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Lecture 5 The diversity of infectious disease agents (I) I can win an argument on any topic, against any opponent. People know this, and steer clear of me at parties. Often, as a sign of their great respect, they don't even invite me. Dave Barry (1947 - ) Next two lectures: • Pathogens in context: the diversity of life on Earth • Bacteria • Viruses • Survey of important human infectious diseases and pathogens (including a few eukaryotic pathogens) The three domains of life • Before molecular sequence-based methods it was not possible to reconstruct the tree of life • 2 kingdoms (from Linnaeus--think Zoology and Botany departments) became 5 (animals, plants, fungi, “protists”, and “monera”) • There was also a more fundamental distinction between organisms with nuclear membranes (eukaryotes) and without (prokaryotes) • The main diversity of life was thought to be in the four eukaryotic kingdoms (particularly the multicellular ones) Whittaker, 1969: the 5 Kingdoms The three domains of life • Carl Woese brought clarity to microbial (and in fact all biological) diversity by comparing fundamental gene sequences shared by all known, non-viral life forms • Ribosomal RNA (rRNA) comparisons indicate that there are three “domains” of life: bacteria, archaea, and eucarya • The phylogenetic tree, based on molecular sequence, became the most powerful tool to reconstruct the history of life The three domains of life BACTERIA ARCHEA * 0.1 CHANGES/SITE EUCARYA The three domains of life • • • • Phylogenetic trees are conceptually simple. They represent educated guesses about the historical diversification, and hence relationships, among taxa Consist of topology plus branch lengths. Aligned sequences are compared and, in general, pairs of sequences with few differences branch together This reflects “evolutionary distance” In reality, no single tree accurately reflects the deep history of life because it was not treelike, but the rRNA tree is still meaningful The three domains of life • It is shocking how much of the diversity of life is microbial • Historically biology has tended to be eukaryotically chauvinistic …why? • The tree of life shows that humans, and our close kin such as plants and fungi, occupy a very narrow slice of biological diversity The three domains of life BACTERIA ARCHEA * 0.1 CHANGES/SITE EUCARYA The three domains of life BACTERIA ARCHEA * 0.1 CHANGES/SITE EUCARYA The three domains of life • Humanity’s place on the tree of life is perhaps as profound an insight as the Copernican revolution • Not only are we floating on a planet orbiting a mediocre star in a mediocre galaxy, but we’re also just a sideshow in the diversity of life on Earth Microbial diversity • Classical microbiology relied on observing bacteria/archaea down a microscope • To do this, it was necessary first to cultivate them in the laboratory • They would put samples of soil, or pus, or whatever, in various kinds of nutrient broth Microbial diversity • Each of would encourage the growth of different sorts of bacteria/archaea depending on the chemical composition • Hence classical microbiology is the study of bacteria/archaea that can be cultured. • Nowadays, we can look directly at bacterial genes without culturing and it turns out we were missing about 99.99% of the diversity • Fossil evidence for prokaryotic life 3.5 billion years ago • It took another 2 billion years or so for the appearance of eukaryotic cells that could give rise to larger animals and plants • Archea may be the most diverse and massive domain, but few are known to cause infectious disease, so we’ll ignore them • There are lots of beneficial bacteria: -nitrogen-fixing bacteria in root nodules of plants -bacteria in rumen of cattle digest cellulose of grass -even in non-ruminants, like us, most gut bacteria appear to be beneficial -fermenting milk into yogurt and cheese -alcohol -recycling waste -synthesizing antibiotics and enzymes • Their metabolic and ecological diversity outstrips eukaryotes • In fact, most of the interesting biochemistry in “higher” organisms is actually done by bacteria Check out the rest of this paper: this is what you should be aiming for with your term paper. Model the format on the “News and Views” format of the journal “Nature”. Look at several such articles. The journal is available online. • Only very few bacteria of the innumerable species are pathogenic • Of the roughly 400 genera less than 40 contain species that regularly cause disease in humans • Other animals have different suites of pathogens • But there is overlap: zoonoses are diseases that jump occasionally from some “natural” non-human host • E.g. plague from rats, brucellosis from goats, TB from cattle (which is why milk is pastuerized) Bacterial classification • Phenotype is actually a pretty bad guide to phylogeny • For example photosynthesis is practiced by species from five bacterial Kingdoms • Traditional microbiologists drew a sharp distinction between “Gram-positives” and “Gram-negatives” • Named after Hans Christian Gram who found that some bacteria, first dyed, then treated with solvent, retain the dye Gram-positives are a coherent group, but Gramnegatives are not As if zoologists had classified animals into “Birds” and “The Rest” • • Spirochaetes •Chlamydiae and sprirochaetes are obligate intracellular parasites of animals Chlamydiae and Spirochaetes •Chlamydia infection is often asymptomatic •Most common bacterial STD in USA, with about 3 million new infections/year •Can cause reproductive problems, pneumonia in newborns •Spirochaetes include the agents of syphilis (Tryponema pallidum) and yaws and the agent of relapsing fever and Lyme disease (Borrelia burgdorferi) Late Syphilis: Gumma On Eye Syphilus: Treponema pallidum Actinobacteria a.k.a. Grampositive, high G-C •Gram-positive bacteria include the agents of tuberculosis, Mycobacterium tuberculosis, and leprosy. M. leprae •These are both “high G-C” Grampositives •What is “high G-C”? •Lots of G’s and C’s relative to A’s and G’s in their DNA Gram-positives Tuberculosis Figure 10-3 part 3 of 3 • The singlemost important bacterial pathogen of humans right now (around 2 million deaths/year) • Most deaths in developing world, but by no means solely there • A.k.a. ‘consumption’: used to kill 5/1000/year in Britain • Accounted for many of those pale, coughing Victorians • Caused by Mycobacterium tuberculosis, a very tough bacterium that is resistant to most host defense mechanisms (why?) Firmicutes (including Clostridia) a.k.a. Grampositive, low GC content •Among the “low G-C” ones are -Bacillus anthracis (anthrax) -Staphylococcus aureus (what you don’t want to get after surgery) -Streptococcus pneumoniae (pneumonia, bacterial meningitis) -Clostridium spp.(anaerobic, spores resist boiling; causes botulism, gas gangrene, tetanus, among other pathologies) -Lactobacillus (on a more friendly note, fermenting agent for making yoghurt) Gram-positives What is Tetanus? Tetanus is an acute, sometimes fatal, disease of the central nervous system, caused by the toxin of the tetanus bacterium Clostridium tetani, which usually enters the body through an open wound. The bacteria then multiply too fast to be destroyed by the immune system. C. tetani releases powerful poisons known as toxins that rapidly destroy tissue.[1] The tetanus bacterium lives in soil and manure, but also can be found in the human intestine and other places. Proteobacteria proteobacteria •Proteobacteria are a diverse and important group also known as purple bacteria •Mitochondria are endosymbiotic proteobacteria •Traditionally divided into alpha, beta, gamma, delta •Epsilon has now been added •Many proteobacteria practice photosynthesis that is distinct from other bacteria proteobacteria •Various alpha proteobacteria form close association with eukaryotes Rhizobium fix nitrogen in root nodules •Agrobacterium is closely related and is a plant pathogen •Rickettsias are intracellular pathogens of animals (e.g. typhus/Rickettsia prowazekii) •Rickettsias dwell within cells and it’s not surprising that mitochondria, which also dwell intimately in eukaryotic cells, are closely related proteobacteria •Typhus (not to be confused with Typhoid fever, caused by Salmonella sp) is a name given to several similar diseases caused by Rickettsia bacteria. •Rickettsia is endemic in rodent hosts, including mice and rats, and spreads to humans through mites, fleas and head, body, and pubic lice. •The insects often flourish under conditions of poor hygiene, such as those found in prisons or refugee camps, amongst the homeless, or until the middle of the 20th Century, in armies in the field. Typhus in history The city-state of Athens in ancient Greece was hit by a devastating epidemic, known as the Plague of Athens, during the second year of the Peloponnesian War (430 BC), which killed, among others, Pericles and his two elder sons. The plague returned twice more, in 429 BC and in the winter of 427/6 BC. Epidemic typhus is one of the strongest candidates for the cause of this disease outbreak Combatant deaths due to typhus were obviously a serious factor during European conflicts. Major outbreaks occurred during the liberation of Spain, the English Civil War, the Thirty Years' War, and during Napoleon's failure in Russia. In World War I, de-lousing stations were established for troops on the Western front but the disease ravaged the armies of the Eastern front, with over 150,000 dying in Serbia alone. Fatalities were generally between 10 to 40 percent of those infected, and the disease was a major cause of death for those nursing the sick. Thousands of prisoners held in appalling conditions in German concentration camps such Theresienstadt and Bergen-Belsen died of typhus during World War II. Typhus was also a killer in civilian populations throughout history. In London, typhus frequently broke out among the ill-kept prisoners of Newgate Gaol and then moved into the general city population. An outbreak in 1557–59 killed about 10 percent of the English population. In Russia after World War I, in the civil war between the White and Red armies, typhus killed three million, largely civilians. •Beta proteobacteria include Neisseria gonorrhea proteobacteria Bordetella pertussis (whooping cough) •Deltas/epsilons include -Bdellovibrioi which acts like a guided missile and attacks other bacteria by rushing at them at 100 cell lengths per second and boring in at 6000 rpm -Helicobacter pylori the agent of stomach ulcers Meningitis Neisseria spp. Haemophilus influenzae •Gamma proteobacteria include several important pathogens, including: proteobacteria -Escherichia coli -Shigella -Salmonella (Typhoid fever) -Vibrio (Cholera) -Legionella -Yersinia pestis (plague) -Haemophilus influenzae (pneumonia) •Supremely important ecologically Cyanobacteria •Used to be called “blue-green algae” •Ubiquitous green scum responsible for a lot of the world’s photosynthesis •Chloroplasts are endosymbiotic cyanobacteria •Anyone know of a pathogenic cyanobacterium? Figure 10-3 part 3 of 3 Figure 10-3 part 3 of 3 Chest X-Ray, with pneumonia. Acute respiratory illnesses Figure 10-3 part 3 of 3 • Respiratory infections, including pneumonia, are a big class of human pathogens • Streptococcus pneumoniae among the most common causes of pneumonia • Causes desperate illness, blue color, gasping for breath • Other important bacterial respiratory pathogens include Bordetella pertussis (whooping cough) • Haemophilus influenzae (pneumonia and meningitis) (Why’s it called that!?) Figure 10-3 part 3 of 3 Diarrheal diseases Figure 10-3 part 3 of 3 • Taken together, pathogens causing diarrhea are among the most lethal • More than 2 million deaths/year, mostly developing world, mostly children • Very easy to prevent and treat in many cases •Epidemic Cholera Vibrio cholerae •Cholera is an acute, infectious disease characterized by extreme diarrhea, vomiting, and cramps. •The cholera bacteria produce a toxin which keeps the human body from absorbing liquids. •It is one of the most rapidly fatal illnesses known. Untreated individuals may die from severe dehydration within two to three hours. This disease has been the killer of millions worldwide. It is endemic in both Bangladesh and Peru • In 1991, a cholera epidemic swept down the west coast of South America. Africa suffered a similar cholera surge in 1991. •It seems that the bacteria prefers brackish coastal waters (moderately salty waters, i.e., coastal estuaries). Epidemic Cholera Vibrio cholerae •The bacteria is controlled by chlorination of water and by waste water management. Of course, the less developed nations with their less developed water and waste systems are more at risk of outbreaks than the more developed nations. •Natural disasters can greatly heighten the cholera risk by damaging the water and waste water systems. •Today . . . “Cholera can be simply and successfully treated by immediate replacement of the fluid and salts lost through diarrhea. Patients can be treated with oral rehydration solution, a prepackaged mixture of sugar and salts to be mixed with water and drunk in large amounts. This solution is used throughout the world to treat diarrhea” Other bacterial diarrhea-causing bugs: •Shigella •Salmonella (including S. typhi, the typhoid bacillus) •E. coli 0157 •Collectively known as the “enterics” •There are also important protozoan and viral agents of diarrhea Figure 10-3 part 3 of 3 Figure 10-3 part 2 of 3