Virulence Factors and Pathogens

• Virulence factors are features that allows microorganisms to infect the body
• This topic covers General Dental Council outcomes for systemic diseases' relevance to oral health, the etiology/pathogenesis of oral disease, and potential transmission routes of infectious agents in dental practice

Intended Learning Outcomes

• Terminology associated with virulence and virulence factors will be defined
• The pathogens that infect the human body will be recalled
• Mechanisms pathogens use to destroy, cause malfunction of host cells, and evade the immune response will be described

Terminology

• Pathogens can cause disease in a host organism
• A primary pathogen is an environmental microbe that can cause disease in otherwise healthy individuals
• An opportunistic pathogen is a normal microbiota member that causes disease in immunocompromised hosts.
• Pathogenicity is the ability of a pathogen to cause disease
• Virulence is the degree or intensity of pathogenicity
• Virulence factors are mechanisms determining the degree a pathogen causes damage, invasion, and infectivity
• The chain of infection consists of agent, virulence, dose, exposure, and susceptibility
• Molecular Koch's postulates must be reviewed

Process of Infection

• Virulence factors allow a pathogen to outcompete host cells and resist defenses
• To survive, pathogens require a suitable environment, a source of nutrients, and protection from harmful elements
• Virulence factor mechanisms include adhesion, evasion of phagocytosis (antiphagocytic factors), immunoevasion, immunosuppression, toxigenicity (exotoxins and endotoxins), and enzymatic actions (exoenzymes)

Pathogen Entry, Adhesion, and Colonization

• Pathogens must first enter, adhere to, and colonize the host

Adhesion

• Bacteria use structures like pili, fimbriae, capsules, and cell walls for adhesion
• Class IV pili enable a 'twitching' motility, found at the poles of bacilli facilitating a 'gliding' motion
• Pili retract and extend, facilitating movement and enabling bacteria to slingshot over the cellular surface

Adhesins

• Cell walls of bacteria contain proteins that are useful
• Streptoccocus pyogenes causes Strep Throat and uses Protein F to bind bind to Respiratory epithelial cells
• Streptococcus mutans causes dental caries and uses Adhesin P1 to bind to teeth
• Neisseria gonorrhoeae causes Gonorrhea and uses Type IV pili to bind to Urethral epithelial cells
• Enterotoxigenic E. coli (ETEC) causes Traveler's diarrhea and uses Type 1 fimbriae to bind to Intestinal epithelial cells
• Vibrio cholerae causes Cholera and uses N-methylphenylalanine pili to bind to Intestinal epithelial cells
• Bacteria may produce capsules, which aid in adhesion act to help in immune evasion, prevent phagocytosis by cells of the immune system
• Capsule composition can prevent adhesion of antibodies and Capsule size can deter phagocytosis
• Fimbriae of some Streptococcus species contain M protein alterations to the bacterium surface, which inhibits phagocytosis
• Mycolic acid is a waxy substance produced within the cell wall by Mycobacterium tuberculosis, that acts as a protective coat which deters the killing mechanisms of phagocytes

Exoenzymes

• Extracellular enzymes are secreted by cells to function outside of those cells, invading host cells and deeper tissues
• Exoenzymes are specific to particular tissue structures and enable invasion, supporting their own growth and defending against the immune system
• Glycohydrolases such as Hyaluronidase S break down hyaluronic acid and facilitate spreading of infectious materials
• Nucleases such as S.aureus degrades trapping DNA from bacteria and host cells to promote further spread
• Phospholipases such as Bacillus anthracis degrade the phospholipid bilayer, causing cellular lysis
• Proteases such as Clostridium perfringens degrade collagen in connective tissue to promote further spread

Toxins

• Toxins are biological poisons produced by some pathogens that invade and damage tissues
• Toxigenicity is the ability of a pathogen to produce toxins that cause damage to host cells They are classified as exotoxins or endotoxins
• Derived from gram-negative bacteria, endotoxins stimulate a general systemic inflammatory response
• Remaining stable at high temperatures, endotoxins require heating at 121°C (250°F) for 45 minutes to inactivate
• A low endotoxin concentration triggers an effective host inflammatory response against infection
• High levels in the blood cause a severe drop in blood pressure, multi-organ failure, and death.
• Potent protein molecules (exotoxins) are produced by a wide variety of pathogenic organisms including: gram-positive bacteria and some gram-negative bacteria
• They are also specific in their action and in the cells they interact with
• Exotoxins target specific receptors on specific cells, damaging those cells through individual molecular mechanisms
• Exotoxins are inactivated by heat greater than 41°C/106°F and are lethal in low concentrations. Exotoxins are grouped into three categories: intracellular targeting, membrane disrupting, and superantigens

Terminology of Pathogens in Bloodstream

• Conditions usually end in "aemia"
• Presence of bacteria in the blood is bacteremia
• Pus-forming bacteria in the blood is pyaemia.
• Presence of toxins in the blood is toxaemia.
• Multiplying bacteria in the blood is septicaemia

Promoting Infection

• Exoenzyme coagulase produced by staphylococcus aureus triggers fibrinogen-to-fibrin cascade, coating bacteria with fibrin clots and preventing phagocytosis
• Kinases stimulate digestion of fibrin clots, therefore depending on conditions, the pathogen needs to escape and spread
• Antigenic variation alters surface proteins, avoiding recognition by the host's immune response
• Destruction of phagocytes occurs with the production of leukocidins
• Destruction of T lymphocytes occurs
• Intracellular position implies immune defenses can't reach invaders
• Pathogens avoid killing methods

Viral Virulence

• Adhesins-mediated viral capsid or membrane envelope interact specifically (tropism) with cell receptors
• Examples of Spike protein hemagglutinin on influenza virus and glycoprotein g20 found on HIV
• Antigenic variation frequently occurs within enveloped viruses.
• Antigenic drift results from minor point mutations that alter their spike proteins.
• Antigenic shift results in major spike protein changes due to gene re-assortment

Virulence Factors in Oral Health

• Porphyrmonas gingivalis uses fimbriae to modulate the hosts immune response
• Gingipains from P.gingivalis breakdown of collagen, elastin, and fibronectin
• Streptococcus Mutans' acidogenicity, adhesion, and acid tolerance are main virulence factors associated with cariogenicity
• pH drops quickly, increasing bacteria and carbohydrate fermentation susceptibility to enamel demineralization increases during proliferation
• Herpes simplex virus hides from the immune system in neurons and non-neuronal cells for decades, emerging as patients show less immune resistance
• Appears clinically as herpes labialis (cold sore)
• Most common etiological factor of opportunistic human fungal infections, Candida Albicans's main virulence factors are exoenzymes and pleomorphism
• Secreted aspartyl proteases are otherwise known as Sap proteins and adhesions
• Candida Albicans also responds and adapts to environmental changes

Conclusion

• Pathogens are always evolving strategies through virulence factors to avoid immune responses.
• Host cell interaction with pathogens is dynamic, with new virulence factors countered by the host.
• Increased T cells in the host allows pathogens to produce escape mutations, not being a future target.
• Pathogens will continue to evolve and emerge, taking advantage of the host without causing death.