The topics of sites of infections and virulence are two fundamental content in the discipline of infectious diseases. As a pharmacist and clinician we have to read and understand them, which can direct our clinical practice at the right direction.
Site of Infection
The type of pathogen (the number of infectious agents absorbed by the host and the virulence of the pathogen), the portal of entry, and the competence of the host’s immunologic defense system ultimately determine the site of an infectious disease. Some pathogens cause local infectious diseases, some tend to disseminate (though the circulatory system) from the primary site of infection to involve other locations and organ systems, which we call systemic infections. In particular situation, the abscess or pus, is a purulent exudate or a localized pocket rich in leukocytes (mostly neutrophils), devitalized tissue and debris of dead cells, and in many cases, microbes.
In this case, the dissemination of the pathogen has been contained by the host, but white cell function within the toxic environment of the abscess is hampered, and the elimination of microorganisms is slowed if not actually stopped. Similarly, infections of biomedical implants such as catheters, artificial heart valves, and prosthetic bone implants are seldom cured by the host’s immune response and antimicrobial therapy (due to the biofilm formed on these devices), which necessitates the removal of the device.
Virulence factors are substances or products generated by infectious agents that enhance their ability to cause disease. Generally, virulence factors can be summarized into four primary categories including toxins, adhesion factors, evasive factors, and invasive factors.
Toxins are substances that alter or destroy the normal function of the host or host’s cells. Toxin production is a trait chiefly monopolized by bacterial pathogens, although certain fungal and protozoan pathogens also elaborate substances toxic to humans. Bacterial toxins have diverse spectrum of activity and exert their effects on a wide variety of host target cells. For classification purposes, however, the bacterial toxins can be divided into two main types: exotoxins, and endotoxins.
Exotoxins are proteins released from the bacterial cell during growth. Bacterial exotoxins enzymatically inactivate or modify key cellular constituents, leading to cell death or dysfunction. Diphtheria toxin, for example, inhibits cellular protein synthesis; botulism toxin decreases the release of neurotransmitter from cholinergic neurons, causing flaccid paralysis; tetanus toxin decreases the release of neurotransmitter from inhibitory neurons, producing spastic paralysis; and cholera toxin induces fluid secretion into the lumen of the intestine, causing diarrhea. Other examples of exotoxin-induced diseases include pertussis (whooping cough), anthrax, traveler’s diarrhea, toxic shock syndrome, and a host of food-borne illnesses (i.e., food poisoning).
In contrast to exotoxins, endotoxins do not contain protein, are not actively released from the bacterium during growth, and have no enzymatic activity. Rather, endotoxins are complex molecules composed of lipid and polysaccharides found in the cell wall of gram-negative bacteria. Studies of different endotoxins have indicated that the lipid portion of the endotoxin confers the toxic properties to the molecule. Endotoxins are potent activators of a number of regulatory systems in humans. A small amount of endotoxin in the circulatory system (endotoxemia) can induce clotting bleeding, inflammation, hypotension, and fever.
No interaction between microorganisms and humans can progress to infection or disease if the pathogen is unable to attach and colonize the host. The process of microbial attachment may be site specific (e.g., mucous membranes, skin surfaces), cell specific (e.g., T lymphocytes, respiratory, epithelium, intestinal epithelium), or nonspecific (e.g., moist areas, charged surfaces). In any of these cases, adhesion requires a positive interaction between the surfaces of host cells and the infectious agent.
The site to which microorganisms adhere is called a receptor, and the reciprocal molecule or substance that binds to the receptor is called a ligand or adhesin. Receptors may be proteins, carbohydrates, lipids, or complex molecules composed of all three. Similarly, ligands may be simple or complex molecules and, in some cases, highly specific structures. After initial attachment, a number of bacterial agents become embedded in a gelatinous matrix of polysaccharides called a slime or mucous layer. The slime layer serves two purposes: It anchors the agent firmly to host tissue surfaces, and it protects the agent from the immunologic defenses of the host. Many viral agents produce filamentous appendages or spikes that recognize carbohydrate receptors on the surfaces of specific cells in human body.
A number of factors produced by pathogens enhance virulence by evading various components of the host’s immune system. The are briefly summarized below.
1.Extracellular polysaccharides, including capsules, slime, and mucous layer, discourage engulfment and killing of pathogens by the host’s phagocytic white blood cells.
2.Some pathogens can avoid phagocytosis by excreting leukocidin C toxins, which cause specific and lethal damage to the cell membrane of host neutrophils and macrophages, etc.
3.Some pahogens are adapted to survive and reproduce within phagocytic white blood cells after ingestion, avoiding or neutralizing the usually lethal products contained within the lysosomes of the cell. An extreme example is the Helicobacter pylori, which produces a urease enzyme on its outer cell wall. The urease converts gastric urea into ammonia, thus neutralizing the acidic environment of the stomach and allowing the organism to survive in this hostile environment.
4.Some pathogens evading immunologic surveillance have evolved ways to avoid recognition by host antibodies. Strains of S. aureus produce a surface protein (protein A) that immobilizes immunoglobulin G (IgG), holding the antigen-binding region harmlessly away from the organisms. Also, this pathogen secretes a unique enzyme called coagulase which converts soluble human coagulation factors into solid clot, which envelops and protects the organism from phagocytic host cells and antibodies.
5.Some agents secrete enzymes that cleave and inactivate secretory IgA, neutralizing the primary defense of the respiratory and genital tracts at the site of infection.
6.Some agents can alter surface antigens during the disease course so that the immunological detection has been avoided.
7.Some viruses, such as HIV, impair the function of immunoregulatory cells. Although this property increases the virulence of these agents, it is not considered a virulence factor in the true sense of the definition.
Invasive factors are products produced by infectious agents that facilitate the penetration of anatomic barriers and host tissue. Most invasive factors are enzymes capable of destroying cellular membranes (e.g., phospholipases), connective tissue (e.g., elastases, collagenases), intercellular matrices (e.g., hyaluronidase), and structural protein complexes (e.g., proteases).
At the end, I want to emphasize that it is the combined effects of these factors above, the amount of pathogen the host absorbing, and the antimicrobial and inflammatory substances released by host cells mediate the pathophysiology of the infectious diseases.