Bacterial Pathogenicity and Virulence

Microorganism and Host

• Saprophytism refers to living on dead or decaying organic matter
• Parasatism refers to living on or within another living organism, resulting in different types of host-parasite relationships
• Commensalism is a relationship where a parasite lives on or in a host without causing any disease
• Symbiosis is a mutually beneficial relationship between organisms
• Opportunistic pathogens are typically harmless but can cause disease under certain conditions, such as gaining access to new sites or tissues
• Obligate pathogens are parasites that always cause disease
• Infectivity is the capacity of an organism to penetrate host tissues, survive host defenses, multiply, and disseminate within the host
• Pathogenicity is the capacity of a microbial species to produce disease

Sources of Infection

• Infections originate from both animal and inanimate sources
• Animal sources include
  • Normal flora
  • Animals in the incubation period of a disease
  • Animals with overt disease
  • Convalescent carrier animals which shed pathogens for weeks/months after clinical recovery
  • Contact/subclinical carriers that acquire pathogenic organisms from infected animals without contracting the disease themselves.
  • The carrier state in these animalscan be temporary
• Inanimate sources (fomites) include contaminated utensils, feed, water troughs, and vehicles

Transmission

• Disease transmission occurs through direct or indirect contact
• Direct contact involves contact with discharges or aerosols from an infected animal, coitus, or vertical transmission from mother to offspring
• Indirect contact involves organisms carried in/on various vehicles like feed, water, litter, clothing, or instruments, which are referred to as fomites

Routes of Entry

• Common routes of entry for pathogens include:
  • Inhalation
  • Ingestion
  • Inoculation through the skin or mucous membrane
  • Coitus or artificial insemination
  • Transplacental or in ovo transmission
  • Hospital-acquired infections (nosocomial infections)
  • Physician-induced infections (iatrogenic infections)

Opportunistic Infections

• Opportunistic infections occur in compromised individuals/animals
• Normal flora can cause opportunistic infections
  • These include skin flora such as Staphylococcus aureus, S. epidermidis, and Propionibacterium acnes
  • In the intestine Bacteroides * High numbers and Enterobacteriaceae * low number are included
• The environment is an opportunistic infection
  • This includes Dermatophytes
• Nosocomial infections can be opportunistic

Pathogenicity

• Pathogenicity is a microbe's ability to cause disease
• It is influenced by virulence factors, a number of initial organisms, and immune status
• Bacteria aim to multiply rather than cause disease, as harming or killing the host is not in their best interest.
• Disease emerges when the balance between bacterial pathogenicity and host resistance is disrupted
• Pathogenic bacteria are grouped by their invasive properties for eukaryotic cells
  • Extracellular
  • Obligate intracellular
  • Facultative intracellular

Terminologies

• Bacteremia is the presence of bacteria in the blood
  • Pathogenic organisms enter through blood capillaries or venules, leading to localized infection or spread
  • Organisms may infect the lymphoid system before accessing the blood
• Septicemia is the presence of actively multiplying bacteria in the blood
  • Anthrax is a severe form, with a high number of bacteria in the blood
  • Septicemic infections often begin as localized infections which become generalized
• Toxemia is the presence of toxins in the blood

Bacterial Disease Mechanisms

• Bacteria cause disease through two basic mechanisms
  • Direct damage of host cells
  • Indirectly stimulating exaggerated host inflammatory/immune response

Virulence

• Virulence is a measure of an organism's pathogenicity
• It describes the difference in disease-causing ability between different strains of the same species
• Virulence is expressed as LD50 (lethal dose for 50% of hosts) or ID50 (infectious dose for 50% of hosts)

Virulence Factors

• Virulence factors are the factors produced by a microorganism that can induce pathology in a host
• Virulence factors aid in: - Invasion of the host - Causing disease - Evading host defenses
• Virulence factors can be classified into two categories
  • Virulence factors that promote bacterial colonization of the host
    • Adherence Factors
    • Invasion and/or Spreading Factors
    • Compete for iron and other nutrients
    • Evasion of host immune responses
  • Virulence factors that damage the host
    • Exotoxins
    • Endotoxins

Genetic Virulence Basis

• Virulence factors in bacteria can be encoded on chromosomal DNA, bacteriophage DNA, plasmids, or transposons
  • The heat-labile enterotoxin (LTI) of E. coli is plasmid encoded
  • The heat-labile toxin (LTII) is encoded on the chromosome
  • Diphtheria toxin of C.diphtheriae is coded by phage
• Virulence factors are acquired by bacteria by vertical or horizontal gene transfer

Factors for Contacting Host Cells

• Bacterial motility is important for virulence
  • Non-motile mutants of Vibrio cholerae are less virulent compared to motile wild types
• Bacterial enzymes facilitate the spread of bacteria
  • Streptococcus pyogenes produces streptokinase to liquefy fibrin clots

Factors for Adherence

• Adhesins are proteins found on bacterial cell walls that bind to specific receptor molecules on host cells
• Adhesins allow bacteria to adhere intimately to cells for colonization and also resisting physical removal
• Common examples of adherence factors:
  • Fimbriae
  • Capsule
  • Biofilm
  • Liptotechoic acid
  • Fibronectin binding protein (FBP), etc.
• Pili (fimbriae) are used as adherence factors
• Capsules are a form of adherence factor (biofilms)

Spreading Factors

• "Spreading Factors" are bacterial enzymes that affect the physical properties of tissue matrices and intercellular spaces
• This promotes pathogen spread
• Hyaluronidase depolymerizes hyaluronic acid, which is produced by streptococci, staphylococci, and clostridia
• Collagenase breaks down collagen produces by Clostridium histolyticum and Clostridium perfrigens
• Neuraminidase degrades neuraminic acid, and is produced by Vibrio cholerae, Shigella dysenteriae, P.multocida, and M.haemolytica
• Streptokinase and staphylokinase converts inactive plasminogen to plasmin which digests fibrin
• Edema factor of B.anthracis, adenylate cyclase activity promotes bacterial invasions

Invasins

• Bacteria initiate phagocytosis in non-phagocytic cells for invasion
  • This can be completed binding to some receptor on cell (eg. Yersinia pestis)
  • Injects invasins, such as Type III secretion system in bacterial cytoplasm (eg. Salmonella.)
• In either case, changes in host cell cytoskeleton cause the bacteria to be ingested
• Pathogens are able to utilize actin fibers intracellularly to move through host cells (transcytosis)
  • Listeria monocytogenes complete this
• Invasins may also mediate uptake of bacteria into professional phagocytic cells in a way that bypasses normal phagosome formation
• Bacteria having the type III secretion system on contact with cells delivers proteins into the cells which cause polymerization and depolymerization of actin filaments resulting in cytoskeletal rearrangement

Competing for Nutrients and Iron

• Bacteria compete for nutrients by synthesizing specific transport systems or cell wall components
• These are capable of binding limiting substrates and transporting them into the cell
  • Siderophores are low molecular weight, that chelate iron with very high affinity (eg. E.coli)
  • Direct binding of host transferrin, lactoferrin, ferritin, or heme by bacterial surface receptors (eg. Yersinia species)
  • Release of Exotoxins, which can lyse host cells (can be used to obtain other nutrients as well)

Evasion of Innate Immune Responses

• They invade or remain confined in regions inaccessible to phagocytes
  • The lumen of glands and the skin are not patrolled by phagocytes
• They avoid provoking an inflammatory response
• Hiding the antigenic surface of the bacterial cell is one factor for Innate Immune Response - S. aureus produces coagulase which clot fibrin on the bacterial surface
• They inhibit chemotaxis of phagocytes
  • Streptococcal streptolysin, fractions of Mycobacterium tuberculosis Clostridium toxin suppresses neutrophil chemotaxis
• Inhibit ingestion by phagocytes - The capsule inhibits recognition and engulfment by phagocytes
• The capsules can block the attachment of bacteria to Phagocytes
• Capsular, LPS, and S-layers of bacteria increase resistance to complement-mediated lysis (serum resistance)
• Extracellular products include enzymes that inactivate C5a chemoattractant (S. pyogenes), toxins that kill phagocytes (leukotoxins) (Mannheimia haemolytica), inhibit migration, or reduce oxidative burst

Surviving Phagocytosis Strategies

• Escape from phagosome before fusion with lysosome - Listeria monocytogenes, mediated by listeriolysin are able to do complete this
• Prevent phagosome-lysosome fusion - Salmonella, Mycobacterium, Legionella and Chlamydia can prevent the phagosome fusion
• Express factors that allow survival in phagolysosome

Evasion of Adaptive Immune Defenses

• Antigen masking occurs when bacteria coat themselves with host proteins such as fibrin, fibronectin, lactoferrin, or transferrin
• This allows them to avoid antibodies
• Antigenic switching or phase variation is where bacteria evade antibodies by changing the adhesive tips of their pili or vary other surface proteins so that antibodies already made will no longer "fit"
• Staphylococcus aureus produces protein A while Streptococcus pyogenes produces protein G binds IgG with very high affinity
• Bacteria release Immunoglobulin proteases like Haemophilus influenzae, Streptococcus pneumoniae, Helicobacter pylori, Shigella flexneri, Neisseria meningitidis, Neisseria gonorrhoeae, and Enteropathogenic E. coli degrade antibodies in body secretion

Virulence Factors that Damage the Host

• Bacterial cell wall components that can bind to host cells thus causing them to synthesize and secrete pro-inflammatory cytokines and chemokines
• These pathogens include:
• Toxins
• Induce autoimmune responses

Synthesis and Secretion of Inflammatory Cytokines and Chemokines

• LPS of Gram-negative bacteria, teichoic acids, and glycopeptides of Gram-positive bacteria induce cytokine production and secretion
• The cytokines, such as TNF-alpha, IL-1, interleukin-6, IL-8, and platelet-activating factor (PAF), promote inflammation and lead to activation of the complement pathways and the coagulation pathway
• Moderate levels of inflammation, products of the coagulation pathway are essential for body defence, these become excessive which leads to MOSF
• Lipoproteins can lead to excessive cytokine production

Bacterial Toxins

• Produced by bacteria (both Gram-positive and Gram-negative)
• Primarily released into the surrounding environment
• Exotoxins are excellent antigens
  • They can trigger the creation of antibodies called antitoxins
• Endotoxins are the lipopolysaccharide components of the outer membrane of the gram-negative bacterial cell
  • Can cause pyrexia, blood changes, and shock
• LPS binds LPS binding proteins (LBP) in plasma which then binds CD14
• LPS, LBP and CD14 complex, binds Toll-like receptor 4 (TLR4) on macrophages and monocytes
• Macrophages and monocytes release and trigger subsequent leukotriene
• Complement and coagulation cascades are activated
• Endotoxic shock
  • Bacterial Products, high cytokine release, activation and coagulation and can potentially collapse the circulatory system

Harmful Effects Of LPS-Endotoxin

• Fever Production
• Inflammation
• Tissue Destruction
• Respiratory Distress
• Capillary Damage
• Intravascular Coagulation
• Hypotension
• Decreased Cardiac output
• Irreversible Shock
• Wasting of the Body
• Diarrhea
• Blood-brain barrier
• Bacterial Toxins Include:
  • Exotoxin
  • Endotoxin

Types of Exotoxins

• On the base of mode of action
  • Super antigens
  • Toxins that act on the extracellular matrix
  • A-B Toxins
  • Exotoxins that damage the host cell membranes
• On the basis of site of action
  • Cytotoxin examples include Diphtheria
  • Nuero
• Exotoxins are heat stable -They elicit specific antibodies called antitoxins -Superantigens
• Bind directly to the MHC -II molecules macrophages
  • Toxic Shock (TSST-1)
• Extracellular matrix cause collagenases
• A-B toxins : Enzymatic
• Two parts : A and B Types of Ab Toxins
• 1 : ADR - ribo
• 2 : Shiga and shiga-like -vero toxins
• 3 : Tetanus Toxins

Toxins Acting on Extracellular Matrix

• Breakdown of proteins and immunoglobulins
• Important role helping dissemination

A-B Toxins

• Consist of A and B, A -enymatic and B -binding
• Host cell specific, the host cell surface
• B components bind exotoxin to a receptor and after translocation occurs
• A component separates
• Component A releases enzymes and catalyzes it to the cytoplasm of the host cell-
• A component catalyzes A ribosylation to cell

Membrane-Damaging Exotoxins

• Cause cell death Three types of membrane-disrupting toxins
• Enzymes that use phospholipids
• That hydrolyze phospholipids which disrupts the membrane
• Pore-Forming Toxin

Virulence and Auto Immune Responses

• Produce cross-reactive antibodies and accidentally cross reacting antigens
• The result stimulates inflammatory response for e.g. Rheumatic Fever
  • Stimulates production for inflammatory responses that destroys the e.g. Glomerulonephritis

Explore bacterial infections, differentiating bacteremia and septicemia. Learn about opportunistic infections, virulence factors, LD50, and mechanisms like Listeria's intracellular spread. Discover how bacterial enzymes contribute to tissue damage and inflammation.