucous membranes e.g. N.gonorrhoeae,H.influenza &Str. pneumoniae. 4- Leucocidins:- Destroy both neutrophilic leucocytes and macrophages. e.g. the periodontopathic organisms (Actinobacillus actinomycetemcomitans)


The polysaccharide capsule:- such as Str. pneumoniae and N. meningitidis ((prevent the phagocyte from adhering to the bacteria)),. Note:- the vaccines against Str.pneumoniae and N.meningitidis contain capsular polysaccharides that induce protective anti capsular antibodies. The cell wall proteins of G+ cocci:- Such as M protein of group A Streptococci and protein A of staphylococci {are also anti phagocytic}
Factors also contribute to invasiveness by interfering with the host defence mechanisms, especially phagocytosis.


1- Pyogenic inflammation (pus-producing neutrophils is the predominant cells of this type of inflammation.) Str. pyoenes, Staph aureus and Str. pneumoniae 2- Granulomatous inflammation (granuloma-forming Macrophages and T cells, the predominante of this type.) e.g. M tuberculosis, here the bacterial antigens stimulate the cell mediated immune system resulting in sensitized T lymphocyte and macrophage activity.
Bacterial infection may lead to 2 categories of inflammation:-

Toxin of bacteria are classified as:

Endotoxin. Exotoxin. Note: Endotoxins ( L.P.S., g+ bacteria don not have endotoxins) but exotoxin can be produced by both G+ and G- bacteria, they are polypeptides
Attenuated exotoxins of bacteria are called toxoids; they are not toxic but are antigenic and hence used in protective vaccine

Biological effect of endotoxin due to factors produced by host as.

Interleukin 1 (IL1). Tumor necrosis factor(TNF) Cell wall component such as teichoic acid and P.G thought to trigger the release of IL1&TNF

*Fever *Hypotension, shock and reduced perfusion of major organs

Biological effect endotoxin include:


#Activation of the alternatives pathway of the complement cascade result in inflammation and tissue damage.
#Generalized activation of coagulation system . #Increase phagocytic activity of macrophages. #Increase anti body production.


*Are polypeptides. *These polypeptodes consist of 2 subunits: 1-One for binding to the cell membrane and entry into the cell. 2-Second possessing the toxic activity. *High toxic. *The toxicity of the polypeptides can be neutralized when treated with formaldehyde or acid or heat.
Exotoxin:

*Neurotoxins. *Enterotoxins. *Miscellaneous exotoxins.

Bacterial exotoxin can be classified as:

*Tetanus toxin. *Diphtheria toxin. *Botulinum toxin.

Neurotoxins:


*This toxin is producing by Cl. tetani. *This toxin prevent release of inhibitory neurotransmitter glycine, thus cause muscle spasms. *Tetanus toxin (tetanospasmin) comprises two polypeptide subunits:
Tetanus toxin:


*Heavy chain: bind to the gangliosides in the membrane of the neuron. *Light chain :the toxic component. The toxin is liberated at the peripheral wound site but transmitted to the neuron of the spinal cord either by retrograde axonal transport or in the blood stream.


* Is producing by Corynebacterium diphtheria. *Synthesized as a single polypeptide with two functional domains: One domain mediates the binding of the toxin to cell membrane receptors. Other domain possesses enzymatic activity and inhibits protein synthesis in all euokryotic cells. * Not:E.coli,V.cholera &Bordetella pertussis also produce exotoxin that act in similar manner.

Diphtheria toxin:

Botulinum toxin:

Enterotoxins:

The net result is fluid and electrolyte loss in the lumen of the cut (diarrhea). 2-The heat stable toxin of Esch. coli: *Not inactivated by boiling for 30 minutes. *Stimulate guanylate cyclase and thus increase the concentration of (cGMP) cyclic guanosine monophosphate, which inhibits the reabsorption of Na ions and causes diarrhea.



*Are produced by Cl. perfringens and other species of clostridia that cause gas gangrene.*These include:1-α toxin(aphospholipase or lecithinase)that hydrolyses (lecithin)&destroy eukaryotic cell membrane).2-Collagenase.3-Protease.4-Hyaluronidase.5-Deoxyribonuclease. (DNase). Miscellaneous exotoxins:

Table (1) Examples of surface virulence factors which interfere with host defenses.

Used in vaccine
Virulence factor
Organism
Bacteria
Yes
Polysaccharide capsule
Streptococcus pneumoniae
No
M protein
Streptococcus pyogenes
No
Protein A
Staphylococcus aureus
Yes
Polysaccharide capsule
Neisseria meningitidis
Yes
Polysaccharide capsule
Haemophilus influenzae
No
Polysaccharide capsule
Klebsiella pneumoniae
No
Protein pili
Escherichia coli
No
Polysaccharide capsule
Salmonella typhi
No
Mycolic acid cell wall
Mycobacterium tuberculosis

Disease

Pathogen
Portal of entry
Tetanus
Clostridium tetani
Skin
Hepatitis B
Hepatitis B virus
Pneumonia
Streptococcus pneumoniae
Respiratory tract
Meningitidis
Neisseria meningitidis
Meningitidis
Haemophilus influenzae
Tuberculosis
Mycobacterium tuberculosis
Influenza
Influenza virus
Common cold
Rhinovirus
Infectious mononucleosis
Epstein –Barr virus Dysentery
Shigella dysenteriae
Gastrointestinal tract
Typhoid fever
Salmonella typhi
Cholera
Vibrio cholerae
Infectious hepatitis
Hepatitis A virus
Poliomyelitis
Poliovirus
Gonorrhoea
Neisseria gonorrhoeae
Genital tract
Syphilis
Treponema pallidum
AIDS
Human immunodeficiency virus
Vaginitis
Candida albicans (fungus)
Table (2) Portals of entry of some common pathogens

Toxoid vaccine

Mode of action
Disease
Organism
Gram - positive
Yes
Elongation factor inactivated by ADP-ribosylation
Diphtheria
Corynbacterium diphtheriae
Yes
Tetanospasmin blocks release of the inhibitory neurotransmitter glycine at motor nerve ends
Tetanus
Clostridium tetani
No
Alpha-toxin – a lecithinase destroys eukaryotic cell membranes Gas gangrene
Clostridium perfringens
No
Binds to class II MHC protein; induces IL -1 band IL- 2
Toxic shock
Staphylococcus aureus
Gram - negative
No
Labile toxin stimulates adenylate cyclase by ADP-ribosylation; stable toxin stimulates guanylate cyclase
Diarrhoea
Escherichia coli
No
Stimulates adenylate cyclase by ADP-ribosylation
Cholera
Vibrio cholerae
No
Stimulates adenylate cyclase by ADP-ribosylation
Whooping cough
Bordetella pertussis
Table (3) Some important bacterial exotoxins and their mode of action