Although the mechanism of infectious process may vary among bacteria, the methods by which bacteria cause disease can, in general, be divided into several stages (Figure 1). Pathogenicity of a microorganism depends on its success in completing some or all of these stages. The terms “virulence” and “pathogenicity” are often used interchange ably. However, virulence can be quantified by how many organisms are required to cause disease in 50 percent of those exposed to the pathogen (ID₅₀, where I = Infectious and D = Dose), or to kill 50 percent of test animals (LD₅₀, where L = Lethal). The number of organisms required to cause disease varies greatly among pathogenic bacteria. For example, less than 100 Shigella cause diarrhea by infecting the gastrointestinal (GI) tract, whereas the infectious dose of Salmonella is approximately 100,000 organisms. The infectious dose of a bacterium depends primarily on its virulence factors. The probability that an infectious disease occurs is influenced by both the number and virulence of the infecting organisms and the strength of the host immune response opposing infection.

Fig1. Mechanism of infectious process.

A. Virulence factors

Virulence factors are those characteristics of a bacterium that enhance its pathogenicity, that is, properties that enable a microorganism to establish itself and replicate on or within a specific host. Some of the more important steps in the infectious process are reviewed below.

1. Entry into the host: The first step of the infectious process is the entry of the microorganism into the host by one of several ports: via the respiratory, GI, or urogenital tract or through skin that has been cut, punctured, or burned. Once entry is achieved, the pathogen must overcome diverse host defenses before it can establish itself. These include phagocytosis; the acidic environments of the stomach and urogenital tract; and various hydrolytic and proteolytic enzymes found in the saliva, stomach, and small intestine. Bacteria that have an outer polysaccharide capsule (for example, Streptococcus pneumoniae and Neisseria meningitidis) have a better chance of surviving these primary host defenses.

2. Adherence to host cells: Some bacteria (for example, Escherichia coli) use pili to adhere to the surface of host cells. Group A streptococci have similar structures (fimbriae). Other bacteria have cell surface adhesion molecules or particularly hydrophobic cell walls that allow them to adhere to the host cell membrane. In each case, adherence enhances virulence by preventing the bacteria from being carried away by mucus or washed from organs with significant fluid flow, such as the urinary and the GI tracts. Adherence also allows each attached bacterial cell to form a microcolony. A striking example of the importance of adhesion is that of Neisseria gonorrhoeae in which strains that lack pili are not pathogenic .

 3. Invasiveness: Invasive bacteria are those that can enter host cells or penetrate mucosal surfaces, spreading from the initial site of infection. Invasiveness is facilitated by several bacterial enzymes, the most notable of which are collagenase and hyaluronidase. These enzymes degrade components of the extracellular matrix, providing the bacteria with easier access to host cell surfaces. Many bacterial pathogens express membrane proteins known as "invasins" that interact with host cell receptors, thereby eliciting signaling cascades that result in bacterial uptake by induced phagocytosis. Invasion is followed by inflammation, which can be either pyogenic (involving pus formation) or granulomatous (having nodular inflammatory lesions), depending on the organ ism. The pus of pyogenic inflammations contains mostly neutrophils, whereas granulomatous lesions contain fibroblasts, lymphocytes, and macrophages.

 4. Iron sequestering: Iron is an essential nutrient for most bacteria. To obtain the iron required for growth, bacteria produce iron-binding compounds, called siderophores. These compounds capture iron from the host by chelation, and then the ferrated siderophore binds to specific receptors on the bacterial surface. Iron is actively transported into the bacterium, where it is incorporated into essential compounds such as cytochromes. The pathogenic Neisseria species are exceptions in that they do not produce siderophores but instead utilize host iron-binding proteins, such as transferrin and lactoferrin, as iron sources. They do so by expressing dedicated receptors that bind to these host proteins and remove the iron for internalization.

5. Virulence factors that inhibit phagocytosis: The most important antiphagocytic structure is the capsule external to the cell wall, such as in S. pneumoniae and N. meningitidis. A second group of antiphagocytic factors are the cell wall proteins of gram-positive cocci, such as protein A of staphylococcus and M protein of group A streptococci .

6. Bacterial toxins: Some bacteria cause disease by producing toxic substances, of which there are two general types: exotoxins and endotoxin. Exotoxins, which are proteins, are secreted by both gram-positive and gram-negative bacteria. In contrast, endotoxin, which is synonymous with lipopolysaccharide (LPS), is not secreted but instead is an integral component of the cell walls of gram-negative bacteria.

a. Exotoxins: These include some of the most poisonous sub stances known. It is estimated that as little as 1 μg of tetanus exotoxin can kill an adult human. Exotoxin proteins generally have two polypeptide components (Figure 2). One is responsible for binding the protein to the host cell, and one is responsible for the toxic effect. In several cases, the precise target for the toxin has been identified. For example, diphtheria toxin is an enzyme that blocks protein synthesis. It does so by attaching an adenosine diphosphate–ribosyl group to human protein elongation factor EF-2, thereby inactivating it. Most exotoxins are rapidly inactivated by moderate heating (60o C), notable exceptions being staphylococcal enterotoxin and E. coli heat stable toxin (ST). In addition, treatment with dilute formaldehyde destroys the toxic activity of most exotoxins but does not affect their antigenicity. Formaldehyde-inactivated toxins, called toxoids, are useful in preparing vaccines . Exotoxin proteins are, in many cases, encoded by genes carried on plasmids or temperate bacteriophages. An example is the diphtheria exotoxin that is encoded by the tox gene of a temperate bacteriophage that can lysogenize Corynebacterium diphtheriae. Strains of C. diphtheriae that carry this phage are pathogenic, whereas those that lack the phage are nonpathogenic.

Fig2. Action of exotoxins. ADP = adenosine diphosphate; ADPR = adenosine diphosphate ribose; NAD+ = nicotinamide adenine dinucleotide.

b. Endotoxins: These are heat-stable, LPS components of the outer membranes of gram-negative (but not gram-positive) bacteria. They are released into the host’s circulation following bacterial cell lysis. LPS consists of polysaccharide composed of repeating sugar subunits (O antigen), which protrudes from the exterior cell surface; a core polysaccharide; and a lipid component called lipid A that is integrated into the outer leaflet of the outer membrane. The lipid A moiety is responsible for the toxicity of this molecule. The main physiologic effects of LPS endo toxin are fever, shock, hypotension, and thrombosis, collectively referred to as septic shock. These effects are produced indirectly by macrophage activation, with the release of cytokines, activation of complement, and activation of the coagulation cascade. Death can result from multiple organ failure. Elimination of the causative bacteria with antibiotics can initially exacerbate the symptoms by causing sudden massive release of endotoxin into the circulation. Although gram-positive bacteria do not contain LPS, their cell wall peptidoglycan and teichoic acids can elicit a shock syndrome similar to that caused by LPS but usually not as severe.

B. Host-mediated pathogenesis

 The pathogenesis of many bacterial infections is caused by the host response rather than by bacterial factors. Classic examples of host response–mediated pathogenesis are seen in diseases such as gram-negative bacterial sepsis, tuberculosis, and tuberculoid leprosy. The tissue damage in these infections is caused by various cytokines released from the lymphocytes, macrophages, and poly morphonuclear leukocytes at the site of infection or in the blood stream. Often the host response is so intense that host tissues are destroyed, allowing remaining bacteria to proliferate.

C. Antigenic variation

 A successful pathogen must evade the host’s immune system that recognizes bacterial surface antigens. One important evasive strategy for the pathogen is to change its surface antigens. This is accomplished by several mechanisms. One mechanism, called phase variation, is the genetically reversible ability of certain bacteria to turn off and turn on the expression of genes coding for surface antigens. A second mechanism, called antigenic variation, involves the modification of the gene for an expressed surface antigen by genetic recombination with one of many variable unexpressed DNA sequences. In this manner, the expressed surface antigen can assume many different antigenic structures .

D. Which is the pathogen?

Isolating a particular microorganism from infected tissue (for example, a necrotic skin lesion), does not conclusively demonstrate that it caused the lesion. The organism could, for example, be a harmless member of the normal skin flora  that happened to be in the vicinity. Alternatively, the organism may not be a natural resident of the skin but an opportunistic pathogen that secondarily infected the necrotic lesion. [Note: An opportunistic pathogen is an organism that is unable to cause disease in healthy, immunocompetent individuals but can infect people whose defenses have been impaired.] Robert Koch, a 19th century German microbiologist, recognized this dilemma and defined a series of criteria (Koch’s postulates) to con firm the causative microbial agent of a disease (Figure 3). [Note: Although these criteria has been successful in establishing the etiology of most infections, it fails if the causative organism cannot be cultured in vitro.]

Fig3. Koch’s postulates.

E. Infections in human populations

Bacterial diseases may be communicable from person to person or noncommunicable. For example, cholera is highly communicable (the disease-causing organism, Vibrio cholerae, is easily spread), whereas botulism is noncommunicable because only those people who ingest the botulinum exotoxin are affected. Highly communicable diseases, such as cholera, are said to be contagious and tend to occur as localized epidemics in which the disease frequency is higher than normal. When an epidemic becomes worldwide, it is called a pandemic. Pandemics, such as the 1918 influenza pan demic, arise because the human population has never been exposed to and, therefore, has no immunity against the specific strain of influenza virus.

مواضيع ذات صلة

The Growth Curve in Batch Culture

The Measurement of Microbial Concentrations

Distribution of Normal Flora in The Body

Cultivation of Bacillus and Similar Organisms

Diagnostic Laboratory Tests for Borrelia Burgdorferi

Bacterial Cell wall

Bacillus cereus

Bacillus anthracis

Antimicrobial Susceptibility Testing and Therapy for Streptococcus,Enterococcus, and Similar Organisms

Serodiagnosis Of Streptococcus,Enterococcus, and Similar Organisms

Approach To Identification of Streptococcus, Enterococcus, and Similar Organisms

Criteria For Identification of Bacteria