1. Host-pathgen relations
Introduction:
The pathogenesis of bacterial infection includes initiation of the infectious process and the mechanisms that lead to the development of signs and symptoms of disease. Characteristics of bacteria that are pathogens include transmissibility, adherence to host cells, invasion of host cells and tissues, toxigenicity, and ability to evade the host's immune system. Many infections caused by bacteria that are commonly considered to be pathogens are inapparent or asymptomatic.

2. Adherence (adhesion, attachment):
The process by which bacteria stick to the surfaces of host cells. Once bacteria have entered the body, adherence is a major initial step in the infection process.
Carrier: A person or animal with asymptomatic infection that can be transmitted to another susceptible person or animal.
Infection: Multiplication of an infectious agent within the body. Multiplication of the bacteria that are part of the normal flora of the gastrointestinal tract, skin, etc, is generally not considered an infection; on the other hand, multiplication of pathogenic bacteria (eg, Salmonella species)—even if the person is asymptomatic––is deemed an infection.

3. Invasion: The process whereby bacteria, animal parasites, fungi, and viruses enter host cells or tissues and spread in the body.
Nonpathogen: A microorganism that does not cause disease; may be part of the normal flora.
Opportunistic pathogen: An agent capable of causing disease only when the host's resistance is impaired (ie, when the patient is "immunocompromised").
Pathogen: A microorganism capable of causing disease.
Pathogenicity: The ability of an infectious agent to cause disease.
Toxigenicity: The ability of a microorganism to produce a toxin that contributes to the development of disease.
Virulence: The quantitative ability of an agent to cause disease. Virulent agents cause disease when introduced into the host in small numbers. Virulence involves invasion and toxigenicity

4. Normal Microbial Flora of the Human Body
The term "normal microbial flora" denotes the population of microorganisms that inhabit the skin and mucous membranes of healthy normal persons. It is doubtful whether a normal viral flora exists in humans.
The skin and mucous membranes always harbor a variety of microorganisms that can be arranged into two groups: (1) The resident flora consists of relatively fixed types of microorganisms regularly found in a given area at a given age; if disturbed, it promptly reestablishes itself (2) The transient flora consists of nonpathogenic or potentially pathogenic microorganisms that inhabit the skin or mucous membranes for hours, days, or weeks; it is derived from the environment, does not produce disease, and does not establish itself permanently on the surface. Members of the transient flora are generally of little significance so long as the normal resident flora remains intact. However, if the resident flora is disturbed, transient microorganisms may colonize, proliferate, and produce disease.

5. Transmission of Infection
Microorganisms can be transmitted from environment (human or animals) and affected another host by aerosol route, oral route, or nosocomial infection and urogenital route these processes can be occurred by several ways:
1- direct contact from infected animal to susceptible person (zoonotic disease). Like Bacillus anthracis (caused anthrax).
2- rodents borne disease like Yersinia pestis.
3- nosocomial disease by hand personal.

6. The Infectious Process
Once in the body, bacteria must attach or adhere to host cell, usually epithelial cells. After the bacteria have established a primary site of infection, they multiply and spread directly through tissues or via the lymphatic system to the bloodstream. This infection (bacteremia) can be transient or persistent. Bacteremia allows bacteria to spread widely in the body and permits them to reach tissues particularly suitable for their multiplication.
Pneumococcal pneumonia is an example of the infectious process. S pneumoniae can be cultured from the nasopharynx of 5–40% of healthy people. Occasionally, pneumococci from the nasopharynx are aspirated into the lungs

7. Adherence Factors
Once bacteria enter the body of the host, they must adhere to cells of a tissue surface. If they did not adhere, they would be swept away by mucus and other fluids that bathe the tissue surface. Adherence, which is only one step in the infectious process, is followed by development of microcolonies and subsequent steps in the pathogenesis of infection. The interactions between bacteria and tissue cell surfaces in the adhesion process are complex. Several factors play important roles: surface hydrophobicity and net surface charge, binding molecules on bacteria (ligands), and host cell receptor interactions. Bacteria and host cells commonly have net negative surface charges and, therefore, repulsive electrostatic forces. These forces are overcome by hydrophobic and other more specific interactions between bacteria and host cells. Bacteria also have specific surface molecules that interact with host cells. Many bacteria have pili, hair-like appendages that extend from the bacterial cell surface and help mediate adherence of the bacteria to host cell surfaces. For example, some E coli strains have type 1 pili, which adhere to epithelial cell receptors containing D-mannose; adherence can be blocked in vitro by addition of D-mannose to the medium. E coli organisms that cause urinary tract infections commonly do not have D-mannose-mediated adherence but have P-pili, which attach to a portion of the P blood

8. Therefore the important adherence factors include:
1- capsule
2-pili like P pili of E.coli
3- interaction between bacterial cell components (ligands) and specific host receptors.
4- different charges between bacterial surface and host cell surface (electrostatic force)

9. Invasion of Host Cells & Tissues
For many disease-causing bacteria, invasion of the host's epithelium is central to the infectious process. Some bacteria (eg, salmonella species) invade tissues through the junctions between epithelial cells. Other bacteria (eg, yersinia species, N gonorrhoeae, Chlamydia trachomatis) invade specific types of the host's epithelial cells and may subsequently enter the tissue. Once inside the host cell, bacteria may remain enclosed in a vacuole composed of the host cell membrane, or the vacuole membrane may be dissolved and bacteria may be dispersed in the cytoplasm. Some bacteria (eg, shigella species) multiply within host cells, whereas other bacteria do not.

10. "Invasion" is the term 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. In many infections, the bacteria produce virulence factors that influence the host cells, causing them to engulf (ingest) the bacteria. The host cells play a very active role in the process.
Toxin production and other virulence properties are generally independent of the ability of bacteria to invade cells and tissues. For example, Corynebacterium diphtheriae is able to invade the epithelium of the nasopharynx and cause symptomatic sore throat even when the C diphtheriae strains are nontoxigenic.

11. M cells normally sample antigens and present them to macrophages in the submucosa. Shigellae are phagocytosed by the M cells, pass through the M cells, and escape killing by macrophages.
L monocytogenes from the environment is ingested in food. Presumably, the bacteria adhere to and invade the intestinal mucosa, reach the bloodstream, and disseminate. The pathogenesis of this process has been studied in vitro. L monocytogenes adheres to and readily invades macrophages and cultured undifferentiated intestinal cells. The listeriae induce engulfment by the host cells.

12. Toxins
Toxins produced by bacteria are generally classified into two groups: exotoxins and endotoxins.
Exotoxins
Many gram-positive and gram-negative bacteria produce exotoxins of considerable medical importance. Some of these toxins have had major roles in world history. For example, tetanus caused by the toxin of C tetani killed as many as 50,000 soldiers of the Axis powers in World War II. Many exotoxins consist of A and B subunits. The B subunit generally mediates adherence of the toxin complex to a host cell and aids entrance of the exotoxin into the host cell. The A subunit provides the toxic activity.
C botulinum causes botulism. It is found in soil or water and may grow in foods (canned, vacuum-packed, etc) if the environment is appropriately anaerobic. An exceedingly potent toxin (the most potent toxin known) is produced. It is heat-labile and is destroyed by sufficient heating.

13. Some S aureus strains growing on mucous membranes or in wounds, elaborate toxic shock syndrome toxin-1 (TSST-1), which causes toxic shock syndrome. The illness is characterized by shock, high fever, and a diffuse red rash that later desquamates; multiple other organ systems are involved as well. TSST-1 is a super antigen and stimulates lymphocytes to produce large amounts of IL-1 and TNF. The major clinical manifestations of the disease appear to be secondary to the effects of the cytokines. TSST-1 may act synergistically with low levels of lipopolysaccharide to yield the toxic effect.

14. Lipopolysaccharides of Gram-Negative Bacteria
The lipopolysaccharides (LPS, endotoxin) of gram-negative bacteria are derived from cell walls and are often liberated when the bacteria lyse. The substances are heat-stable, have molecular weights between 3000 and 5000 (lipooligosaccharides, LOS) and several million (lipopolysaccharides), and can be extracted (eg, with phenol-water).
The pathophysiologic effects of LPS are similar regardless of their bacterial origin except for those of bacteroides species, which have a different structure and are less toxic. LPS in the bloodstream is initially bound to circulating proteins which then interact with receptors on macrophages and monocytes and other cells of the reticuloendothelial system. IL-1, TNF, and other cytokines are released, and the complement and coagulation cascades are activated. The following can be observed clinically or experimentally: fever, leukopenia, and hypoglycemia; hypotension and shock resulting in impaired perfusion of essential organs (eg, brain, heart, kidney); intravascular coagulation; and death from massive organ dysfunction.

15. Differences between exo and end
endotoxin
exotoxin
proberty
Bacterial chromosome
Plasmid or bacteriophage
Gene location
lps
proteins
composition
Non specific fever and shock
specific
Action
Stable at 100 C° for 1 hr
Labile destroyed at 60C°
Heat stability No
yes
diffusibility
Weak
Strong
Antigenicity
Toxicity no
Yes
Convertibility to toxoid
Gram -ve
Mainly G+ve
Produced by

16. Peptidoglycan of Gram-Positive Bacteria
The peptidoglycan of gram-positive bacteria is made up of cross-linked macromolecules that surround the bacterial cells. Vascular changes leading to shock may also occur in infections due to gram-positive bacteria that contain no LPS. Gram-positive bacteria have considerably more cell wall-associated peptidoglycan than do gram-negative bacteria. Peptidoglycan released during infection may yield many of the same biologic activities as LPS, though peptidoglycan is invariably much less potent than LPS.

17. Enzymes
Many species of bacteria produce enzymes that are not intrinsically toxic but do play important roles in the infectious process for examples : -
Tissue-Degrading Enzymes
Many bacteria produce tissue-degrading enzymes. The best-characterized are enzymes from C perfringens), S aureus , group A streptococci , and, to a lesser extent, anaerobic bacteria. The roles of tissue-degrading enzymes in the pathogenesis of infections appear obvious but have been difficult to prove, especially those of individual enzymes. For example, antibodies against the tissue-degrading enzymes of streptococci do not modify the features of streptococcal disease.
In addition to lecithinase, C perfringens produces the proteolytic enzyme collagenase, which degrades collagen, the major protein of fibrous connective tissue, and promotes spread of infection in tissue.

18. S aureus produces coagulase, which works in conjunction with serum factors to coagulate plasma. Coagulase contributes to the formation of fibrin walls around staphylococcal lesions, which helps them persist in tissues. Coagulase also causes deposition of fibrin on the surfaces of individual staphylococci, which may help protect them from phagocytosis or from destruction within phagocytic cells.
Hyaluronidases are enzymes that hydrolyze hyalouronic acid, a constituent of the ground substance of connective tissue. They are produced by many bacteria (eg, staphylococci, streptococci, and anaerobes) and aid in their spread through tissues.

19. IgA1 Proteases
Immunoglobulin A is the secretory antibody on mucosal surfaces. It has two primary forms, IgA1 and IgA2, that differ near the center, or hinge, region of the heavy chains of the molecules. IgA1 has a series of amino acid in the hinge region that are not present in IgA2. Some bacteria that cause disease produce enzymes, IgA1 proteases, that split IgA1 at specific proline-threonine or proline-serine bonds in the hinge region and inactivate its antibody activity. IgA1 protease is an important virulence factor of the pathogens N gonorrhoeae, N meningitidis, H influenzae, and S pneumoniae. .

20. Antiphagocytic Factors
Many bacterial pathogens are rapidly killed once they are ingested by polymorphonuclear cells or macrophages. Some pathogens evade phagocytosis or leukocyte microbicidal mechanisms by adsorbing normal host components to their surfaces. For example, S aureus has surface protein A, which binds to the Fc portion of IgG. Other pathogens have surface factors that impede phagocytosis—eg, S pneumoniae, N meningitidis; many other bacteria have polysaccharide capsules. S pyogenes (group A streptococci) has M protein. N gonorrhoeae (gonococci) has pili. Most of these antiphagocytic surface structures show much antigenic heterogeneity. For example, there are more than 90 pneumococcal capsular polysaccharide types and more than 80 M protein types of group A streptococci. Antibodies against one type of the antiphagocytic factor (eg, capsular polysaccharide, M protein) protect the host from disease caused by bacteria of that type but not from those with other antigenic types of the same factor.
A few bacteria (eg, capnocytophaga and bordetella) produce soluble factors or toxins that inhibit chemotaxis by leukocytes and thus evade phagocytosis by a different mechanism.

21. Intracellular Pathogenicity
Some bacteria (eg, M tuberculosis, brucella species, and legionella species) live and grow in the hostile environment within polymorphonuclear cells, macrophages, or monocytes. The bacteria accomplish this feat by several mechanisms: They may avoid entry into phagolysosomes and live within the cytosol of the phagocyte; they may prevent phagosome-lysosome fusion and live within the phagosome; or they may be resistant to lysosomal enzymes and survive within the phagolysosome.

22. Antigenic Heterogeneity
The surface structures of bacteria (and of many other microorganisms) have considerable antigenic heterogeneity. Often these antigens are used as part of a serologic classification system for the bacteria. The classification of the 2000 or so different salmonellae is based principally on the types of the O (lipopolysaccharide side chain) and H (flagellar) antigens. Similarly, there are more than 100 E coli O types and more than 100 E coli K (capsule) types. The antigenic type of the bacteria may be a marker for virulence, related to the clonal nature of pathogens .

23. Quiz