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Enterobacteriaceae Transmitted by the fecal-oral route Primary pathogens Organisms capable of causing disease in anyone Shigella Opportunistic pathogens Organisms that can only cause disease under certain conditions or in certain hosts E. coli Salmonella Yersinia Providencia Klebsiella pneumoniae Morganella Proteus Enterobacter Senatia Characteristics shared by all members of family Enterobacteriaceae G-, non-spore forming rods Peritrichous flagella -shigella: nonmotile Facultative anaerobe Not fastidious Active metabolism - All ferment glucose; - All reduce nitrates to nitrites; - All oxidase negative - Lactose fermentation: the key measure to isolate and identify the Enterobacteriaceae +: nonpathogenic -: pathogenic EMB plate MacConkey agar Triple sugar iron agar (TSI) Antigenic structures LPS (endotoxin) – O antigen. Most are motile by peritrichous flagella --H antigens. Capsule – K antigen ( Vi for Salmonella). Cell envelope (wall) various outer membrane proteins. Pili - various antigen types, some encoded by plasmids Enterobacteriaceae: gastrointestinal diseases – Escherichia coli – Salmonella – Shigella – Yersinia entercolitica Serotypes • reference laboratory – antigens • O (lipopolysaccharide) • H (flagellar) • K (capsular) O6:K15:H6 (I) Escherichia coli Medical significance Normal flora E. coli is the majority of GI normal flora Opportunistic pathogen pathogen Extraintestinal infection Intestinal tract infection Urinary tract infection Septicemia Neonatal meningitis ETEC EIEC EPEC EHEC EAggEC Escherichia coli • Toxins: two types of enterotoxin; Shiga-type toxin; Enteroaggregative ST-like toxin; Hemolysins; Endotoxin • Type III secretion system • Adhesions: colonization factors ; both pili or fimbriae; nonfimbrial factors involved in attachment. There are at least 21 different types of adhesions. • Virulence factors that protect the bacteria from host defenses: Capsule/Iron capturing ability (enterochelin) • Outer membrane proteins What is the pathogenesis of these five groups of pathogenic E. coli? Gastroenteritis caused by E. coli Enterotoxigenic E. coli (ETEC) • A watery diarrhea, nausea, abdominal cramps and low-grade fever for 1-5 days. • Travellers diarrhea and diarrhea in children in developing countries • Transmission is via contaminated food or water. • diarrhea like cholera • milder • nursery travellers diarrhea • caused by LT, ST, or LT/ST. Enterotoxigenic E. coli (ETEC) • Heat labile toxin • like choleragen • Adenyl cyclase activated • cyclic AMP • secretion water/ions • Heat stable toxin • Guanylate cyclase activated • cyclic GMP • uptake water/ions LT vs ST activity Enteroinvasive E. coli (EIEC) • The organism attaches to the intestinal mucosa via pili • Outer membrane proteins are involved in direct penetration, invasion of the intestinal cells, and destruction of the intestinal mucosa. • There is lateral movement of the organism from one cell to adjacent cells. • Symptoms include fever, severe abdominal cramps, malaise, and watery diarrhea followed by scanty stools containing blood, mucous, and pus. • resembles shigellosis Enteroinvasive E. coli (EIEC) • Dysentery - rearrangement of intracellular actin - resembles shigellosis - elder children and adult diarrhea Enteropathogenic E. coli (EPEC) • Malaise and low grade fever diarrhea, vomiting, nausea, nonbloody stools • Bundle forming pili are involved in attachment to the intestinal mucosa. • This leads to changes in signal transduction in the cells, effacement of the microvilli, and to intimate attachment via a non-fimbrial adhesion called intimin. • This is a problem mainly in hospitalized infants and in day care centers. Enteropathogenic E. coli (EPEC) • • • • • • fever infant diarrhea vomiting nausea non-bloody stools Destruction of surface microvilli - loose attachment mediated by bundle forming pili (Bfp); - Stimulation of intracellular calcium level; - Rearrangement of intracellular actin Enterohemorrhagic E. coli (EHEC) • Hemorrhagic – bloody, copious diarrhea – few leukocytes – afebrile • Hemolytic-uremic syndrome – hemolytic anemia – thrombocytopenia (low platelets) – kidney failure Enterohemorrhagic E. coli (EHEC) • Vero toxin – “shiga-like” • Hemolysins • younger than 5 years old,causing hemorrhagic colitis Enterohemorrhagic E. coli (EHEC) • Usually O157:H7 Transmission electron micrograph Enteroaggregative E. coli (EaggEC) • a cause of persistent, watery diarrhea with vomiting and dehydration in infants. • That is autoagglutination in a ‘stacked brick’ arrangement. • the bacteria adheres to the intestinal mucosa and elaborates enterotoxins (enteroaggregative heat-stable toxin, EAST). • The result is mucosal damage, secretion of large amounts of mucus, and a secretory diarrhea. Enteroaggregative E. coli (EaggEC) • Mucous associated autoagglutinins cause aggregation of the bacteria at the cell surface and result in the formation of a mucous biofilm. • The organisms attach via pili and liberate a cytotoxin distinct from, but similar to the ST and LT enterotoxins liberated by ETEC. • Symptoms incluse watery diarrhea, vomiting, dehydration and occasional abdominal pain. Summary of E. coli strains that cause gastroenteritis. Organi sm Virulence factors Adherence ETEC Colonization factors of adherence (CFAs) Type 1 pili EIEC Type 1 pili Afimbrial adhesins EPEC Bundle-forming pili (BFP) Type 1 pili Intimin Type 1 pili Afimbrial adhesins EHEC EaggEC Mucus-associated autoagglutination Type 1 pili Toxins invasion Endotoxin Noninvasive Heat-labile enterotoxin (LT) Heat-stable enterotoxin (ST) Endotoxin Very invasive Type III secretion system Endotoxin Poorly invasive serovar O6:K15:H6 28 2, 55 Shiga toxin Endotoxin Probably poorly O157:H7 invasive Endotoxin Cytotoxin (enteroaggregative STlike toxin) Noninvasive O42 organism Site Disease pathogenesis Traveler’s diarrhea, infant diarrhea Heat-stable and/or heatEnterotoxigenic E. Small labile enterotoxins, coli (ETEC) intestine in under developed countries, watery diarrhea, cramps, nausea, low-grade fever Enteroinvasive E. coli (EIEC) Fever, cramping, watery diarrhea Large intestine followed by development of Enteropathogenic E. coli (EPEC) Infant diarrhea with fever, nausea, Small intestine vomiting, nonbloody stools stimulate guanylate or adenylate cyclase activity with fluid and electrolyte loss Plasmid-mediated invasion and destruction dysentery with scant, bloody stools of epithelial cells lining colon plasmid-mediated adherence and destruction of epithelial cells Hemorrhagic colitis with severe Mediated by cytotoxic Enterohemorrhagi Large c E. coli (EHEC) intestine abdominal cramps, watery diarrhea “vero-toxin” initially, followed by grossly bloody diarrhea, little or no fever, hemolytic uremic syndrome (HUS) Persistent infant diarrhea, Enteroaggregative Small E. coli (EAggEC) intestine sometimes with gross blood, lowgrade fever Aggregative adherence mediated by plasmid Various Types of E. coli “Nonintimate” association: bacteria attach to host cell by bundleforming pili Bacterial attachment: signal transduction event stimulated; host cell tyrosine kinase activated; Ca2+ levels increase “Intimate” contact: pedestallike structure (composed of actin fibers) forms in host cell under bacteria (intimin) Escherichia coli • In the diagnostic laboratory generally the groups are not differentiated and treatment would be on symptomatology. • Generally fluid replacement is the primary treatment. • Antibiotics are generally not used except in severe disease or disease that has progressed to a systemic stage (e.g.hemolytic-uremia syndrome). • Two major classes of pili are produced by E. coli : mannose sensitive and mannose resistant pili. The former bind to mannose containing glyocoproteins and the latter to cerebrosides on the host epithelium allowing attachment. This aids in colonization by E. coli. Sanitary significance • Total bacterial number: number of bacteria contained per ml or gm of the sample; the standard of drinking water is less than 100. • Coliform bacteria index: the number of coliform bacteria detected out per 1000 ml sample; the standard of drinking water is less than 3 (II) Shigella dysentery bacterium Genral features • Pili. • Most strains can not ferment lactose; S. sonnei can slowly ferment lactose. • According to O antigen, 4 groups • Easily causing drug-resistence. Classification Serogroup Species Number of serotypes A S. dysenteriae 10 B S. flexneri 13 C S. boydii 18 D S. sonnei 1 The classification is based on O antigens What disease is caused by Shigella species? Bacillary dysentery shigellosis Bacillary dysentery • Source - humans are the only reservoir • Transmission - the fecal-oral route • Clinical findings -watery diarrhea -abdominal cramps -tenesmus -bloody stool with mucus and pus -fever • Clinical types - acute dysentery acute toxic dysentery -chronic dysentery Shigellosis • within 2-3 days – epithelial cell damage • bloody feces • intestinal pain • pus Shigellosis • Invasiveness • Endotoxin • Exotoxin: Shiga toxin - S. dysenteriae - neurotoxic, enterotoxic and cytotoxic Shiga toxin • enterotoxic • cytotoxic • inhibits protein synthesis – lysing 28S rRNA Clinical significance • man only "reservoir" • mostly young children – fecal to oral contact – children to adults • transmitted by adult food handlers – unwashed hands Clinical significance • The infective dose required to cause infection is very low (10200 organisms). • There is an incubation of 1-7 days followed by fever, cramping, abdominal pain, and watery diarrhea (due to the toxin)for 1-3 days. • This may be followed by frequent, scant stools with blood, mucous, and pus (due to invasion of intestinal mucosa). • Is is rare for the organism to disseminate. • The severity of the disease depends upon the species one is infected with. S. dysenteria is the most pathogenic followed by S. flexneri, S. sonnei and S. boydii. immunity • Primary immunity defense - SIgA • Immunity intensity - Limited - reasons surface infection various types Diagnosis of Shigella infection • Specimen: stool. • Culture and Identification • Quick immunological methods: - Immunofluorescent “ball” test; - Coagglutination. Prevention & Treatment • streptomycin dependent (SD) dysentery vaccine. • manage dehydration • patients respond to antibiotics , Problem of drugresistance – disease duration diminished Summary Shigella • Shigella (4 species; S. flexneri, S. boydii, S. sonnei, S. dysenteriae) all cause bacillary dysentery or shigellosis, (bloody feces associated with intestinal pain). • The organism invades the epithelial lining layer, but does not penetrate. • Usually, within 2-3 days, dysentery results from bacteria damaging the epithelium lining layers of the intestine often with release of mucus and blood (found in the feces) and attraction of leukocytes (also found in the feces as "pus"). Summary Shigella • Shiga toxin (chromosomally encoded) is neurotoxic, enterotoxic and cytotoxic plays a role. The toxin inhibits protein synthesis (acting on the 80S ribosome and lysing 28S rRNA). • This is primarily a disease of young children occurring by fecal- oral contact. Adults can catch this disease from children. However it can be transmitted by infected adult food handlers, contaminating food. The source in each case is unwashed hands. Man is the only "reservoir". • Patients with severe dysentery are usually treated with antibiotics (e.g. ampicillin). In contrast to salmonellosis, patients respond to antibiotic therapy and disease duration is diminished. (III) Salmonella Salmonella •More than 2000 serotypes •Transmitted by the fecal-oral routed •Salmonellosis may present as one of several syndromes including gastroenteritis, enteric (typhoid) fever or septicemia. •Zoonosis Antigenic composition of Salmonella • O antigen • H antigen • Vi antigen - S. typhi and S. hirschfeldii - Pathogenicity - Screening of carriers (titer≥1:10) - Inhibition of the agglutination of O Ags and the O Abs The antigenic structures of salmonellae used in serologic typing Pathogenicity • Virulence factors • Endotoxin – may play a role in intracellular survival • Capsule (for S. typhi and some strains of S. paratyphi) • Adhesions – both fimbrial and non-fimbrial • Enterotoxin - may be involved in gastroenteritis • Outer membrane proteins - involved in the ability of Salmonella to survive inside macrophages • Flagella – help bacteria to move through intestinal mucous Pathogenicity • Virulence factors • Type III secretion systems and effector molecules – 2 different systems may be found: – One type is involved in promoting entry into intestinal epithelial cells – The other type is involved in the ability of Salmonella to survive inside macrophages Disease caused by Salmonella Disease Gastroenteritis Septicemia Enteric fever pathogens S. enteritidis, S. typhimurium, S. choleraesuis S. choleraesuis, S. typhimurium, S. enteritidis, S. hirschfeldii S. typhi, S. paratyphi A, S. schottmuelleri, S. hirschfeldii Gastroenteritis • The most common form of salmonellosis and generally requires an 8-48 hour incubation period and may last from 2-5 days. • Symptoms include nausea, vomiting and diarrhea (non-bloody stool). Salmonella enteritidis is the most common isolate. • poultry, eggs. no human reservoir • self-limiting (2 - 5 days) Gastroenteritis • The most common form of salmonellosis (70%) • Self-limited (2-5 d) • Not enter into blood • Culture - blood (-) - stool (+) Septicemia • Salmonella septicemia (bacteremia) may be caused by any species but S. choleraesuis is common. • This disease resembles other G- septicemias and is characterized by a high, remittent fever with little gastrointestinal involvement. Septicemia • 5-10% of salmonellosis • Intestinal manifestations: often absent • Culture - blood (+) - stool (-) Enteric fever The pathogenesis of typhoid Enteric or typhoid fever • Enteric or typhoid fever occurs when the bacteria leave the intestine and multiply within cells of the reticuloendothelial system. • The bacteria then re-enter the intestine, causing gastrointestinal symptoms. • Typhoid fever has a 10-14 day incubation period and may last for several weeks. • Salmonella typhi is the most common species isolated from this salmonellosis. • Human reservoir: carrier state common • Contaminated food: water supply • Poor sanitary conditions Typhoid -Therapy • Antibiotics – essential • Vaccines Vi (capsular) antigen :protective What does the pathogenesis imply in terms of collection of clinical samples? Diagnosis • Specimens a) Enteric fever: blood, bone marrow, stool, urine. b) Food poisoning: stool, vomitus, suspected food. c) Septicemia: blood. • Culture and identification • Widal test Widal test A quantitative agglutination test for typhoid and paratyphoid, in which detects a patient’s antibodies to the specific O antigen of S. typhi and H antigens of S. typhi, S. paratyphi A, S. schottmuelleri and S. hirschfeldii How to interpret the results of Widal test? • Consider the manifestaton, course, history, and local epidemiological conditions How to interpret the results of Widal test? TO<1:80,TH<1:160, PH<1:80 Normal value TO≥1:80 & TH≥1:160 or Typhoid fever TO≥1:80 & PH≥1:80 Paratyphoid fever TO≥1:80 & TH <1:160 or Early stage of infection or cross- TO≥1:80 & PH <1:80 reaction of O antigen with other salmonellae TO < 1:80 & TH ≥1:160 or Vaccination or nonspecific memory TO < 1:80 & PH ≥ 1:80 reaction How to interpret the results of Widal test? • Dynamic observation -antibody titer give a rise gradually -titer of convalescence serum≥4 times than that of early specimen • False negative -pre-antobiotic -immunosuppressed immunity Primary immunity defense - CMI Immunity intensity - strong and permanent Salmonella • Using appropriate antibodies more than 2000 antigenic “types” have been recognized. There are, however, only a few types that are commonly associated with characteristic human diseases (most simply referred to as S. enteritidis, S. cholerae-suis and S. typhi). • Salmonellosis, the common salmonella infection, is caused by a variety of serotypes (S. enteritidis) and is transmitted from contaminated food (such as poultry and eggs). It does not have a human reservoir and usually presents as gastroenteritis (nausea, vomiting and non-bloody stools). The disease is usually selflimiting (2-5 days). Like Shigella they invade the epithelium and do not produce systemic infection. In uncomplicated cases of salmonellosis, which are the vast majority, antibiotic therapy is not useful. S. choleraesuis (seen much less commonly) causes septicemia after invasion. In this case, antibiotic therapy is required. . Salmonella • The severest form of salmonella infections "typhoid" (enteric fever), caused by Salmonella typhi. • The organism is transmitted from a human reservoir or in the water supply (if sanitary conditions are poor) or in contaminated food. • It initially invades the intestinal epithelium and during this acute phase, gastrointestinal symptoms are noted. The organism penetrates, usually within the first week, and passes into the bloodstream where it is disseminated in macrophages. Typical features of a systemic bacterial infection are noted. The septicemia usually is temporary with the organism finally lodging in the gall bladder. Organisms are shed into the intestine for some weeks. At this time the gastroenteritis (including diarrhea) is noted again. The Vi (capsular) antigen plays a role in the pathogenesis of typhoid. • A carrier state is common; thus one person e.g. a food handler can cause a lot of spread. Antibiotic therapy is essential. Vaccines are not widely effective and not generally used Summary • Common members of Enterobacteriaceae to cause human diseases • Common properties of Enterobaceriaceae • The medical significance of E. coli • The opposite traits of Shigella and Salmonella in terms of pathogenesis and immunity • Widal test: definition, result determination