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Infectious Disease

This tutorial will help you

• compare and contrast different human and animal pathogens.
• understand how the body encounters pathogens.
• Understand how pathogens cause disease.
• Understand how disease is spread and diagnosed.

Introduction to the Pathogens
Normal Flora
Infection and Pathogenesis
Disease Spread
Disease Diagnosis and Treatment
Key Concepts

To fully appreciate the immune response against pathogens, one must have some basic knowledge of pathogens and how they cause disease. This tutorial summarizes key information about human and animal pathogens. More detailed information can be found in the references cited below and in most microbiology texts.

Introduction to the Pathogens

Disease-causing microorganisms (pathogens) can be classified as viruses, bacteria, fungi, or protozoan parasites. Macroscopic helminth (worm) parasites can also cause infection.

Viruses are obligate intracellular parasites, meaning they can only be replicated inside living cells using the host cell's metabolic machinery. They range in size from 20 nm to 1,000 nm (1 mm) in diameter and come in many different shapes (http://www.virology.net/garryfavwebindex.html). Viruses are composed of a nucleic acid (DNA or RNA) genome, a protein coat (capsid), and sometimes a lipid envelope which has been modified from the host cell's plasma membrane. The outermost layer of the virus (capsid or envelope) has protein receptors that must bind to specific host cell membrane glycoproteins before the virus can enter the cell and begin its replication cycle. The virus enters via endocytosis or by fusing the viral envelope with the host cell membrane. Once inside the host cell, uncoating removes the capsid and exposes the nucleic acid. Host cell enzymes under viral control, along with viral enzymes in some cases, replicate the viral nucleic acids and synthesize mRNA and viral proteins. In general, DNA viruses are replicated and assembled in the host cell nucleus (proteins are made on the ribosomes and migrate into the nucleus), while RNA viruses are replicated and assembled in the host cell cytoplasm. Virus subunits are combined assembly-style to make new virions. One infecting virion provides the information for the cell to make thousands to millions of progeny virions. Enveloped virions leave the cell by budding, taking with them a covering of host cell membrane modified with virus receptor proteins. Infected cells may produce enveloped viruses for many hours or days before they die. Non-enveloped virions usually accumulate in the cell to a large "burst size", at which point the cell lyses and the virions are free to bind and infect other cells. Important antigens recognized by the immune system include external envelope or capsid proteins, structural proteins inside the virion, and viral enzymes required for replication.

Pathogenic bacteria (singular: bacterium) are single celled microorganisms (http://www.cellsalive.com/cells/bactcell.htm) . Bacteria may be free-living in the environment or in plant, insect, or animal hosts. Some are obligate pathogens that depend on hosts for some key nutrients but living outside host cells, while others are obligate intracellular parasites that require some nutrients or enzymes found only inside host cells. Bacteria are prokaryotic organisms that have a circular DNA genome and enzyme systems inside a lipid bilayer plasma membrane, covered with a cell wall of peptidoglycan that gives the cells their characteristic shape (see http://www.bact.wisc.edu/MicrotextBook/BacterialStructure/CellWall.html) . Mycoplasmas are unusual in lacking a cell wall. Bacteria range from 100 nm to 5 mm in size. They are classified by their shape (rod/bacillus, sphere/coccus, or spiral/spirillum) and by the structure of their cell wall. Gram positive bacteria have a thick peptidoglycan layer outside their plasma membrane (http://www.rkm.com.au/CELL/Bacteria/bacterialimages/Gram-positive-wall-500.jpg). Gram negative bacteria have a thin peptidoglycan layer and an outer (lipid bilayer) membrane (OM) containing Lipopolysaccharide (LPS) (http://www.rkm.com.au/CELL/Bacteria/bacterialimages/Gram-negative-wall-500.jpg). Some bacteria also have a carbohydrate capsule, slime layer, or waxy coating to protect them from drying and from the immune system. Some bacteria have short hairy processes called fimbriae (singular fimbria) or pili (singular: pilus) that allow them to adhere to host tissues. Some have long flagella (singular: flagellum) for locomotion. Bacteria reproduce by binary fission, each parent cell giving rise to two identical daughters. The immune system recognizes many antigens on bacteria, including LPS, sugars, and proteins of pili and flagella.

Fungi (singular: fungus) are eukaryotic organisms (http://www.tulane.edu/~dmsander/WWW/MBChB/6a.html). They have a lipid bilayer plasma membrane and membranes surrounding organelles in the cytosol. Their genetic material is DNA, which they transcribe into messenger RNA and translate into proteins. They may be unicellular (yeasts), multicellular (filamentous fungi), or exist in both forms (dimorphic fungi). Most pathogenic fungi are opportunistic pathogens: they cause disease only when the host's immune system is weakened. Of the true fungal pathogens, most can live freely in the environment and do not need humans to survive (http://www.kcom.edu/faculty/chamberlain/Website/fungi.htm). Of those that are found only on humans, all are extracellular pathogens; many live on the outer surfaces of the body. Fungi can reproduce by sexual or asexual processes.

A wide range of sizes and life styles is found in the protozoan parasites (http://www.ourfood.com/Parasites_Pathogenic_Protoz.html). Protozoan parasites are unicellular eukaryotic organisms. They often have several life cycle stages that have different appearances, antigens, and habitats. During some stages sexual reproduction takes place, while during other stages reproduction is asexual. Some protozoan parasites can live freely in the environment as well as inside a host. Some depend on insect or arthropod vectors to transmit them from host to host and to complete their life cycle. Some are obligate human or animal parasites.

Helminth (worm) parasites are macroscopic, ranging in size from 0.3 mm to 25 meters long. They are multicellular with specialized organs and undergo sexual reproduction. Many helminths can infect humans and domestic animals, causing serious disease (http://www.path.cam.ac.uk/~schisto/General_Parasitology/Hm.helminths.html). In addition, they can provoke allergic reactions by their persistent presence in host tissues. Helminths often live freely or attached in the intestine, but some can also penetrate into the body where they can seriously damage internal organs and the brain.

Normal Flora

Think of the body as an elongated donut, with the digestive tract forming the hole and therefore "outside" the body. Other external regions that do not completely penetrate the body are the respiratory tract, the urogenital tract, and the conjunctiva of the eye. The respiratory, urogenital, and much of the digestive tract are composed of specialized epithelial cells forming mucous membranes. Mucin, cilia, and tight junctions between the cells block entry of microorganisms. All internal regions of the body, including the circulation, brain and spinal column, organs, bone, fat, and connective tissue, should be free of microorganisms (sterile). The presence of microbes in blood, urine, or cerebrospinal fluid is indicative of infection.

Beginning at birth, the skin and mucous membranes of humans and animals are colonized with microbes, mostly bacteria. In general, normal flora are not invasive and do not usually cause disease. They occupy niches which supply their requirements for nutrients, oxygen and space to reproduce. They may provide some benefits to the host in the form of secreted vitamins, or some discomfort as they produce gas from undigested food. Cellulose-digesting microbes are essential for ruminant animal nutrition. Normal flora physically block the attachment of pathogens or secrete bacteriocins, molecules that inhibit pathogen growth. Prolonged antibiotic treatment that kills normal flora can result in serious disease from pathogens that now find living space. Normal flora can be opportunistic pathogens, causing disease if they enter the body through a wound, surgical incision, following dental work, or on a catheter.

Infection and Pathogenesis

Infection comprises several steps: pathogen attachment and entry, local or general spread, multiplication, evasion of host defenses, shedding from the body, and damage to the host (Mims et al., 2001). Most human acute infections are either respiratory or gastrointestinal; viruses are the most common infectious agents. Virulence or pathogenicity is the ability of the infecting organism to cause disease symptoms.

Adhesion is the first and perhaps most crucial step in infection. Without adhesion to host tissues, microbes are removed by the motion of cilia, reflexes (sneezing, coughing and swallowing), or intestinal peristalsis. Molecules on the pathogen surface bind to proteins or carbohydrates on the plasma membrane of host cells. Virus adhesins are capsid or envelope proteins. Adhesins determine virus tissue tropism (specificity). For example, HIV only infects cells with membrane proteins CD4 plus either CX4 or CXCR5. Bacterial adhesins include LPS, outer membrane proteins, and proteins on fimbriae and flagella.

Some pathogens enter the body through breaks in the skin or mucous membranes which occur due to accidental trauma, injections, or insect, arthropod, or animal bites. Many viruses can infect mucosal epithelial cells and from there infect adjacent cells. Lung damage due to viruses, asbestos, and smoking can allow entry of bacteria. Bacteria and protozoan parasites may enter by being phagocytosed by M cells, part of the immune system in intestinal tissue. Other pathogens appear to stimulate their own uptake by inducing macropinocytosis by intestinal cells. Once in the body, pathogens can spread by moving directly from one cell to adjacent cells, in the blood and lymph circulation, along nerves, within the pleural or peritoneal cavity, and in pregnant women across the placenta into the fetus. Some pathogens can cause disease without entering the body through the actions of secreted toxins.

Many microbes can infect without causing significant damage to the body; their pathogenicity (virulence) is low. Pathogens damage host tissue by directly killing cells or by inducing apoptosis (programmed cell death). Bacteria that cause dental caries produce acid which attacks the tooth enamel. One of the most damaging products of bacterial infection is exotoxin, a secreted toxin that can spread throughout the body. Common bacterial exotoxins and endotoxin are listed below.

Pathogens also cause host disease indirectly by stimulating immune responses that damage host tissue. Inflammation results in fluid and leukocyte movement into the infection site. Cell damage results from proteases and toxic oxygen products released by neutrophils and macrophages, and from complement activation. For more details on these innate immune mechanisms, see Innate Immunity. Prolonged inflammation can cause periodontal disease, arthritis, and kidney failure. For more information on immunopathology, see Allergy and Hypersensitivity. Finally, pathogens damage the body by causing hemorrhage, release of stress hormones, placental damage, tumor formation, or suppression of the immune system.

Immune system evasion by pathogens is discussed in The Big Picture: Immunity to Infection. Examples of immune evasion include avoiding phagocytosis or destruction within phagocytes, altering antigens or persisting without replication to avoid immune recognition, and suppressing immunity.

Infectious disease is classified as acute (occurs over a relatively short time period like a cold or the flu) or chronic (when the pathogen evades the immune system and persists in the body for months to years as in Lyme disease or tuberculosis). Diseases acquired in utero may be persistent because the immune system does not recognize the pathogen as foreign; an example is congenital rubella. Viruses in particular may cause latent infections, where the virus remains in host cells without replicating (Herpes viruses). If the virus is later activated to begin replicating, recurring infection is seen (shingles and cold sores). Some viruses are oncogenic (cancer-causing); an example is Human Papilloma Virus that causes genital warts and cervical cancer.

Disease Spread (Epidemiology)

In order to survive in nature, a pathogen must be able to replicate in the host and spread to other hosts. Spread may be horizontal, from individual to individual, or vertical from parent to offspring. Transmission may also involve insect or arthropod vectors: bites from mosquitos, ticks, sand flies, or lice. Zoonoses are diseases which can be transferred from animals to humans.

The mode of spread is related to the tissues infected. Microbes can be spread into the respiratory tract via respiratory secretions, saliva, skin shedding, or dried urine. Fomites are materials contaminated with the infectious agent. Touching a contaminated surface and then touching the mucous membranes of the nose or mouth is an efficient way to spread respiratory pathogens. Pathogens can also enter the digestive tract by the fecal-oral route spread between mucous membranes by venereal (sexual) contact, and enter the circulation by contact with contaminated needles (i.v. drugs, transfusions, tattooing) or via wounds or animal bites.

Pathogens can persist in asymptomatic carriers, who are infectious without being ill, in asymptomatic animals, or in the environment (soil and water). Nosocomial infections are acquired in health care settings.

Disease Diagnosis and Treatment

Since Koch demonstrated in the 1880's that microbes caused disease, most common diagnostic tests for bacteria involve culturing a sample from the ill individual in the laboratory to get enough microbes for direct microscopic observation and biochemical or immunochemical identification. With the advent of molecular technology, diagnosis and especially epidemiology also utilize PCR and nucleic acid hybridization. Many of the immunological and nucleic acid tests which can be used to identify specific pathogens are described in the ToolBox.

Infectious diseases may be self-limiting, meaning the immune system can successfully eliminate the pathogen. Many viruses diseases are-self limiting. Other infections may required treatment with antimicrobial drugs appropriate to the specific pathogen.

Key Concepts of Infectious Disease

• The four groups of microscopic pathogens are viruses, bacteria (prokaryotes), fungi (eukaryotes), and protozoan parasites (eukaryotes). Each group has characteristic structures and physiology. Macroscopic helminths also cause infectious disease.
• Pathogens may be opportunistic pathogens, obligate extracellular pathogens, or obligate intracellular pathogens.
• Normal flora are present from birth on skin and mucous membranes. They compete with pathogens for space and nutrients and can cause opportunistic infections.
• To cause disease, pathogens must attach to and penetrate the skin or mucous membranes, spread locally or throughout the body, multiply, evade host defenses, damage the host, and be shed to infect new hosts. Adhesion molecules are responsible for the tissue specificity of viruses.
• Pathogens damage host tissue directly with exotoxins and by interfering with host cell metabolism to cause apoptosis. Pathogens can also cause indirect damage by activating the immune system to damage host tissue via inflammation; a few can cause cancer.
• Diseases are spread in characteristic ways depending on the part of the body infected and the biology of the pathogen.
• Infectious diseases are diagnosed by culture and biochemical characteristics, immunological tests for antigen types, and PCR and nucleic acid hybridization for genotype similarity. Diseases may be self-limiting or require treatment with antimicrobial drugs.

References

Cossart, P., P. Boquet, S. Normark, and R. Rappuolo. Cellular Microbiology. ASM Press, Washington, DC, 2000.

Kaufmann, S. H. E., A. Sher and R. Ahmed. Immunology of Infectious Diseases. ASM Press, Washington, DC, 2001.

Madigan, M. T., Martinko, J. M., and J. Parker. Brock Biology of Microorganisms. Prentice Hall, Upper Saddle River, NJ, 1997

Mims, C., A. Nash, and J. Stephen. Mims' Pathogenesis of Infectious Disease. Academic Press, San Diego, CA. 2001.

Prescott,L. M., J. P. Harley, and D. A. Klein. Microbiology (3rd edition) Wm. C. Brown Publishers, Dubuque, IA, 1996.

Salyers, A. A. and D. D. Whitt. Bacterial Pathogenesis. A Molecular Approach. ASM Press, Washington, DC, 1994.

Tortora, G. J., B. R. Funke, and C. L. Case. Microbiology, An Introduction. (7th edition) Benjamin Cummings, San Francisco, 2002.

American Veterinary Medical Association http://www.avma.org/

Centers for Disease Control and Prevention http://www.cdc.gov/

World Health Organization http://www.who.int/home-page/

Kirksville College of Osteopathic Medicine http://www.kcom.edu/faculty/chamberlain/Default.stm

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