Pathogenesis of bacterial infection Overview The pathogenesis of

Pathogenesis of bacterial infection

Overview • 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. • Pathogenic bacteria: the bacteria that have evolved specific virulence factors that allow them to multiply in their host or vector without being killed or expelled by the host's defenses. • Opportunistic pathogen: An agent capable of causing disease only when the host’s resistance is impaired (ie, when the patient is “immunocompromised”). • Infection: Multiplication of an infectious agent within the body. Multiplication of the bacteria that are part of the normal flora is generally not considered an infection.

TRANSMISSION OF INFECTION • Bacteria (and other microorganisms) can adapt to a variety of environments that include external sources such as soil, water and organic matter or internal milieu as found within insect vectors, animals and humans • Microorganisms that normally live in people enhance the possibility of transmission from one person to another. • Example : Neisseria meningitidis, colonize the uperresepratory tract of healthy individual and transmit to another host via aerosols. • The bacteria in some cases can overcome the immune system and invade the body to cause either bacteremia or meningitidis

• Some bacteria that commonly cause disease in humans exist primarily in animals and incidentally infect humans. • For example, Salmonella and Campylobacter species typically infect animals and are transmitted in food products to humans. • The Clostridium species are ubiquitous in many environmental sources and are transmitted to humans by ingestion (eg, C perfringens gastroenteritis and C. botulinum [botulism]) or when wounds are contaminated by soil (eg, C perfringens [gas gangrene] and C tetani [tetanus]). • Clostridium species elaborate spores to protect the organisms from harsh environmental factors such as ultraviolet light, desiccation, chemical detergents, and p. H extremes. So it can survive in the extreme conditions • After being ingested or inoculated, the spores germinate into the vegetative, metabolically active form of the pathogen

• Many opportunistic pathogens that cause nosocomial infections are transmitted from one patient to another on the hands of hospital personnel. o A person with S. aureus carriage in the anterior nares may rub his nose, pick up the staphylococci on the hands, and spread the bacteria to other parts of the body • The clinical manifestations of diseases (eg, diarrhea, cough, genital discharge) produced by microorganisms often promote transmission of the agents. • Examples: o Vibrio cholerae can cause voluminous diarrhea, which may contaminate salt and fresh water; drinking water or seafood may be contaminated; o ingestion of contaminated water or seafood can produce infection and disease

THE INFECTIOUS PROCESS • 1 - Colonisation : • The infection begin when the bacteria successfully enter the body, grow and multiply • Pathogens usually colonize host tissues that are in contact with external environment • The entrance generally occur through mucosa or orifices such as oral cavity, nose, eyes, genetalia, anus, or the through the open wounds • The entrance is followed by adherence of the bacteria to host cells, usually epithelial cells. • Organisms that infect these regions have usually developed tissue adherence mechanisms and some ability to overcome host defense mechanisms at the surface. • .

2. Invasion • After the successful colonization of bacteria, they multiply and then invade the body by spreading through tissues or via the lymphatic system to the bloodstream and cause bacteremia • 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. • Most bacterial pathogens do not invade cells, proliferating instead in the extracellular environment enriched by body fluids. • Sme bacteria survive intracellularly within the body cells such as macrophage and are shielded from humoral antibodies and can be eliminated only by a cellular immune response. • these bacteria must possess specialized mechanisms to protect them from the harsh effects of the lysosomal enzymes encountered within the cell

• Some of bacteria (e. g. , V. cholerae ) do not enetrate body tissues or cells, but, rather, adhere to epithelial surfaces and cause disease by secreting potent protein toxins. • The infectious process in cholera involves ingestion of V cholerae, chemotactic attraction of the bacteria to the gut epithelium, motility of the bacteria by a single polar flagellum, and penetration of the mucous layer on the intestinal surface. • The V cholerae adherence to the epithelial cell surface is mediated by pili and possibly other adhesins. Production of cholera toxin, causing diarrhea and electrolyte imbalance

BACTERIAL VIRULENCE FACTORS • Many factors determine bacterial virulence or the ability to cause infection and disease • These factors icnlude:

Adherence Factors • To cause infection, many bacteria must first adhere to a mucosal surface • Without adherence, they would be swept away by mucus and other fluids that bathe tissue surface. • Adherence, is followed by development of microcolonies and subsequent steps in the pathogenesis of infection. • bacterial adherence or attachment to a eucaryotic cell or tissue surface requires the participation of two factors: a receptor and a ligand. • The receptors : specific carbohydrate or peptide residues on the eucaryotic cell surface. • The bacterial ligand, called an adhesin, is a macromolecular component of the bacterial cell surface which interacts with the host cell receptor.

• Adhesins and receptors interact in a complementary and specific fashion with specificity comparable to antigen-antibody reactions. • Many bacteria have pili, thick rodlike appendages or fimbriae, shorter “hairlike” structures that extend from the bacterial cell surface and help mediate adherence of the bacteria to host cell surfaces. • For example • N gonorrhoeae uses pili as primary adhesins and opacity associated proteins (Opa) as secondary adhesins to host cells. • Certain Opa proteins mediate adherence to polymorphonuclear cells. Some gonococci survive after phagocytosis by these cells. • Group A streptococci (Streptococcus pyogenes) have fimbriae, • Lipoteichoic acid, protein F, and M protein are found • on the fimbriae. • The lipoteichoic acid and protein F cause adherence of the streptococci to epithelial cells

invasion virulence factors I. Toxins • Toxins produced by bacteria are generally classified into two groups: exotoxins and endotoxins.

i. Exotoxins: • Are proteins that are most often excreted from the cell. • However some exotoxins accumulate inside the cell and are either injected directly into the host or are released by cell lysis • These toxins are produced by Many gram positive and gramnegative bacteria • can be grouped into several categories (e. g. , neurotoxins, cytotoxins, and enterotoxins) based on their biologic effect on host cells.

• Neurotoxins: are exemplified by the toxins produced by Clostridium spp. • for example, the botulinum toxin formed by C. botulinum. • This neurotoxin acts on motor neurons by preventing the release of acetylcholine at the myoneural junctions, thereby preventing muscle excitation and producing flaccid paralysis. • Cytotoxins: constitute a larger, more heterogeneous grouping with a wide array of host cell specificities and toxic manifestations. • One cytotoxin is diphtheria toxin, which is produced by Corynebacterium diphtheriae. • This cytotoxin inhibits protein synthesis in many cell types by catalyzing the ADP-ribosylation of elongation factor II, which blocks elongation of the growing peptide chain

• Enterotoxins: stimulate hypersecretion of water and electrolytes from the intestinal epithelium and thus produce watery diarrhea. • Some enterotoxins are cytotoxic (e. g. , shiga-like enterotoxin from E. coli), while others perturb eukaryotic cell functions and are cytotonic (e. g. , cholera toxin). • Enterotoxins also can disturb normal smooth muscle contraction, causing abdominal cramping and decrease transit time for water absorption in the intestine

ii. Endotoxin is comprised of toxic lipopolysaccharide components of the outer membrane of Gram-negative bacteria. • It is released after lysis of bacteria and it exerts profound biologic effects on the host and may be lethal • Because it is omnipresent in the environment, endotoxin must be removed from all medical supplies destined for injection or use during surgical procedures. •

• The molecular complex can be divided into three regions • (1) the O-specific chains, which consist of a variety of repeating oligosaccharide residues, • (2) the core polysaccharide that forms the backbone of the macromolecule, • (3) lipid A, composed usually of a glucosamine disaccharide with attached long-chain fatty acids and phosphate. • The polysaccharide portions are responsible for antigenic diversity, whereas the lipid A moiety confers toxicity.

Pathophysiologic Effects Of Endotoxin • They 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 neutrophils and other cells of the reticuloendothelial system. • Proinflammatory cytokines such as IL-1, IL-6, IL-8, TNF-α, and other cytokines are released • 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

Enzymes • Many species of bacteria produce enzymes that are not intrinsically toxic but do play important roles in the infectious process. Some of these enzymes are discussed in the next slides.

A. Tissue-Degrading Enzymes • • • Many bacteria produce tissue-degrading enzymes. And their role in the pathogenesis of infections appear obvious Ex: collagenase, proteolytic enzyme produced by C perfringens degrades collagen, the major protein of fibrous connective tissue, and promotes spread of infection in tissue. coagulase , produced by S aureus which work in conjunction with blood factors to coagulate plasma. Coagulase contributes to the formation of fibrin walls around staphylococcal lesions, which helps them persist in tissues Hyaluronidases , hydrolyze hyaluronic 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.

B. Ig. A 1 Proteases • Ig. A 1 protease is an important virulence factor of the pathogens N gonorrhoeae, N meningitidis, H influenzae, and S pneumoniae. • The enzymes are also produced by some strains of streptococci associated with dental disease, and a few strains of other species that occasionally cause disease. • Immunoglobulin A is the secretory antibody on mucosal surfaces. It has two primary forms, Ig. A 1 and Ig. A 2 • Ig. A 1 proteases, splits Ig. A 1 at specific peptide bonds (proline–threonine or proline–serine ) in the hinge region and inactivate its antibody activity • Production of Ig. A 1 protease allows pathogens to inactivate • the primary antibody found on mucosal surfaces and thereby • eliminate protection of the host by the antibody

Capsules and Other Surface Components • Encapsulated strains of many bacteria (e. g. , pneumococci) are more virulent and more resistant to phagocytosis and intracellular killing than nonencapsulated strains. • Organisms that cause bacteremia (e. g. , Pseudomonas) are less sensitive than many other bacteria to killing by fresh human serum containing complement components, and consequently are called serum resistant. • 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 Ig. G. • A few bacteria (eg, Capnocytophaga and Bordetella species) produce soluble factors or toxins that inhibit chemotaxis by leukocytes and thus evade phagocytosis

References 1 - Jawetz, M. & Adelberg’s. 2013. Medical Microbiology , Twenty -Sixth Edition. The Mc. Graw-Hill Companies, Inc. USA 2 - Website: https: //www. ncbi. nlm. nih. gov/books/NBK 8526/

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