Bacterial Pathogenesis:
Pathogenesis is the combination of two words “Pathos” which mean disease and “Genesis” which means creation. The process by which a bacteria operate to produce diseased condition and clinical manifestations or sometimes produce structural and functional abnormalities is called bacterial pathogenesis.
Major Mechanisms:
There are three major mechanisms for the bacterial pathogenesis;
1. Invasion, Inflammation and intracellular survival.
2. Toxin production ( Exotoxin, Endotoxin )
3. Immunopathogenesis
Each of the above are explained in detail in the next paragraphs but here is the general overview.
» In invasion, inflammation method the bacterial invade a particular target of the host and release some enzymes causing inflammation and all this is for the reason to find the place for survival.
» In toxin production method bacteria may produce exotoxin or endotoxin to cause disease. The hundreds of peptides produced by bacterial cell starting and stopping different process while endotoxins are the lipopolysaccharides (LPS) of the gram negative bacteria in which lipid A is actually the causative agent for pathogenesis.
»In Immunopathogenesis, the body response badly to the presence of the foreigner agent and cause disease which may not be normally cause by that agent itself.
Stages of pathogenesis:
There are several stages of the bacterial pathogenesis, these are the steps which are generally followed by the bacteria to cause disease. The major of them are elaborated as under.
1. Transmission:
For a bacterial to cause disease it must be first transmitted to the host where it will produce infection where it will produce infection.
The infectious organisms may reserve in some particular area which may be animate or inanimate things called reservoir. A pathogen may be picked from the reservoir and transferred to the host.
Animate things: They are humans and animals
Inanimate things: They are nonliving things (Water, Soil, Food )
Sometimes insects like ticks, bugs and mosquitos are the transmission source of the disease. These are the special source of transmissions which themselves are not affected by the pathogen and cause the disease in the others are called carriers.
Disease that primary occurs in population of animals and transferred to human is called Zoonosis while other transferred from hospital acquired infection is known as nosocomial infection.
The mechanism by which a pathogen is picked up by a host is referred to as mode of transmission, with the main mechanisms listed below:
A. Direct contact:
It is host to host direct contact as kissing or sexual intercourse in which a person skin come in contact with other person’s skin or bodily fluid.
Sometimes mother can transmit disease to her infant by vertical transmission where she is pregnant or during birth.
B. Droplet transmission:
The disease causing agent may be transmitted through the respiratory droplets during sneezing or coughing. In case if a disease is highly communicable is called contagious disease.
C. Airborne transmission:
This transmission is due to small pathogens that are sometimes suspended in the air or move with air when it move from one place to another. In case of high risk social distancing is effective to prevent the spread of the disease.
D. Indirect transmission:
It involves the surface of the nonliving things, i.e. fomite which are inanimate things have pathogens on its surface and come in contact with the healthy person just by touching surfaces.
E. Carriers borne or vectorborne:
As mentioned earlier that it may be an insect, bug, tick or other mosquitos that are not themselves affected by the disease but cause disease in other by just transmitting the pathogen which is a causative agent of the disease.
2. Portals of entry of bacteria:
Some of the most important paths, way of passages for the bacteria to get entry to the human beings are the following:
A. Respiratory tract:
Some pathogens i.e. Streptococcus pneumonia and mycobacterium tuberculosis enter to the body through respiratory tract and cause infection in the target area.
B. Gastrointestinal tract:
Use any possible passage in the GIT. Some of the bacteria that enter through GIT are; Salmonella typhi and Shigella dysentriae etc.
C. Skin:
For many reason, skin is the most dangerous and easy way of bacterial to get entry especially during a little injury, abrasion or cut because there is a chance of bacteria to get way to enter blood which is then called septicemia and consider a lethal condition. Some bacterial that enter through the skin are; Closteridium tetani and Rickettsia recketsii etc.
D. Genital tract:
It include all the genital organs of the male and female, which may cause the disease by allowing bacterial pathogen to enter the body.
E.g. Neisseria gonorrhea and Treponema palladium.
3. Adherence to the cell:
For a bacteria to cause disease it must be first attached to the cell. For this purpose, it may use its polysaccharide layer such as capsule or glycocalyx while other time it may be specialized structure of attachment called pili. E.g. Pili of Neisseria gonorrhea. The other chemicals that cause the adhesion of the bacteria to the cell are called adhesins.
After the attachment of bacteria takes place it may produce a protective layer around itself called biofilm which protect bacteria from both antibiotic and neutrophils as well.
4. Invasion and inflammation:
As we mentioned earlier that there are three mechanisms of bacterial pathogenesis, it is the first of the three mechanism by which a bacteria cause disease.
Invasion refers to the ability of the pathogen to spread to other locations in the host, by invading host cells or tissue. It is typically at this point when disease or obvious signs/symptoms of illness will occur. Among the most prominent methods for invasion and inflammation are;
A. Collagenase and Hyaluronidase production:
These enzymes produced by the bacteria cause to degrade collagen and Hyaluronic acid respectively allowing bacteria to spread through subcutaneous tissues, connective tissues.
B. Coagulase production.
It is another factor produced by bacteria such as streptococcus aurous and cause the formation of fibrin clot around the organism for its protection.
C. Immunoglobulin protease production:
Some bacteria produced enzymes that degrade antibodies of the host cell making them unable to attack on bacteria such as Neisseria gonorrhea, Homophiles influenza and Streptococcus pneumonia that produced IgA and IgG protease that result in the degradation of the respective immunoglobulins.
D. Stopping phagocytosis:
Some bacteria produce chemicals that make the phagocyte unable to engulf the bacteria.
• The most important one is capsule of the bacteria i.e. Neisseria manigetidis and Streptococcus pneumonia.
• Some bacteria from gram positive group have M protein in their cell wall which is antiphagocytic.
• In bacterial cell wall there is protein A which combine with the immunoglobulin G (IgG) of the host cell and stop the phagocytic process.
E. Leukocidins production:
Leukocidins are special protein produced by bacteria which form pores in the membranes of macrophages and neutrophils and cause inflammations. Two different types of inflammations are caused by bacteria.
• Pyogenic inflammation: It is pus formic inflammation where neutrophils are predominant.
• Granulomatous inflammation: It is cause after the destruction of bacteria by macrophages, so we can say that macrophages are predominant in this type of inflammation.
5. Intracellular Survival:
Bacteria use different mechanisms for the intracellular survival, some of the crucial are given as under.
A. As normally bacteria or other foreigner agent is phagocytized and then fused with lysosomes for its destruction while in this case the mechanism by which phagosome is fused with the lysosome is inhibited.
B. Inhibition of acidification of phagosomes which contain different degradative enzymes.
C. Escape from phagosomes into the cytoplasm where, there are no degradative enzymes to destroy the bacteria.
E.g. Mycobacterium and Leginella use the first and second mechanism while the Listeria specie use the third mechanism to live in intracellular environment.
6. Toxin production:
Toxins are a very specific virulence factor produced by some bacterial pathogens, in the form of substances that are poisonous to the host. Toxigenicity refers to an organism’s ability to make toxins. For bacteria, there are two categories of toxins, the exotoxins and the endotoxins.
A. Exotoxins:
They are polypeptides whose genes are located on the plasmid or lysogenic bacterial virus such as bacteriophage. These incredibly potent substances can spread throughout the host’s body, causing damage distant from the original site of infection. There are many gram +ve and gram –ve bacteria that release exotoxins causing diseases such as Botulism, diphtheria and Tetanus etc.
Major types of Exotoxins:
i. Type I (Surface Active)
These toxins attach to some receptors activating or inhibiting it. I.e. In case of cholera the GCPR is activated while cause the continuous opening of the channels resulting in the massive fluid loss.
Cholera toxins >>>>> Watery diarrhea
They sometimes stimulate T cells signaling molecules “cytokines” are produced in excessive amount from T cell causing tissue damage and massive inflammation.
ii. Type II :
These toxins produce pores in the cell membrane of host cell resulting cell lysis, inflammation and pain receptors activation.
iii. Type III :
The third and most complex and important one is the intracellular type which has two subunits. Subunit A and Subunit B. Subunit-A has toxic activity while Subunit-B has binding ability and will find the correct place to bind with.
General example of Exotoxin action:
Tetanus toxin from Closteridium tetani once delivered to neuron, the A subunit will cleave the cellular synaptobreven resulting in a decrease neurotransmitter release. This result in septic paralysis of the host. Each AB toxin is associated with a different disease.
Secretion System:
Exotoxins are released by bacteria through special structure called secretion systems. Some of them transfer exotoxins to the extracellular space while others transport them directly to the mammalian cell and this category is much more effective.
Six different secretion system are yet identified of which the secretion system III is most important, sometimes called Injectosomes. Secretion of this exotoxin is carried out by needle like projection that mediate its secretion.
i. Gram +ve Exotoxin mechanisms:
Some gram positive bacteria which are far more common, have the following mechanism of action.
• Inhibiting protein synthesis by inactivating EF-2 protein.
• Toxic shock syndrome toxin (TSST) cause the release of high quantity of cytokines from helper T cells and macrophages.
All of the above mentioned toxins have their own pathophysiology.
ii. Gram –ve Exotoxin mechanism:
Two very important exotoxin produced by from –ve bacteria are;
• Enterotoxin: Produce by E.coli and V.Cholera (Cholera toxin) cause rising the amount of cyclic AMP in the enterocytes regulating watery diarrhea.
• Shigella toxin: Produce by E.coli cause bloody diarrhea and are cause of outbreak associated with undercooked meat. This toxin is named due to similarity with toxin produced by Shigella dysentriae.
• Perthssis toxin: produced by B.pertussis which cause whooping cough. Catalyze the transfer of ADP ribose from NAD to inhibitory G protein. Inactivation of this inhibitory regulator has two effects. One is to stimulate adenylyl cyclase activity cause rise in cyclic AMP while other is to block the signal transduction pathway.
B. Endotoxins:
Endotoxins are only produced by gram –ve bacteria as actually the outer membrane of it. The chemical nature of the endotoxin is Lipopolysaccharide (LPS) which is combination of Lipid A and O antigen. The pathogenic effect of the endotoxin is produced by Lipid A.
LPS acts as the prototypical endotoxin because it binds the CD14/TLR4/MD2 receptor complex in many cell types, but especially in monocytes, dendritic cells, macrophages and B cells, which promotes the secretion of pro-inflammatory cytokines, nitric oxide, and eicosanoids.
The important thing about the lipid A is that it produce the same effect regardless of type of bacteria that produce it. The more highlighted effects produced by endotoxins are:
• Fever
• Diarrhea
• Weakness
• Blood coagulation
• Endotoxin shock
• Autoimmune diseases
• Obesity
In above all the endotoxemia, endotoxin in blood cause septic shock, is most dangerous and can suddenly cause death.
Endotoxin may work on any of the following three major mechanisms.
a) Activate macrophage: It activate macrophages to release;
i. Interleukin -1 (IL1) cause fever.
ii. Tumor Necrosis Factor (TNF) cause fever and hypotension.
iii. Nitric oxide which dilate blood vessel cause hypotension.
b) Activate Complement system: Release of the following chemical occurs;
i. C3A cause hypotension and edema.
ii. C5A cause neutrophil chemotaxis.
c) Activate Tissue Factor: Activation of tissue factors cause coagulation cascade to start.
I.e. Disseminated Intravascular coagulation (DIC).
7. Immunopathogenesis:
Sometimes the organisms which invade host does not cause symptoms of disease itself but the
Immune system response to the presence of the external agent cause the disease. The most general and famous example of this response is the Rheumatic fever in which antibodies are formed against M-Protein of Streptococcus pyogenes but unfortunately it cross react with the joints, heart and brain tissue and damage them. Inflammation occurs resulting in the arthritis, cardiatis and Cholera that are similar to findings of a disease.
By: Shaheed Ullah Khyber Medical University Peshawar. (KMU)
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