Selected Microbial and Viral diseases
Last revised: Thursday, April 24, 2003
Reading: Ch. 28, 29 in text

Respiratory Diseases

• Air inside building contains 500-1000 microbes/cubic meter of air, and humans breathe 6 liters/min at rest. So up to 10,000 microbes per day enter lungs. Air contains fungal spores, some bacteria.
• But most infections occur by coming in contact with fluids from sneezes, coughs, hands of other infected people.
• Respiratory infection long thought to be by inhalation, but studies show very few people develop colds just from inhaling droplets via sneezing or coughing. Hand contact is much more frequent, and rubbing eyes after contact is an especially effective way of getting virus into body.
• Best defenses: Frequent hand washing and avoidance of close contact with infected people.
• Examples of respiratory tract pathogens
  • Common cold
  • The most common of all infectious diseases. Average American gets 2/year.
  • Over 200 different viruses may cause cold. Most are RNA viruses in rhinovirus or adenovirus family. View rhinovirus electron micrograph; view adenovirus electron micrograph
  • Reproduce best at temperatures cooler than body temp. (33°C rather than 37°C), which is nasal pathway temp., so most infections occur in epithelial lining of nasal passageway.
  • Infection usually last a week or so, until antibodies to virus are made.
  • Pneumonia
  • One disease (inflammation in alveoli of lungs) -- many possible causes. Normally occurs as secondary infection following viral infection or other ilness. Over 300,000 cases/year in U. S., 10-20% fatal.
  • Most frequent pathogen in U. S. (70% of cases) = Streptococcus pneumoniae. Gram-positive diplococcus. View SEM of S. pneumoniae. Bacterium grows rapidly in alveoli, protected from phagocytosis by capsule. Lung spaces fill with blood, bacteria, phagocytes fluid buildup lung inflammation. View chest X-ray showing pneumonia in lung.
  • Pneumocystis pneumonia
    • a fungal disease, caused by Pneumocystis carinii, a yeast. Used to be rare, but since AIDS, disease has exploded into prominence. In early days of AIDS, 80% of patients developed this type of pneumonia.
      
      Light micrograph of Pneumocystis carinii
      
    • At first, thought to be a protist, but RNA homology studies place this in fungi
    • Not clear whether this organims is normal microbiota or not
    • Many people have inapparent infections -- most children have antibodies to Pneumocystis carinii by age 4.
    • In lung, Pneumocystis carinii elicits intense inflammatory response, produces foamy exudate of fluid. As infected cells die, leaves honeycomb appearance.
    • See X-ray of infected patient.
    • Can be treated with certain antifungal antibiotics.
  • Other causes of pneumonia:
    Staph. aureus, often after influenza infection.
    Legionella pneumoniae, first isolated in 1976 at a Legionnaire's convention. Bacteria can grow in water-cooling towers used for air conditioners, was spread as fine aerosol in closed buildings.
    Mycoplasma pneumoniae, often spread by people living in close quarters (schools, military barracks)
• Diphtheria
  • Caused by bacterium Corynebacterium diphtheriae.
  • Infection can lead to a "pseudomembrane" covering the posterior pharynx (back of the throat to you non-clinical types).
  • Clinical syndromes are determined not by the bacteria, but by a class of virus called a B phage. Only strains of C. diptheriae infected with the phage produce the diptheria toxin, responsible for most damage. Strains that lack the phage cause only minor health problems.
  • Diphtheria toxin: Toxins released by the organism create an inflammation on the pharyngeal mucosal surfaces. The pseudomembrane may obstruct breathing to the point of asphyxation and death. The toxin may travel to the heart and lead to heart failure. View diagram of toxin action.
  • See Corynebacterium diphtheriae lecture notes from Bacteriology 330, Univ. of Wisconsin for more details.
• Streptococcal diseases
• Streptococcus pyogenes (Group A streptococcus) is present in microbiota of 5-15% of humans, usually in respiratory tract, usually not producing obvious disease. Diseases can occur when host is compromised.
  
  Hemolysis produced by colonies of Streptococcus pyogenes
  
• Streptococcal membranes contain some antigens very similar to antigens in human muscle and nerve tissues, which can lead to reduced immunological activity by host ("molecular mimicry")
• Streptococcal infections can produce a family of diseases - examples:
  • suppurative (pus-forming) infections
  • pharyngitis (sore throat)
  • scarlet fever (extensive skin rash)
  • impetigo (infection of superficial skin layers
  • cellulitis (infection of deep skin layers)
  • necrotizing fasciitis (bacteria attack and destroy muscle tissue)
  • streptococcal toxic shock syndrome
• Many virulence factors, including: exotoxins, invasive enzymes, capsules, adherence proteins.
• See Streptococcus pyogenes lecture notes from Bacteriology 330, Univ. of Wisconsin for more details.
• Tuberculosis
• M. tuberculosis is a strictly aerobic bacterium, with a very slow doubling time (12-18 hours)
• View electron micrograph of M. tuberculosis
• Mycobacteria have very waxy coats (made of mycolic acid compounds). They resist destaining with acid and alcohol, and are called the acid-fast bacteria. Their waxy coats resist uptake of many antibiotics.
• TB has a long latent period; first detectable signs of antibody response are 8-12 weeks after infection.
• TB is usually asymptomatic; only 10-20% of infected persons become diseased.
• How does M. tuberculosis cause disease? Almost any tissue can become infected, but lung is common focus of infection, so consider sequence of infectious TB in lung:
  1. Bacterium is taken up inside phagosome by macrophage (first stage of phagocytosis)
  2. Bacterium secretes proteins that block fusion of phagosome with lysosome. See Dr. Terry's animation of phagocytosis, click link "Mycobaterium tuberculosis infects a macrophage."
  3. Bacterium slowly grows and replicates inside macrophage host cell, gradually turning cell into a bacterial replicator.
  4. In some cases, mature tubercules are formed as firm outer layer of macrophages "wall off" inner mass of infected macrophages. Center of tubercule liquiefies, forms air-filled cavity that promotes growth of bacteria, liquefaction of tubercule contents.

     View cross-section of normal lung
     View cross-section of lung with TB

  5. Rupture of tubercule can allow bacteria to enter bronchioles, spread through respiratory system and other tissues
  6. Patients with pulmonary TB have respiratory problems, cough up mucus secretions frequently. TB can attack many other sites in body as well as lungs.
• TB is one of the most common diseases world-wide. Some official statistics (probably way too low):
  Since you started reading this page
  people have been infected with TB.
  • Worldwide annual deaths from TB: 3 million (98% in developing countries)
  • Worldwide annual reported disease cases: 8 million
  • Worldwide incidence of infection: somewhere between 1 in 10 to 1 in 3 people
  • U.S. incidence in 1995: 22,860 cases (8.7 cases per 100,000 population)
  • View world map showing incidence of new cases
• Want to play doctor? Practice your diagnostic skill with a Web-based case study of a patient with TB.
• See Tuberculosis lecture notes from Bacteriology 330, Univ. of Wisconsin for more details.
• Leprosy
• Casuative organism = Mycobacterium leprae, rod-shaped bacterium in same genus as the tubercule bacillus.
• Bacterium cannot be grown in culture, only in footpads of armadillos (lower body temperatures).
• One of the most dreaded (and joked about) of diseases. Still a major problem, 14 million people worldwide, including about 100 new cases every year in U. S.
• Transmission is still a mystery. Most people who come in contact with lepers do not get infected. Lepers have high bacterial counts in nasal discharges, but disease does not spread in epidemic fashion.
• Disease manifestation: 2 types
1. Lepromatous leprosy. The worst form of the disease, bacteria spread to every organ and part of body. Can lead to loss of fingers, toes, nasal deformation, eventually death. See photo of leper's hands.
2. Tuberculoid leprosy. Mild disease, symptoms due to delayed hypersensitivity to proteins. Full recovery often occurs.

Bacterial Diseases of the GI tract

• GI tract infections are transmitted by contaminated food or water. Certain foods contain higher levels of microbes than others (e.g., ground meats contain more than steaks). Food handlers pose the highest risk, especially after defecating. Unless hands are washed thoroughly with soap and water, infected food handler may introduce pathogens into food being handled.
• Some fraction of population always contain GI tract pathogens. When water supplies fail (e.g. during floods, after crisis like earthquake or war), water will become contaminated. Outside the developed world, most water supplies are contaminated much of the time.
• Stomach acids and bile salts in intestines (detergent) kill most microbes. Dose of microbes critical to establishment of disease. May need to ingest as many as 10⁸ bacteria to get enough survivors into intestine to cause disease.
• Stomach was long thought to be too acidic for bacterial survival. Recently, Helicobacter pylori found to be able to grow in stomach and to cause ulcers.
• Some Gram-negatives have efficient mechanisms to survive exposure to bile salts (includes group known as "enterics": Shigella, Salmonella, etc.), certain strains can cause disease.
• Lining of intestinal tract is shed every 3 days, so pathogens must continue to grow and reproduce or they will lose their "place".
• Examples of GI tract pathogens
• Staphyloccocus aureus. Aside from its many other diseases (see boxed essay in lecture notes on introduction to pathogens), S. aureus is common source of food poisoning. Common scenario: food preparers transmit bacteria to appropriate foods (e.g. mayonnaise, custard, creamy foods) from hands or nasal secretions, then bacterium has time to grow and produce enterotoxin. Unlike many toxins, the staphylococcal enterotoxin is stable to both heat and acids. Symptoms include nausea, vomiting, and diarrhea, usually within a few hours of ingesting contaminated foods. Antibiotics are ineffective since the problem is a toxin, not a bacterium. Disease is self-limiting and individuals usually recover with 24 h.
• Cholera. Pathogen is bacterium Vibrio cholera - see micrograph. Secretes potent enterotoxin, causes massive diarrhea. For further information, see WHO fact sheet.
• Campylobacter jejuni: flagellated bacterium, common in chicken and raw milk; also in domesticated animals. View micrograph. As few as 10 ingested bacteria can lead to disease. Symptoms include bloody diarrhea, fever, nausea, cramps. Severity can match that of cholera, due to a potent enterotoxin. For further information, see WHO fact sheet.
• Botulism
• Major virulence factor: botulin (aka botox): most poisonous toxin known. 28 grams of botulin toxin could kill the entire human race (5.8 billion people).
• toxin blocks transmission from nerves to muscles, produces flaccid paralysis, progressive muscular weakness and respiratory arrest. Recovery may take months.
• View movie showing botulin toxin activity (requires free Shockwave plug-in)
• Causative organism: Clostridium botulinum. Sporeformer, widely found in soils. But obligate anaerobe, only grows when oxygen not available.
  
  
• Typical transmission routes:
  1. Food-borne botulism from improperly canned foods. Spores survive heating, grow in food ( bulges in metal cans, due to gas buildup).
  2. Infant botulism (most common) from honey fed to infants (under one year), bacteria grow in anerobic gut, toxin produced and travels into bloodstream
• Prevention: toxin is inactivated by heat, 100^oC for 10 minutes is adequate. Canned foods should always be cooked if any hint of gas or improper sterilization. Can't be treated with antibiotic (not due to growth of bacteria).
• Some other bacterial common causes of food- or water-borne infections: Bacillus cereus, Clostridium botulinum, Clostridium perfringens, Shigella dysenteriae, Escherichia coli (strains carrying enterotoxins on plasmids or lysogens).
• Hepatitis A virus (HAV). Hepatitis is a family of unrelated diseases that attack the liver. HAV is transmitted by the fecal-oral route, unlike Hepatitis Viruses B and C, which are spread by contaminated blood or blood-derived body fluids. View incidence of different hepatitis viruses in U. S.. In past decade, U.S. has experienced an estimated 125-200,000 HAV infections.
• Giardiasis
• Pathogen is a protist Giardia lamblia ; widespread, lives in GI tract of animals, eggs shed as cysts, can survive 2 months out of host
• View electron micrograph of giardia.
• Ingested by water or food. Very infectious: study with prison volunteers showed as few as 10 cysts ingested could produce disease.
  
• View life cycle of Giardia
• Often transmitted by water supply, by drinking water in remote areas. Also from food handlers. Amount of chlorine in public water supply not adequate to kill cysts. Assume all water in remote regions is contaminated; can kill cysts by boiling, ozone, or iodine treatment.
  
• Disease: diarrhea, abdominal pain, flatulence. Can be cured by certain drugs.
Urinary Tract Infections (UTIs)

• Access to the urinary tract differs widely in men and women. View diagram.
1. Males: urethra is separated from body by penis, longer channel for washout, infections rare
2. Females: urethra is next to opening of vagina, with a rich microbiota. Also fairly close to anus, possibility of infection with microbes from GI tract.
   Result: women get more UTIs than men. In younger women, 20% have at least one UTI/year. UTIs account for more than 8.3 million doctor visits annually in U. S.
• If bacteria manage to travel up urethra, reach bladder. Bladder infections may cause discomfort but not serious health risks. But infections may travel up ureters to kidney, which can produce very serious infection. View possible sites of UTI infection.
• Typical infectious organisms:
• E. coli is by far the most frequent infection outside hospitals (up to 80%).
• Staphylococcus saprophyticus (gram + bacterium) is second.
• In hospitals, some UTIs also due to Pseudomonas, Enterococcus, and Candida albicans (a yeast).
Sexually Transmitted Diseases (STDs)

• Sites of infection differ in men and women.
1. Males: most infections affect urethra or surface of penis
2. Females: most infections affect vagina or labia. Mucus plug in cervix prevents infection of upper tract, but varies during monthly cycle. See examples of cervical mucus .
• Typical infectious organisms:
• Genital Herpes Virus
• Herpes virus family causes a variety of diseases: cold sores, venereal herpes, chickenpox, shingles, infectious mononucleosis, and cancer
• Genital Herpes caused by Herpes Simplex Type 2 (HSV-2).
• View EM of herpesvirus
• Diesase is transmitted by sexual contact, produces blisters in genital tract.
• Virus then migrates to sacral nerve ganglion, remains in latent state. Can re-emerge as new blisters after stress, caused by: emotional upset, fatigue, menstruation, other infections.
• View movies of stages of Herpes Virus (requires Flash 3 plug-in)
• Can be transmitted to fetus during delivery -- may be fatal; if not, causes herpes lesions on all organs including brain. If woman has herpes lesions, Cesarean section recommended.
• No known cure; outbreaks can be treated with acyclovir.
• HIV.
• Incidence: 45,000 new cases/year in U. S.
• Not every exposure to HIV results in infection; on average, 8 exposures are needed. Lesions (e.g. from Herpes virus infection, anal intercourse) make entry much easier. Also, if another infection is in progress, T-cells will be in the region, making infection easier. Incidence of HIV infection could be reduced up to 90% by preventing Herpes and bacterial infections in genital tract! See lecture notes on viruses for more details.
• Gonnorhea and Nongonococcal urethritis (NGU).
• Incidence: 1.4 million new cases of gonorrhea/year in U. S.; 4 million new cases of NGU (50 million new cases of NGU occur yearly worldwide).
• Gonorrhea caused by Neisseria gonorrhoeae, gram- bacterium. View infected tissue. View SEM showing diplococcus arrangement.
• NGU caused by Chlamydia trachomatis, "gram- bacterium" but lacks cell wall and cannot grow outside host cells. View infected tissue.
• Symptoms are identical: in males, painful urination, thick milky discharge. In females, no symptoms in 85%; some women experience abdominal pain, increase discharge. View symptoms of some STDs (Caution: very graphic images, observe at your own risk).
• Gonorrhea can also be acquired by oral sex, leads to sore throat, often not correctly diagnosed.
• Both diseases can be cured by appropriate antibiotics: ciprofloxacin for gonorrhea, doxycycline for Chlamydia. But some strains antibiotic resistance, require other antibiotics. Azithromycin is effective against both bacteria, but expensive.
• Biggest risk of untreated infection is Pelvic Inflammatory Disease (PID). At least 1 million cases of PID/year in U. S.! Causes abdominal pain, bleeding during middle of menstrual cycle. May lead to scarring of fallopian tubes and infertility.
Nosocomical & Iatrogenic Infections

• About 2 million people in U. S. hospitals acquire new infections each year at a cost in excess of $4.5 billion. How?
1. During surgery (some surgeries more at risk than others)
2. In Intensive Care Unit (ICU); risks include equipment such as indwelling catheters, venous catheters, respiratory ventilators. Major problem is biofilms that produce sizable bacterial populations.
3. In neonatal ICUs. Newborns are at particular risk, especially in today's world where many are born to mothers with drug problems.
4. As a result of cancer chemotherapy. Chemical or radiation treatments kill not only cancer cells but other rapidly dividing cells, such as neutrophils, the major circulating phagocyte. Patients with low white cell counts are much more vulnerable to infection.
5. As a result of burns. Once skin barrier is gone, bacteria can easily enter tissues. Most common infections due to Staph aureus and Pseudomonas, very common bacteria.
Vector-Borne Diseases

• Biting arthropods can penetrate skin, inject pathogens directly into tissues of bloodstream. Contact with animals exposes humans to animal diseases. Both are major sources of infection
• Bubonic Plague
• 1894, French scientist Yersin discovered cause = bacterium Yersinia pestis. Normally found in rodents, transmitted by fleas.
• Bacterium binds to macrophages, uses Type III secretory system to inject toxic molecules (YOPs = Yersinia Outer Proteins) into cell. Macrophages die in great numbers.
• View animation of Y. pestis infecting a macrophage (by Tom Terry)
• Name comes from large, painful swellings ("buboes") in lymph nodes of neck, groin, or armpit. 3 days later, high fever, delirious, black splotches due to hemorrhaging under skin. Often buboes would burst, agonizing frenzy for victims.
• 1346-1352: "The Great Pestilence", killed one out four people in Europe, N. Africa & Middle East. 70-80% of those who got it died within 5 days.
  
  
• Fleas that ingest bacteria get bacterial growth in gut, blocks food flow. Fleas become ravenously hungry, go on feeding frenzy, repeatedly biting victim, spreading disease. When too few rodents to infect, will spread to other warm-blooded hosts (e.g. humans).
• If humans have lung infections, can spread person-to-person by droplets, extremely rapid spread possible. Otherwise only by flea bites.
• Note: plague still around, occurs regularly in Africa, S. America, and SW U.S. (10 cases reported in 1986). But never likely to approach epidemic status since we know how it spreads, how to treat cases as they occur.
• For further reading
  1. visit "Plague and Public Health in Renaissance Europe", including narrative accounts of the great plague epidemic of 1348 in several European cities.
  2. Visit CDC fact sheet on Plague
• Lyme Disease:
• Bacterial pathogen: Borrelia burgdoferi (a spirochete = spiral-shaped bacterium).
  
  
• affects CNS, may lead to long term debilitating illness, arthritis, heart problems, and more
• In 75% of untreated patients, disease persists despite immune system -- after weeks, months or even years, can get neruological problems, heart problems, and arthritis. Probably due to cross reaction with antigens to Borrelia -- don't usually find the organism at this stage.
• Typical transmission routes: carried by deer tick. Normal host = field mice in nymphal stage, then shed as adults in woods, climb on larger animals, most commonly deer, where mating and eggs are produced and shed to infect other mice. Humans are accidental host.
• Prevention: avoid tick bites, scan self after outdoor exposure. New vaccine is available, but only 75% effective, still not clear how useful this will be.
• Treatment: penicillin or tetracycline
• For further information:
  • Also Lyme Disease Web page, from University of Wisconsin Department of Bacteriology.
  • Visit CDC information page on Lyme Disease
• Malaria
History
• Most significant impact on human history of all infectious diseases.
• Contributed to fall of Greek and Roman empires.
• Major problem in U.S. Civil war--more than 1/4 of hospital admissions were malaria patients.
• Major problem in WWII-- 1/2 million American soldiers were hospitalized with malaria during WW II.
• Name comes from 17th cent. Italy: "mal-aria", bad air, because of assn. with evil-smelling vapors from swamps
• Major breakthrough in epidemiology in 1880: French surgeon Charles Laveran observed exflagellated gametocytes in fresh blood. 5 yrs. later, Italian histologist Golgi observed multiplication of asexual blood forms.
• Late 1890's, Patrick Manson postulated transmission by mosquitoes. Dr. Ronald Ross observed developing plasmodia in intestine of mosquitoes, established major features of life cycle. Nobel prize 1902.
• Although largely eliminated from Europe and North America (only 1000 cases reported in U.S. per year), it is still the most serious infectious disease in tropical and subtropical regions of the world.
  
  Geographic distribution of malaria, from Carlo Denegri Foundation, Italy
• On a worldwide basis there are still 150 million clinically ill cases a year. Over 1 million people die each year from malaria (mostly young children in Africa)
• Because malaria produces lethargy to total incapacitation, has been blamed for impeding development of entire nations.
Medical Symptoms
• 3 and 4 day cycles
• Successive stages: fever, chill, fever, exudation
• Enlarged spleen, sallow complexion
• Affects young children especially; can cause severe anemia (blood loss) and death
The Malaria Parasite
• Visit Malaria web page (Course 224 from University of Leicester)
• 4 species of protozoa called Plasmodium cause malaria in Humans:
  • P. falciparum. Accounts for 50% of all cases, including the most serious.
  • P. malariae
  • P. vivax
  • P. ovale
• View life cycle of plasmodium
• Plasmodium passes through 2 hosts: female Anopheles mosquito and human
  1. In the Anopheles mosquito:
     • View Anopheles mosquito feeding
     • In the gut of the Anopheles mosquito, fertilization of plasmodium gametocytes occurs and the zygotes of the parasite develop into oocysts which encysts in the gut wall. After about 12 days the oocysts mature and are released as numerous sporozoites
     • The spindle shaped sporozoites migrate to the mosquito salivary glands and are introduced into a new host by a mosquito bite, along with anticoagulant.
  2. In human body
     • The sporozoites travel through the blood and enter the liver (a few hours)
     • They reproduce asexually by multiple fission in the host's liver cells (for a week or two) and develop into forms called schizonts, each of which eventually ruptures and releases 20,000 merozoites
     • Each merozoite enters a red blood cell (or another liver cell), repeats sequence of development into schizonts and merozoites, released to infect yet other cells.
     • View infected blood cells, containing malaria parasites. P. falciparum trophozoites are small rings with single or double small chromatin dots.
     • Repeated cycles of rupture and invasion occur every 2 - 3 days, producing the symptoms of malaria: periodic bouts of shaking, chills, fever, and sweating
     • Some of the merozoites in the red blood cells develop into gametocytes which then mature into male and female gametocytes. These are released into the blood circulation where they can be taken up by a female mosquito
Controlling Malaria
• In 1955, WHO began worldwide malaria eradication program. DDT spraying to kill mosquitoes. Chloroquine to treat people. Initially very successful--1 billion people were spared from malarial infection. But program was abandoned by 1969. Why?
• Massive use of DTT introduced many new problems. Fat soluble compound, so it accumulated in bodies of insects. In Malaysia, cockroaches adsorbed DDT but were not killed; they were eaten by lizards, and lizards by cats. Cats died from excess DDT poisoining, leading to population explosion of rats, who spread typhus and plague.
• Most critical problem: DDT-resistant strains of mosquitoes, chloroquine resistant strains of Plasmodium evolved. Most lethal strain (Plasmodium falciparum) is now genetically resistant to chloroquine worldwide.
• Mosquitoes and 4 disease causing strains of Plasmodium threaten to regain the ground lost in the 50s and 60s. The situation may be as bad as 2 decades ago
• Attempts to develop a vaccine have so far failed. The plasmodium changes its coat protein too often.
• Anthrax
• Caused by Bacillus anthracis, gram+ bacterium, endospore former. See gram stain.
• Normally found in lower vertebrates, including cattle, camels, goats, sheep, other herbivores. Can infect humans.
• Endospores last in soils for years.
• Disease symptoms: 3 types (see chart)
1. Cutaneous: most anthrax infections due to entry or bacteria through cut or other abrasion in skin. After a few deays, leads to painful swelling with black center filled with dead tissue. If untreated, 1 in 5 cases are fatal. See picture of necrotic anthrax infection.
2. Inhalation: when endospores are inhaled, can infect lung, usually fatal. Virulence factors include "lethal toxin", attacks many cells in body, produces serious breathing problems, shock.
3. Intestinal: eating contaminated meat can cause acute inflammation of intestinal tract, nausea, vomiting (including vomiting blood), severe diarrhea. If untreated, 50% or more cases are fatal.
• Anthrax was developed as potential weapon by scientists in Soviet Union and U.S. The Anthrax scare of fall 2001 in the U.S. illustrates how vulnerable civilian populations are. Potential as a bioterrorist weapon is significant.
• Vaccine has been developed, but not fully tested or used. U.S. tried to vaccinate soldiers during Gulf War, but many refused. Currenly only one company licensed to manufacture vaccine, in facilities that are outdated. Major push is underway to accelerate new anthrax vaccine production.

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