I. BACTERIAL PATHOGENESIS

C. VIRULENCE FACTORS THAT DAMAGE THE HOST

1. Producing Cell Wall Components (Pathogen-Associated Molecular Patterns or PAMPs) that Bind to Host Cells Causing them to Synthesize and Secrete Inflammatory Cytokines and Chemokines

a. An Overview

The overall purpose of this Learning Object is:
1) to introduce how various cells involved in body defenses are able to recognize conserved molecules common to many microbes and subsequently produce cytokines that initiate innate immune defenses such as the inflammatory response, the complement pathways, and the coagulation pathway;
2) to introduce how innate immune defenses such as the inflammatory response, the complement pathways, and the coagulation pathway work to remove microbes and protect the body; and
3) to introduce how innate immune defenses such as the inflammatory response, the complement pathways, and the coagulation pathway can be harmful to the body if there is an excessive production of cytokines.

LEARNING OBJECTIVES FOR THIS SECTION

In this section on Bacterial Pathogenesis we are looking at virulence factors that damage the host. Virulence factors that damage the host include:

1. The ability to produce cell wall components (Pathogen-Associated Molecular Patterns or PAMPs) that bind to host cells causing them to synthesize and secrete inflammatory cytokines and chemokines;

2. The ability to produce harmful exotoxins.

3. The ability to induce autoimmune responses.

We will now look at the ability of bacteria to produce cell wall components that bind to host cells and cause them to synthesize and secrete inflammatory cytokines and chemokines.

The Ability to Produce Cell Wall Components (Pathogen-Associated Molecular Patterns or PAMPs) that Bind to Host Cells causing them to Synthesize and Secrete Inflammatory Cytokines and Chemokines

a. An Overview

In order to protect against infection, one of the things the body must initially do is detect the presence of microorganisms. The body does this by recognizing molecules unique to microorganisms that are not associated with human cells. These unique molecules are called pathogen-associated molecular patterns (PAMPs). (Because all microbes, not just pathogenic microbes, possess PAMPs, pathogen-associated molecular patterns are sometimes referred to as microbe-associated molecular patterns or MAMPs.)

Molecules unique to bacterial cell walls, such as peptidoglycan monomers, teichoic acids, LPS, porins, mycolic acid, and mannose, are PAMPs that bind to pattern-recognition receptors (PRRs) on a variety of defense cells of the body causing them to synthesize and secrete a variety of proteins called cytokines (def). These cytokines can, in turn promote innate immune defenses such as inflammation, fever, and phagocytosis. The binding of PAMPs to PRRs also leads to activation of the complement pathways (def) and activation of the coagulation pathway (def).

Cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interleukin-8 (IL-8) are known as inflammatory cytokines (def) because they promote inflammation. Some cytokines, such as IL-8, are also known as chemokines (def). Chemokines promote an inflammatory response by enabling white blood cells to leave the blood vessels and enter the surrounding tissue, by chemotactically attracting these white blood cells to the infection site, and by triggering neutrophils (def) to release killing agents for extracellular killing.

 

At moderate levels, inflammation, products of the complement pathways, and products of the coagulation pathway are essential to body defense. However, these same processes and products when excessive can cause considerable harm to the body.

During minor local infections with few bacteria present, low levels of cell wall PAMPs are released leading to moderate cytokine production by defense cells such as monocytes, macrophages (def), and dendritic cells (def) and, in general, promoting body defense by stimulating inflammation and moderate fever, breaking down energy reserves to supply energy for defense, activating the complement pathway (def) and the coagulation pathway (def), and generally stimulating immune responses (see Fig. 1). Also as a result of these cytokines, circulating phagocytic white blood cells such as neutrophils (def) and monocytes stick to the walls of capillaries, squeeze out and enter the tissue, a process termed diapedesis (def). The phagocytic white blood cells such as neutrophils then kill the invading microbes with their proteases and toxic oxygen radicals. These defenses will be covered in greater detail in Units 4 and 5.

However, during severe systemic infections with large numbers of bacteria present, high levels of cell wall PAMPs are released resulting in excessive cytokine production by the defense cells and this can harm the body (see Fig. 2). In addition, neutrophils (def) start releasing their proteases and toxic oxygen radicals that kill not only the bacteria, but the surrounding tissue as well. Harmful effects include high fever, hypotension (def), tissue destruction, wasting, acute respiratory distress syndrome (ARDS) (def), disseminated intravascular coagulation (DIC) (def), and damage to the vascular endothelium. This can result in shock (def), multiple system organ failure (MOSF), and death.

YouTube animation illustrating macrophages releasing cytokines. Nucleus Medical Art, www. nucleusinc.com

 

 

Keep in mind that a primary function of the circulatory system is perfusion, the delivery of nutrients and oxygen via arterial blood to a capillary bed in tissue. This, in turn, delivers nutrients for cellular metabolism and oxygen for energy production via aerobic respiration to all of the cells of the body.

Sepsis is an infection that leads to a systemic inflammatory response resulting in physiologic changes occurring at the capillary endothelial level. This systemic inflammatory response is referred to as Systemic Inflammatory Response Syndrome or SIRS.

Based on severity, there are three sepsis syndromes based on severity:

1. Sepsis. SIRS in the setting of an infection.

2. Severe sepsis. An infection with end-organ dysfunction as a result of hypoperfusion, the reduced delivery of nutrients and oxygen to tissues and organs via the blood.

3. Septic shock. Severe sepsis with persistent hypotension (def) and tissue hypoperfusion (def) despite fluid resuscitation.

We will now take a look at the underlying mechanism of SIRS that can result in septic shock.

 

Systemic Inflammatory Response Syndrome (SIRS) Resulting in Septic Shock

During a severe systemic infection, an excessive inflammatory response triggered by overproduction of inflammatory cytokines such as TNF-alpha, IL-1, IL-6, IL-8, and PAF in response to PAMPs often occurs.

The release of inflammatory cytokines eventually leads to vasodilation of blood vessels. Vasodilation (def) is a reversible opening of the junctional zones between endothelial cells (def) of the blood vessels and results in increased blood vessel permeability. Normally, this fights the infection by enabling plasma, the liquid portion of the blood, to enter the surrounding tissue.The plasma (def) contains defense chemicals such as antibody molecules (def), complement proteins (def), lysozyme (def), and beta defensins (def). Increased capillary permeability also enables white blood cells to adhere to the inner capillary wall, squeeze out of the blood vessels, and enter the tissue to fight infection, a process called diapedesis (def).

Excessive productions of cytokines during a systemic infection results in the following events:

1.During diapedesis (def), phagocytic WBCs called neutrophils (def) adhere to capillary walls in massive amounts.

2. Prolonged vasodilation (def) and the resulting increased capillary permeability causes plasma (def) to leave the bloodstream and enter the tissue. Activation of the complement pathways and production of vasodilators such as C5a, C3a, prostaglandins, and leukotrienes further contributes to fluid loss.

Prolonged vasodilation also leads to decreased vascular resistance within blood vessels.

3. At high levels of TNF, vascular smooth muscle tone and myocardial contractility are inhibited.

Cytokine-induced overproduction of nitric oxide (NO) by cardiac muscle cells and vascular smooth muscle cells can also lead to heart failure.

4. Activation of the blood coagulation pathway can cause clots called microthrombi to form within the blood vessels throughout the body. This is called disseminated intravascular coagulation (DIC) (def).

5. In the lungs, the increased capillary permeability as a result of vasodilation in the lungs, as well as neutrophil-induced injury to capillaries in the alveoli (def) leads to acute inflammation, pulmonary edema (def), and loss of gas exchange in the lungs. Thiscondition is called acute respiratory distress syndrome (ARDS) (def).

6. In the liver, hypoperfusion (def) and capillary damage results in impaired liver function and a failure to maintain normal blood glucose levels.

7. Hypoperfusion can also leads to kidney and bowel injury.

8. The combination of hypotension (def), hypovolemia (def), DIC (def), ARDS (def), and the resulting hypoperfusion (def) leads to acidosis (def).

 

In summary, the release of excessive levels of inflammatory cytokines results in:

Collectively, this can result in :

For more on SIRS and Septic Shock, see Septic Shock.

 

Septicemia (def) is a condition where bacteria enter the blood and cause harm. There are approximately 750,000 cases of septicemia per year in the U.S. and the mortality rate is between 20% and 50%. Over 210,000 people a year in the U.S. die from septic shock. Approximately 45% of the cases of septicemia are due to gram-positive bacteria, 45% are a result of gram-negative bacteria, and 10% are due to fungi (mainly the yeast Candida).

 

We will now look at various bacterial cell wall components that lead to cytokine production, inflammation, and activation of the complement and coagulation pathways.

 

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Updated: Aug., 2012
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