Pathogens and Virulence Factors

Terminology

• A pathogen refers to a microorganism capable of causing disease
• Opportunistic pathogens rarely cause disease in immunocompetent people but can cause serious infection in immunocompromised patients
• Virulence is a quantitative measure of pathogenicity, measured by the number of organisms needed to cause disease
• LD50, or the 50% lethal dose, refers to the number of organisms needed to kill half the hosts
• ID50, or the 50% infectious dose, refers to the number of organisms needed to cause infection in half the hosts
• Example: an infectious dose of Shigella is less than 100 organisms
• Example: an infectious dose of Salmonella is 100,000 organisms
• The infectious dose of bacteria depends on virulence factors such as the ability of pili to adhere to mucous membranes
• Production of exotoxins or endotoxins, the presence of a capsule for phagocytosis protection, and the ability to survive host defenses like stomach acid are also virulence factors
• A parasite organism grows, feeds, and shelters itself on another organism without contributing to the host's survival, and can cause damage
• Obligate intracellular parasites can only grow within host cells, e.g., Chlamydia and Rickettsia
• Facultative parasites can grow within or outside cells, or on bacteriologic media
• The term "parasite" can refer to protozoa and helminths

Bacterial Infections

• Infection has multiple meanings
• Either an organism has entered the body and causes asymptomatic infection
• Or a general term to describe an infectious disease

Mechanisms of Disease

• Bacteria cause disease through toxin production (exotoxins and endotoxins) and invasion and inflammation
• Exotoxins are polypeptides
• Endotoxins are lipopolysaccharides (LPS) found only in Gram-negative rods and cocci and they are not actively released from the cell
• Endotoxins cause fever, shock, and other generalized symptoms
• Both exotoxins and endotoxins themselves can cause symptoms without the bacteria's presence
• Invasive bacteria grow locally and induce an inflammatory response, causing erythema, edema, warmth, and pain

Disease Transmission

• Communicable infections can spread from host to host, e.g., tuberculosis via airborne droplets
• Botulism is not communicable because the exotoxin affects only those eating contaminated food
• A "contagious" disease is highly communicable
• An epidemic occurs much more frequently than usual
• A pandemic has worldwide distribution
• An endemic infection is constantly present at a low level in a specific population

Bacterial Pathogenesis

• Bacterial pathogenesis involves transmission from an external source into the portal of entry and avoidance of primary host defenses, such as skin or stomach acid
• Adherence to mucous membranes, usually via bacterial pili, is a key step
• Colonization occurs through bacterial growth at the site of adherence
• Disease symptoms are caused by toxin production or invasion accompanied by inflammation
• Host responses, both nonspecific and specific immunity happens during stages 3, 4, and 5
• The final stage involves progression or resolution of the disease

Determinants of Bacterial Pathogenesis

• Transmission occurs from human-to-human, non-human sources like soil, water, and animals, or fomites (inanimate objects like towels)
• Interrupting the chain of transmission prevents infectious diseases
• Some infections are caused by normal flora, but most are acquired from external sources
• Screening of donated blood has greatly reduced infection risks
• Vertical transmission occurs from mother to offspring across the placenta, within the birth canal, or via breast milk
• Person-to-person transmission that is not from mother to offspring, is horizontal transmission
• Four important portals of entry into the body are the respiratory, gastrointestinal, and genital tracts, and the skin

Adherence to Cell Surfaces

• Bacteria have specialized structures (pili) or substances (capsules, glycocalyces) that facilitate adherence to human cells and cause disease
• Mutants lacking these mechanisms are often nonpathogenic
• Molecules mediating adherence to cell surfaces are adhesins
• Biofilms protect bacteria from antibodies and antibiotics, playing an important role in pathogenesis

Enzymes in Pathogenesis

• Invasive bacteria secrete enzymes that play a crucial role in pathogenesis
• Collagenase degrades collagen
• Hyaluronidase degrades hyaluronic acid
• Coagulase forms a fibrin clot, protecting bacteria from phagocytosis
• Immunoglobulin A (IgA) protease degrades IgA, facilitating bacterial adherence to mucous membranes
• Leukocidins destroy neutrophilic leukocytes and macrophages

Factors of Invasiveness

• Several virulence factors enhance invasiveness by limiting host defense mechanisms, especially phagocytosis
• Capsules (polysaccharide capsule)
• Cell wall proteins of gram-positive cocci, such as M protein which is antiphagocytic, and protein A which binds to IgG and prevents the activation of complement

Inflammation

• Pyogenic inflammation involves pus-producing neutrophils as predominant cells
• Granulomatous inflammation predominantly involves macrophages and T cells
• No bacterial enzymes or toxins induce granulomas
• Bacterial antigens stimulate the cell-mediated immune system, resulting in sensitized T-lymphocyte and macrophage activity
• Phagocytosis by macrophages kills most bacteria, but some survive and grow within macrophages in the granuloma

Intracellular Survival

• Intracellular pathogens commonly cause granulomatous lesions
• Mechanisms aid bacteria in surviving and growing intracellularly
• Inhibition of fusion of the phagosome with the lysosome prevents exposure to degradative enzymes
• Inhibition of acidification of the phagosome reduces the activity of lysosomal degradative enzymes
• Escape from the phagosome into the cytoplasm avoids degradative enzymes

Cell Invasion

• Invasion of cells by bacteria depends on the interaction of specific bacterial surface proteins named invasins and specific cellular receptors
• The genes that encode virulence factors are clustered in pathogenicity islands
• Genes encoding adhesins, invasins, and exotoxins are adjacent to each other on these islands

Toxin Production

• Toxin production is a major mechanism by which bacteria cause disease, through exotoxins and endotoxins

Exotoxins

• Many exotoxins have an A–B subunit structure, where the A subunit has toxic activity and the B subunit is responsible for binding the exotoxin to specific receptors on the membrane of the human cell
• Important exotoxins with an A–B subunit structure including diphtheria toxin, tetanus toxin, botulinum toxin, cholera toxin, and the enterotoxin of E. coli
• Lecithinase hydrolyzes lecithin in the cell membrane resulting in widespread cell death
• Superantigens a class of antigens which cause non‐specific activation of T‐cells resulting in polyclonal T cell activation and massive cytokine release

Endotoxins

• Endotoxins are integral parts of the cell walls of Gram-negative rods and cocci
• Fever and hypotension are salient features of septic shock, which has an estimated mortality rate of 30–50%
• Gram-negative bacteria's endotoxins are the most common cause of septic shock, but gram-positive bacteria can also cause septic shock
• Septic shock differs as the bacteria are in the bloodstream and blood cultures are positive
• Septic shock can cause death even if treated because cytokines continue to act
• Biologic effects of endotoxin are fever (interleukin-1), hypotension (bradykinin-induced vasodilation), and disseminated intravascular coagulation (DIC) due to the coagulation system through Hageman factor (factor XII)

Septic Shock Treatment

• Treatment involves preventing DIC with Protein C therapy
• Protein C is often used because it functions as anticoagulants
• Also enhances fibrinolysis

Infection Associations

• Certain bacteria infections are associated with cancer
• Helicobacter pylori infection causes gastric carcinoma and gastric mucosal