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Praveen Rao, Sophia W. Riccardi, Danielle Birrer
Seminar in Nucleic Acids-Spring 2004 Prof. Zubay
• • •
Overview History and Epidemiology Molecular Biology Clinical Weaponization
Salmonella is a rodshaped, gramnegative, facultative anaerobe in the family Enterobacteriaceae
H and Vi. The simplified version: Salmonella typhi. which also involves immunoreactivity of three surface antigens. In the U. • Over 2000 strains are grouped into S.S. bongori (CDC). • • • • .Salmonella Taxonomy • The genus Salmonella is divided into two species. O. Taxonomy has been revised several times. enterica and S. S. due to the degree of DNA similarity between genomes.. enterica. For example. All strains that are pathogenic to humans are in species S. For example. another legitimate species name for enterica is choleraesuis. subgroup 1 (also called enterica). This species is further divided into six subgroups based on host range specificity. enterica. enterica. serovar typhi. the correct taxonomic name for the organism that causes typhoid fever is Salmonella enterica ssp.
a U. Heating at 57-60°C or 134-140°F has shown to be effective in killing the bacteria. who discovered and isolated the strain enterica or choleraesuis from the intestine of a pig in 1885. as of 2001.Other Facts • Bacterium of 2501 identified strains. They are ingested orally by contaminated food or water. Salmon.S.400 serotypes of this bacteria genus. veterinary surgeon.6°F • • • . “Salmonella” derived from Dr. Many different diseases are caused by more than 1. Optimal growth: 37°C or 98. Refrigeration prevents growth but does not kill bacteria.
• . ranging from mild to serious infections.Disease-associated facts • • “Salmonellosis”: Any of several bacterial infections caused by species of Salmonella. a needle-like multi-protein complex that is associated with transferring toxic proteins to host cells. diseases is the Type III Secretion System. The main feature for S. Two main kinds in humans: enteric fever (typhoid and paratyphoid) and gastroenteritis (non-typhoidal).
and in the intestinal tracts of a wide variety of animals.Principal habitats in different types of Salmonella • Their principal habitat is the intestinal tracts and bloodstream of humans.Typhoidal (enteric) Salmonella (example: S. The WHO groups Salmonella into 3 types: . typhi) ٠causes typhoid and paratyphoid fever ٠restricted to growth in human hosts ٠principal habitat is in intestinal tracts and the bloodstream • • • • • • .
S. mainly gastroenteritis. seafood ٠house and exotic pets. typhimurium) ٠prevalent in gastrointestinal tracts of a broad range of animals.fruits. through certain food products: fresh meat.. contamination through contact with their feces . including mammals. eggs and milk . reptiles.Nontyphoidal Salmonella (example: S. birds and insects. ٠usually transferred animal-to-person. enteritidis. vegetables. ٠cause a whole range of diseases in animals and humans. poultry.
. such as cattle and pigs. .Salmonella mostly restricted to certain animals. infrequently in humans. if these strains do cause disease in humans. it is often invasive and life-threatening.
Salmonella • • • • • Overview History and Epidemiology Molecular Biology Clinical Weaponization .
During the Victorian era. based on a description of Alexander’s symptoms written by the Greek author Arrian of Nicomedia. • . died of a Salmonella infection in 1861. the consort of Queen Victoria. a group of doctors at the University of Maryland suggested that S.000 cases per year occurred in England.C.History of Salmonella Some historical figures are believed to have been killed by • Salmonella: • Alexander the Great died mysteriously in 323 B. an estimated 50. In 2001. • Prince Albert. was the cause of death.
1.738 recruits contracted the disease (82% of all sick soldiers). .590 died (yielding a mortality rate of 7.7%) .In all. .History Scholars working on the history of Jamestown. believe that a typhoid outbreak was responsible for deaths of over 6000 settlers between 1607 and 1624.A significant number of these deaths actually occurred at training areas in the southeastern United States. Virginia. Typhoid Epidemic in the Spanish-American War (1898) . 20.It accounted for 87% of the total deaths from disease.
.more soldiers suffered from typhoid fever than from battle wounds.outbreak was largely due to unsanitary towns and farms throughout Africa. .000 men to typhoid.000 battle deaths. and polluted soil was washed into the network of streams and rivers during the rainy season. .British troops lost 13.History Typhoid outbreak in British camps during the South African War (18991902) . as compared to 8. Epidemic potential during a war prominent because of the disposal problems of men’s discharges.
History Similar problems of sanitation occurred in urban areas.Dr.reports show that in the nineteenth century. published them in the Lancet. William Budd (1811-1880): documented his observations. . . population seemed powerless against this disease even though they knew it was perfectly preventable. Many historic documents report about typhoid outbreaks in England: . It was known then that polluted water can spread the disease.with the introduction of piped and filtered water supplies in most urban areas. Budd urged for more disinfection and water treatment . its prominence as a cause of death had diminished. .Most outbreaks that were reported could be traced back to unsanitary water supplies or polluted milk supplies.
a way around the problem of sanitation and cleanliness. as an antityphoid vaccine was developed by the British surgeon Almroth Wright.Salmonella vaccine First preventive measure against Salmonella was discovered in 1896. most soldiers refused to be immunized because of violent reaction following injection. possible contraction Urban outbreaks: opposition to any type of vaccination. British War Office authorized it on a voluntary basis only. . Early wars: -Immunization known. rudimentary killed whole-cell bacteria. but new -the minimum dosage had not been clearly refined. Vaccine consisted of heat-denatured. said to be highly effective. It was seen as a disease of “defective civilization …due to defective sanitation”.
typhi). Vaccine was successfully used during World War I to reduce the number of soldiers who died of enteric fever (S. in the scientific as well as military world.Salmonella vaccine • Between 1904-1914. • . the vaccine had become respectable.
Army of Medical Department Professional Service Schools . U. 1944 Division of Biologic Products.S. 1909 United States Army Medical School Bottling typhoid vaccine.First typhoid inoculation.
S.1% of those infected with nontyphoidal salmonellae become chronic carriers which may last for a few weeks to years. who was hired as a cook at several private homes in the new York area in the early 1900’s. These cases serve as natural reservoir for the disease. “Typhoid Mary” Mallon was the first famous carrier of typhoid fever in the U. they contract only mild or asymptomatic disease. typhi and 0. . Approximately 3% of persons infected with S.History in the U. Known as “chronic carriers”. Some individuals have natural immunity to Salmonella. but still carry the bacteria in their body for a long time.S. One such case was Mary Mallon.
. moving from household to household. she had worked for 7 families. NY. She was finally overtaken by the authorities in 1907 and committed to an isolation center on North Brother Island. always disappearing before an epidemic could be traced back to the particular household Mary was working in. where she lived until her death in 1938. There she stayed until she was released in 1910.History: Mary Mallon Mary Mallon caused several typhoid outbreaks. All together. on the condition that she never accept employment involving food handling. But: She was found to work as a cook and to cause typhoid outbreaks again. with 22 cases of typhoid and one death. She was admitted back to North Brother Island.
a salmonellosis (S.Recent outbreaks More recently reported outbreaks in the U.S.000 confirmed cases in 6 states by low fat milk and whole milk from one Chicago dairy. involve different kinds of Salmonella strains. typhimurium. Investigations discovered that raw and pasteurized milk had been accidentally mixed. In 1985. predominantly S. enteritidis and S. typhimurium) outbreak involving 16.S. Largest outbreak of food-borne salmonellosis in the U. .
were involved with outbreaks of S. typhimurium .Oregon: Intentional Contamination of Restaurant Salad Bars In September of 1984. Oregon. 10 area restaurants in The Dalles.
Outbreaks • January 2000: infant aged 1 month visited a clinic with fever and diarrhea. • . One week before illness onset. A stool specimen yielded Salmonella serotype Tennessee. Blood and stool cultures yielded Salmonella serotype Poona (from pet Iguana). the infant's family moved into a household that contained a bearded dragon (i.e. abdominal cramps. During June 2002. and bloody diarrhea. a child aged 21 months was admitted to a hospital with fever.. Pogona vitticeps).
about 30% of people suffer from foodborne diseases each year.1 million people died of foodborne illness in industrialized countries.000 in death. of which 325. around 76 million cases occur each year. (WHO. 2002) .Foodborne diseases • • WHO: in 2000 that globally about 2.000 result in hospitalization and 5.
Why do foodborne diseases emerge ? • Globalization of food supply: for example.S. Poona infections associated with eating Cantaloupe from Mexico (2000-2002) Unavoidable introduction of pathogens into new geographic areas: for example. Travelers. . development of antibiotic resistance. multistate outbreaks of S. Changes in microorganisms: evolution of new pathogens. changes in the ability to • • • survive in adverse environmental conditions. vibrio cholerae introduced into waters off the coast of southern U. by cargo ship (1991). refugees and immigrants exposed to unfamiliar foodborne hazards.
• . more likely to succumb to bacterial infections.Why do foodborne diseases emerge ? • Changes in human population: population of highly susceptible people is expanding. In many countries. the boom in food service establishments is not matched by effective food safety education and control. Changes in lifestyle: Great amount of people eat prepared meals.
Shows decrease of 7% compared to 1992. Salmonella accounts for the majority of food poisoning cases in the U.000 population. a total of 32. Estimate: 2 to 4 million cases of salmonellosis occur in the U. .S. annually (reported and unreported). The national rate of reported isolates was 11.5 per 100.308 cases were reported from health laboratories in 50 states.S.S Latest numbers: In 2002. slight increase of 2% from 2001.Relative Frequency of the disease in the U.
in history and present: . typhimurium The “top 20” serotypes accounted for 80% of all isolates reported in the U. enteritides and S. typhi .S.S. .S. in 2001.Epidemiology The most commonly reported serotypes.
2001.5 1.614 3..7 10 5.9 1.S.Top 15 Salmonella Serotype list in the U.9 3.067 626 595 583 514 469 466 440 388 370 343 17. 2001 Country.4 2 1.S.A.4 1.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Enteridites Newport Heidelberg Javiana Montevideo Oranienburg Muenchen Thompson Saintpaul Paratyphi B tartrate positive Infantis Braenderup Agona Typhi 5.884 1.675 1 Typhimurium 6. Control and Prevention-FDDB Epi.2 1. Human Total Serot ped Rank Serotype Count % of Total Serotyped 31..5 1.999 22.8 1.1 . Institution. Biological origin U.158 1.2 1. Centers of Disease Control.6 1.
. Since improvements in food handling. piped and filtered water supplies as well as water/sewage treatment have been made. typhi (typhoidal Samonella) Causes enteric fever Have no known hosts other than humans. enteric fever has become relatively rare in developed countries. most cases of disease result from digestion of contaminated food or water.Epidemiology S. Transmission through close contact with infected or chronic carriers. While direct person-to-person transmission through the fecal-oral route is rare.
.000 result in death. . and 70% of these cases are acquired while traveling internationally. However.S. In comparison. The WHO estimates that there are worldwide about 16 million of clinical cases annually. of which about 600. about 400 cases occur each year in the U. typhoid fever is still a big health-problem in developing countries.
the contaminated surface water further contaminates water supplies.Salmonella typhi in developing countries Contaminated water is a common cause in the spread of typhoid fever. Morbidity and complication rate is much higher than in Europe and North America due to lack of antibiotics supply. . sterilization of water and sanitation. At the time of rain. water filtration and treatment. Severity.
S. Typhi in the U.S.
Almost 30% of reported cases in the U.S. are domestically acquired. Although most cases are sporadic, large outbreaks do occur. For example, outbreak linked to contaminated orange juice in N. Y., caused by a previously unknown chronic carrier (1991). Multi-drug resistance: recent trend toward an increased incidence of multi-drug resistant S. typhi in developing countries is reflected by increase in the proportion of U.S. cases: 0.6% in 1985-1989 to 1.2% in 1990-1994.
S. enteriditis and typhimurium (non-typhoidal S.):
- are the 2 top serotypes in the U.S. since 1980’s
- cause gastroenteritis following ingestion of the bacteria on or in food or on fingers and other objects - cause the majority of cases of zoonotic salmonellosis in many countries.
by R. Wayne Edwards January 1999
transmitted to humans by contaminated foods of animal origin, predominantly eggs. Raw eaten or undercooked eggs that have been infected in the hen’s ovaries can cause gastroenteritis
Humpty Dumpty lay on the ground A crushed and broken fella. No one wanted to put him together 'Cause he had salmonella.
but now it is increasing in other parts of the country as well. United States. 1985–1999 . Salmonella Enteritidis Infections. illness related to contaminated eggs occurred most frequently in the northeastern United States. During the 1980s.
rate still decreasing due to prevention and control efforts by the government.000 eggs may be internally contaminated. 2002: In the Northeast. In 1999: 1. CDC. .000 population. approximately one in 10.9 per 100.98 per 100.000. one in 50 average consumers could be exposed to a contaminated egg each year. In 1995: high of 3.
1988 In 1997.S.S. due to antibiotic resistant strains intensive animal maintenance. . the WHO stated that some countries in Europe had a staggering 20-fold increase in incidences between 1980 and 1997. and a 5-fold increase in the U. typhimurium has been reported increasingly frequently as the cause of human and animal salmonellosis since 1990. which initially emerged in cattle in England. due to antibiotic resistance Predominant multi-drug resistant strain DT 104. between 1974 and 1994.
It is recommended to organize temporary water purification and sanitation facilities until longer term measures can be implemented. Food and water samples should be taken from suspected sources of the outbreak.Epidemic measures Salmonellosis is a reportable disease. Samples of stool or urine may be taken after one week of onset for effective confirmation. . Samples of blood can be taken immediately for confirmation and for testing for antibiotic sensitivity. An intensive search should be conducted for the source of an infection and for the means (food or water) by which the infection was transmitted.
is estimated a total of almost $400 Million. .000 to more than $20 Million.Cost Estimates The cost per reported case of human salmonellosis range from US $100 to $1300 in North America and Europe. The total annual cost in the U.S. The costs associated with individual outbreaks in North America and Europe range from around $60.
Salmonella • • • • • Overview History and Epidemiology Molecular Biology Clinical Weaponization .
Salmonella Microbiology .
rod 2-3 µm in length Flagellated • Many serovars • • • Typhi Typhimurium Enteriditis .Classification • Enterobacteria • • • Gram-negative Facultative anaerobes • Glucose-fermenting • • Straight.
typhi) • • Coded for by rfb locus on chromosome Lipid core of LPS highly conserved across serovars.LPS on Surface • Lipopolysaccharide • • Protective outer layer of most strains (not S. but polysaccharide side chains are highly polymorphic (nature of rfb gene) .
) • • • Memory immune response and antibodies directed against LPS Polymorphic nature of side chains is advantageous for bacteria Since Typhi has outer capsule.LPS (cont. . this infection is worse.
Infection • • • • • Ingestion of contaminated food or water Passes through mucosa of intestine to epithelial cells Causes membrane ruffling Releases effector proteins through Type III Secretion system Endocytosis .
Salmonella Entry .
Membrane Ruffling .
Virulence Factors • • • Genes for virulence factors cluster in pathogenicity islands (PI) Genes acquired through lateral transfer Bacteriophage and transposon insertion sequences flank PI • Maybe vehicles for transfer of PI to Salmonella at one time • Acquisition of PI enhances virulence of bacteria .
Horizontal Transfer • Transformation • • Uptake of naked DNA Mediates exchange of any part of DNA F+ to FRequires cell to cell contact – conjugation bridge Transfer of DNA by a phage New phage: viral coat with bacterial DNA • Conjugation • • • Transduction • • .
Salmonella Pathogenicity Islands • Salmonella Pathogenicity Island 1 (SPI-1) • • • Salmonella Pathogenicity Island 2 (SPI-2) • entry into intestinal epithelium Enables pathogen to exploit host intestinal environment • intracellular bacterial replication and initiation of systemic infection Do not influence enteropathogenesis to any great extent .
Type III Secretion System (TTSS) • • Main way Salmonella delivers virulence factors to host Made up of 20 proteins • PrgI Assemble in step-wise order • PrgI is a needle structure extended by protein base. forms a channel to host .
other on SPI-2 Starts bacteria-mediated endocytosis SPI-1 TTSS probably causes initial interaction • Entry activates SPI-2 TTSS to cause thorough infection .Salmonella-host Interaction • • • Two forms of TTSS • One encoded on SPI-1.
resembling ruffling This triggers endocytosis into vesicles Slightly different from receptor-mediated endocytosis .Membrane Ruffling • • • • • Cytoskeleton-associated proteins relocate to site of bacterial entry Bacterial effector proteins trigger cytoskeleton rearrangements Apical membrane surface undergoes structural changes.
Salmonella enters a SCV through bacteria-mediated endocytosis Lives and multiplies in SCV Very little known about SCV or how bacteria exist inside A method to avoid host immune response Phagosome: maturing SCV .Salmonella Containing Vesicle • • • • • After ingestion.
then polymerize Aides in cytoskeleton rearrangements in membrane ruffling .SPI-1 Effector Proteins • SipA • • • • SipC • • • Binds actin and stabilizes filaments Allows actin to polymerize more easily Maximizes efficiency of Salmonella invasion Aides in entry of other SPI-1 effector proteins Activtes G-actin to form F-actin.
SopB • • • • Main virulence factor Encoded by SPI-5 An enterotoxin associated with SPI-1 TTSS Induces an increase in concentration of cellular inositol polyphosphate • • • Increased chloride secretion into lumen Na+ follows to balance charge Water follow to balance osmolarity diarrhea .
Activated once bacteria enters cell Necessary for systemic infection SPI-2 TTSS secretes effector proteins from phagosome into cytosol
Interfere with maturation of phagosome
No fusion with lysosome How Salmonella avoids degredation in cell
Another antigen Host cytotoxic T-cell response directed against flagellar epitopes N- and C- termini are highly conserved Middle of flagellum is variable
Phase I / II Flagella
Operon encoding Phase I flagella also encodes for a protein that represses trascription of Phase II The switch mediated by an enzyme that inhibits Phase I, allowing Phase II May help Salmonella avoid cell-mediated immune response
Tumor Necrosis Factor-α • • • Flagella from S. Typhimurium induces expression of TNF-α through cell-mediated reponse Phase II flagella are less-potent inducers Switching mechanism may provide bacteria with a way to down-regulate inflammatory response within host .
macrophages. causing cell-mediated response by Tcells Antibodies from B cells attach to bacteria. B cells Two types of B cells: one to attack now. and neutrophils to kill the organism .Immune Response • • • • White blood cells recognize – trigger T cells. secrete interleukins. one for memory Macrophages and neutrophils attack bacteria. allowing cytotoxic T cells.
typhi) . causing systemic infection (only in S.Inside Macrophages • • SPI-2 TTSS works in macrophages as well Bacterium produces enzymes that inactivte toxic macrophage compounds • • Homocysteine (Nitric Oxide antagonist) Superoxide dismutase (inactivates reactive peroxides) • Salmonella must produce additional factors to survive limited nutrient base • Allows bacteria to travel throughout body.
Septicemia • • • • • Invasion of bloodstream spv genes causes detachment of cells to ECM and apoptosis Spreads infection Bacteria can enter bloodstream and lymphatic system Main cause of death by Salmonella .
How do we respond? • Microbiological view • • • Vaccines Dam Antibiotics .
Salmonella Vaccine Strategy Delete chromosomal regions that code for independent and essential functions. chickens.low probability of acquiring both traits . growth is reduced .only a low level of infection is established . sheep. This results in: .immune system can mount a response Vaccine suitable for humans and mice.can be grown on complete medium in lab .both traits: * aro genes: aromatic compound biosynthesis * pur genes: purine metabolism biosynthesis Deletion strains . cattle .in vivo.
DNA adenine methylase (Dam) • Enzyme that methylates specific adenine residues in Salmonella genome • Disrupts regulation of DNA replication and repair • • • Regulates expression of about 20 bacterial genes active during infection Dam (-) mutants are not virulent • Good antimicrobial potential Current “hot topic” of research .
or metabolism MIC: Minimum Inhibitory Concentration • the minimum amount of agent needed to inhibit the growth of an organism .Antibiotics • • • Antibiotics are selective poisons • Do not harm body cells Target different aspects of bacteria. such as ability to synthesize cell wall.
Antibiotic Resistance • Bacteria can counteract antibiotics by: • • • Preventing antibiotic from getting to target Changing the target Destroy the antibiotic Horizontal transfer from another bacteria Vertical transfer due to natural selection • Bacteria can acquire resistance • • .
Salmonella • • • • • Overview History and Epidemiology Molecular Biology Clinical Weaponization .
Dairy: eggs Pet turtles and lizards .How Do You Catch Salmonella? Food borne Transmitted via improperly prepared. pork . previously contaminated food or water . wild birds.Meat: poultry.
Choleraesius) .Septicemia (S.e.Gastroenteritis (S.How does Salmonella affect the body? Three clinical forms of salmonellosis .Enteric Fevers (i. S. typhi – Typhoid Fever) . typhimurium) .
infants. immunocompromised patients (AIDS. sickle cell anemia) .Who Can Be Infected? Everyone Especially: the elderly.
Factors Increasing Susceptibility .
confirmed by antigenic analysis of O (somatic) and H (flagellar) antigens Test for antigens: .Identification I Laboratory identification of genus Salmonella: biochemical + serological tests HOW? . green agars. MacConkey) Suspect colonies further analyzed by triple sugar iron agar/ or lysine-iron agar .stool or blood specimens are plated on agar media (bismuth sulfite.
Identification II Use phenol red test: .if negative. diagnose (presence of red spots surrounded by a bright red zone) Salmonella typhimurium .testing for lactic acid production .
small turtles ban. General Symptoms: diarrhea with fever. abdominal cramps.Nontyphoidal Salmonella General Incubation: 6 hrs-10 days. Duration: 2-7 days Infective Dose = usually millions to billions of cells Transmission occurs via contaminated food and water Reservoir: a) multiple animal reservoirs b) mainly from poultry and eggs (80% cases from eggs) c) fresh produce and exotic pets are also a source of contamination (> 90% of reptile stool contain salmonella bacterium). nausea and sometimes vomiting .
especially with multi-drug resistant S.Nontyphoidal Salmonella Caused by S. Warm season of temperate climates Growing rapidly in the U. typhimurium and S. Typhimurium known as Definitive Type 104 (DT 104) .: five-fold increase between 1974-1994 Centralization of food processing makes nontyphoidal salmonellosis particularly prevalent in developing countries Resistance is a concern.S. enteritidis Rainy season of tropical climates.
bloody stool.Nontyphoidal Salmonella: Gastroenteritis Incubation: 8-48 hrs . nausea. Pseudoappendicitis (rare) Stool culture will remain positive for 4-5 weeks < 1% will become carriers .5-102. abdominal cramps and fevers of 100. for fever Inoculum: large Limited to GI tract Symptoms include: diarrhea. Also accompanied by loose. Duration: 3-7 days for diarrhea & 72 hrs.2ºF.
preexisting heart valve disease risk factor Arteritis: Elderly patients with a history of back/chest + prolonged fever or abdominal pain proceeding gastroenteritis are particularly at risk. 5-10% of septicemia patients develop localized infections Endocarditis: Salmonella often infect vascular sites. but can cause complications that may lead to death .Nontyphoidal Salmonella: Bacteremia and Endovascular Infections 5% develop septicemia.Both are rare. .
and anemia . death . choleraesius causes septicemia: . anorexia.lesions in other tissues .Septicemia Serotype S.septic chock. chills.prolonged state of fever.
Incidence of S. Enteritidis .
hydrocephalous. mental retardation.Nontyphoidal Salmonellosis: Localized Infections INTRAABDOMINAL INFECTIONS: Rare.g. sickle cell disease Treatment: surgery to correct anatomic damages and drain abscesses CENTRAL NERVOUS SYSTEM INFECTIONS: Usually meningitis (in neonates. seizures. paralysis) or cerebral abscesses PULMONARY INFECTIONS: Usually lobar pneumonia Risk factors: preexisting lung abnormalities. glucocorticoid usage . abdominal abnormalities. sickle cell disease. present with severe symptoms e. usually manifested as liver or spleen abscesses Risk factors: hepatobiliary.
Duration: several days Infective Dose = 105 organisms Symptoms: a) 1st week: slowly increasing fever. confusion. nose bleeds. enlargement of the spleen/liver. Anorexia. variable GI symptoms. and bradycardia neuropsychiatric symptoms: delirium and mental confusion Long term effects: arthritis . bronchitis b) 2nd week: Apathy. stupor c) 3rd week: rose spots (1-2 mm diameter on the skin): duration: 2-5 days. malaise. such as abdominal tenderness (majority). abdominal pain (20-40% of cases) and diarrhea. headache.Typhoidal Salmonellosis: Enteric Fever Incubation: 7-14 days after ingestion.
perocardium. but milder with a lower mortality rate Majority of bacteria gone from stool in 8 weeks. symptoms of paratyphoid fever are similar to typhoid fever. endocardium. meninges. myocardium. lungs and parotid gland and hepatic/splenic abscesses In general. kidneys. joints. However. testes. bones. liver.Typhoidal Salmonellosis Late stage complications include intestinal perforation and gastrointestinal hemorrhage Immediate care such as increase antibacterial medications or surgical resection of bowel Other rare complications include inflammation of the pancreas. 15% become asymptomatic chronic carriers: gallbladder is the primary source of bacterium .
and an increase in the air-fluid level in the abdomen .Typhoidal Salmonella Chest PA view shows pleural effusion. medial and downward shift of bowel gas. left lower pulmonary lobe atelectasis.
with necrotic foci often accompanied by colonies of bacteria (arrow in right photo). multiple white to yellow foci occur in the liver.Pictures (A) (B) (A) In sub-acute infections. . and mesenteric lymph nodes may be enlarged (B) Histopathological examination may reveal necrotizing splenitis and hepatitis. spleen is enlarged.
usually 10-14 days (5-7 days for uncomplicated cases) Multi Drug Resistant (MDR) strains of S. septic shock): dexamethasone treatment Chronic carriers: 6 weeks of treatment with either oral amoxicillin. norfloxacin Surgical intervention to remove damaged cells . ciprofloxacin.Treatment of Typhoidal Salmonellosis Third generation cephalosporins or quinolones is the current treatment IV or IM ceftriaxone (1-2g) is also prescribed. typhi (NARST) must be tested for sensitivity to determine course of treatment Sever typhoid fever (altered consciousness. typhi: quinolones are the only effective oral treatment Nalidixic acid resistant S.
Education of general public.avoid risky foods & drinks: buy bottled water or boil water for at least 1 minute.Generally treated with antibiotics .vaccinations available. COOK and CLEAN food thoroughly.WASH YOUR HANDS WITH SOAP AND WATER!!! . avoid raw vegetables and fruits .Prevention Typhoidal S.: . especially in developing countries. identification of all carriers and sources of contamination of water supplies . the CDC currently recommends vaccination for persons traveling to developing countries .
Preventive measures for non-typhoidal S.
- pasteurization of milk-products; Eggs from known infected commercial flocks will be pasteurized instead of being sold as grade A shell eggs. - tracebacks, on-farm testing, quality assurance programs, regulations regarding refrigeration, educational messages for safe handling and cooking of eggs - Cross-contamination: uncooked contaminated foods kept separate from cooked, ready-to-eat foods.
Salmonella Vaccines I
Poultry vaccine: Megan™Vac 1
- applied to baby chicks via drinking water and cattle. It stimulates immunity in the chickens, preventing Salmonella infection during the growing period which may result in contamination and subsequent food borne infection of humans
- targets S. Enteritidis - Salmonella infection is stopped at lower levels of the food chain will mean increased productivity for the farmer and a break in the cycle of Salmonella transmission from animals à humans
Salmonella Vaccines II
Today, three types of Typhoid Vaccines are available: (1) inactivated whole-cell vaccine: 2 doses/ 4wks. Apart; single booster dose recommended every 3 years (2) Ty21a: a live, attenuated S. typhi vaccine. Administered orally (4 doses). Efficacy: 7 years (3) Vi polysaccharide vaccine: from purified Vi polysaccharide from S. typhi. Administered subcutaneously or intramuscularly. To maintain protection, revaccination recommended every 3 years.
These vaccines have been shown be 70-90% effective.
Salmonella • • • • • Overview History and Epidemiology Molecular Biology Clinical Weaponization .
spp. paratyphi (Type A. cholerasuis. and typhimurium Salmonella typhi is the only species that requires import and/or export permit from CDC and/or Department of Commerce. meleagridis. gallinarum-pullorum. typhi.CDC classification Category B agent: includes microorganisms that are moderately easy to disseminate. have moderate morbidity (i.e. but require enhanced disease surveillance.B. enteritidis.C). has high droplet or aerosol production potential .. ability to cause disease) and low mortality.. Biosafety Level 2 Risk Level 2: associated with human disease that is rarely serious and prophylactic intervention is often available. 9 different species: Salmonella arizonae.
WHO Global Salm Surv (GSS) GSS is an international Salmonella surveillance program initiated in January 2002. . A total of 138 laboratories were enrolled in the GSS in September 2003. It collects annual summary data from member institutions all over the world. serotyping and antimicrobial resistance testing and leading local interventions that reduce the human health burden of Salmonella. The goal is to enhance the quality of Salmonella surveillance.
large agricultural area heavy reliance on monoculture of a restricted range of genotypes major agricultural exporter. or the target of international terrorism.Salmonella as a Bioterrorist Weapon: What states are most at risk? The states most vulnerable to terrorist attack on the agricultural sector are those with several or most of the following attributes: High density. or unfriendly neighbor of states likely to be developing BW programs . or heavily dependent on a few domestic agricultural products suffering serious domestic unrest.
prisoners were infected with Salmonella typhosa among other biological agents Additionally.700 deaths among the Japanese troops. Cultures were also tossed into homes and sprayed from aircraft Due to inadequate preparation. and/or lack of proper equipment. training. a number of Chinese cities were attacked. Japan conducted biological warfare experiments in Manchuria At Unit 731.First Use of Salmonella as a Bioterrorist Weapon From 1932-1945. The Japanese contaminated water supplies and food items with Salmonella.000 biological casualties and 1. the Chekiang Campaign in 1942 led to about 10. a biological warfare research facility. .
Oregon 1984: a religious cult known as the Rajneeshees. In 1984. typhimurium as this type . Ten restaurants were hit and more than 700 people got sick. • First large scale bioterrorism attack on American soil • A communitywide outbreak of salmonellosis resulted. a Buddhist cult sought to run the whole country by wining the local election in 1984 using salmonella bacteria. but put the blame on food handlers. They brewed a "salsa" of salmonella and sprinkled it on the town's restaurant salad bars. at least 751 cases were documented in a county that typically reports fewer than five cases per year. who could have imagined bioterrorism? • caused by S. • Health officials soon pinned down salmonella as the cause of the sudden outbreak.
Salmonella as a Bioterrorist Weapon Wide distribution of food: contaminated food produced in one country can cause illness in other countries Traceability Antimicrobial resistance: strains of Salmonella are being found that have multiple drug resistance Capacity building: Salm-gene project used to enhance outbreak detection by routinely sub-typing certain salmonellas using molecular methods .
then a terrorist should have no problem recreating these outbreaks over and over in any number of American cities. . If numerous food-borne outbreaks occurred across the country. If Mother Nature can do this repeatedly. people have reason to worry: all these contaminations have occurred naturally every year.Salmonella as a Bioterrorist Weapon Contaminating unguarded food supplies Some terrorist acts may be designed purely to spread panic: contaminating the food supply could bring economic and agricultural production to a standstill EX. people would soon fear their meals Unfortunately.
4 million salmonella infections occur each year. food that is tampered with can be widely + quickly distributed Terrorist groups could use infectious disease agents to confuse public health officials into believing that outbreaks are naturally occurring: it is estimated that 1. but the CDC gets reports of only about 38. only 32% of the reported outbreaks have a known etiology.Salmonella as a Bioterrorist Weapon readily accessible and easy to grow or make Centralized food production: largely unmonitored food supply. .000 annually According to the Centers for Disease Control (CDC).
Fresh-produce wholesalers and distributors are notorious for employing illegal immigrants and not checking their background information. Even processed foods aren’t safe: Terrorists could use heat-stable toxins that would survive the packaging process. especially hard-to-clean off-season fruits and vegetables.Salmonella as a Bioterrorist Weapon No food product is safe: vegetables and fruits are the easiest to contaminate. As more of our food becomes imported. bioterrorists don’t even have to be inside the United States to do damage .
2.Salmonella as a Bioterrorist Weapon: Who might be tempted to initiate an attack on the agricultural sector? Terrorist groups might be interested in agricultural bioweapons for a variety of reasons: 1. anti-GMO groups for their potential value in deterring farmers from the use of genetically engineered crops or animals . international terrorist organizations: cause harm/injury to enemy states or peoples . Extreme activist groups: .EX.in an ideologically-motivated terrorist attack there would be willing assumption of responsibility by the perpetrator OR an attempt to disguise the outbreak as natural.
This is turn would open up or close markets for others.Salmonella as a Bioterrorist Weapon: What goals might an attack on the agricultural sector serve? Food attack by a terrorist group: initiate point-source epidemics using available Salmonella strains Destabilize a government by initiating food shortages/unemployment: the potential for immense economic damage due to contamination of the food supply Alter supply and demand patterns for a commodity: an outbreak can trigger the imposition of trade restrictions. .
and disseminate Few technical obstacles to weaponization: it would not be difficult to obtain Salmonella strains on the open market. a deliberately instigated outbreak could be mistaken for a natural one Multiple point source outbreaks can be initiated by contaminating imported feed or fertilizer.Salmonella as a Bioterrorist Weapon: What are the special features of an attack on the agricultural sector? Salmonella is not hazardous to perpetrators: easy to produce. without even entering the country: allows the possibility of initiating multiple outbreaks over a large geographic area. in a way that mimics a natural event . Low security of vulnerable targets: Fields. Point source to mimic natural introduction: Because of the high incidence of naturally-occurring diseases. restaurants have essentially no security at all. supermarkets. stockpile.
. but support development of salmonella specific-drugs .long run: leaves us at the mercy of multi-drug resistant salmonella strains ranging from incapacitating to lethal Alternative 2: Disseminate genomic knowledge. but it provides us with the opportunity to defend against all salmonella infection.Salmonella Dilemma Dissemination of genomic knowledge of salmonella can facilitate bioweapons development: Alternative 1: Restrict dissemination of genomic knowledge .knowledge may provide a terrorist org.short term: hinders development of a “super-Salmonella” terror weapon . with the ability to develop “super-Salmonella” terror weapons.
and crops. poultry. Chips could be used during various steps of food processing to ensure quality control and food safety. .Combating Salmonella Bioterrorism Establish a national disease surveillance system that could not only help uncover a terrorist attack but also recognize naturally occurring outbreaks that now go undetected New technology: creating a diagnostic gene chip covering all major diseases could give the health care provider instant diagnoses. Similar gene chips could monitor the health of livestock.
storage and packaging areas: rerouting traffic. installing locks Randomized safety checkpoints: will increase fear of detection COSTS: Increase work force Sampling and test costs Record keeping .Lines of Defense Food processors should limit access to their production.
and is responsible for the quality of slaughtered and processed meat. . promotes better food preparation techniques in restaurants and food processing plants. milk pasteurization plants. and regulates the sale of turtles and it also regulates the use of specific antibiotics as growth promotants in food animals USDA monitors the health of food animals. EPA regulates and monitors the safety of our drinking water supplies.Government Action CDC monitors the frequency of Salmonella infections in the country and assists the local and State Health Departments to investigate outbreaks and devise control measures FDA inspects imported foods. inspects egg pasteurization plants.
today. production and stockpiling of biological weapons . in Egypt. without checking the identities of the purchasers” (from the trials of the largest fundamentalist org.however.Biological Weapon Prevention BTWC (Biological and Toxin Weapons Convention): drafted in 1972 . such as E-Coli and Salmonella. Abu-al-Dahab) . 159 countries have signed the convention and 141 have ratified it .pathogens or toxins in quantities that have no justification for protective or peaceful services are to be eliminated . more can be done: “ Factories in the former Eastern Europe supply viruses that cause fatal diseases.intended to prevent the development.
Acknowledgements • • • Dr. Geoffrey Zubay Salwa Touma Kathleen Kehoe .
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