Salmonella Infections in Humans

Mark Pallen

Salmonella infections in humans

Enteric fever
typhoid and paratyphoid fevers S. typhi, paratyphi A, B, C systemic infection infects only humans GI symptoms may not be evident

Salmonella gastroenteritis
non-typhi serovars zoonosis: predominantly food-borne can be complicated by septicaemia
more common with some serovars, e.g. S. dublin (15% mortality rate when septicemic in the elderly) Metastatic disease, e.g. osteomyelitis

Overview
Bacteriology Epidemiology Clinical features Pathogenesis Diagnosis Treatment Prevention

Bacteriology
Salmonella enterica
one species, ~2000 serovars Non standard nomenclature common
S. enterica serovar Typhimurium or S. typhimurium

rod-shaped, non-spore-forming Gram-negative bacterium belongs to the family Enterobacteriaceae

close relative of E. coli

Motile by peritrichous flagella (H antigen).

nonmotile exceptions: S. gallinarum and S. pullorum

Antigenic Structure
Kauffmann-White antigenic scheme
agglutination reactions with specific antisera against Salmonella antigens

O antigens
characteristic sequence of repeating polysaccharide units in LPS.

H antigens
flagellar antigens (protein) and may occur in one of two phase variations.

Vi antigen
a capsular polysaccharide homopolymer of N-acetyl galactosamineuronic acid

Epidemiology Enteric fever

person-to-person spread
no animal reservoir

contamination with human faeces

usual vehicle contaminated water. occasionally, contaminated food (usually handled by an individual who harbours S. typhi)

Epidemiology Non-typhoidal serovars

zoonosis with enormous animal reservoir
common animal reservoirs are chickens, turkeys, pigs, and cows

contaminated food is major vehicle, usually:

red and white meats, raw eggs, milk & dairy products many other possibilities, from spices or chocolate to cannabis can follow direct contact with infected animals (e.g. farm trip, reptiles as pets)

Epidemiology Non-typhoidal serovars

outbreaks common In Catering establishments In Hospitals
Stanley Royd Hospital outbreak now careful attention to hospital kitchen hygiene

Epidemiology Non-typhoidal serovars

Food-borne transmission by
contamination of cooked food by raw food failing to achieve adequate cooking temperatures.

secondary cases by person to person spread are common in outbreaks food handlers who practice good hygiene very rarely responsible for outbreaks

Salmonella in eggs

various Salmonella serovars isolated from the outside of egg shells S. enteritidis PT4 present inside the egg, in the yolk vertical transmission
deposition of the organism in the yolk by an infected layer hen prior to shell deposition.

Infectious dose
typically about 1,000,000 bacteria much lower if the stomach pH is raised much lower if the vehicle for infection is chocolate
protects the bacteria in their passage through the stomach an infectious dose of about 100 bacteria

Epidemiology carrier states

carrier state may last from many weeks to years with faecal shedding
convalescent carrier

chronic carrier
~3% of persons infected with S. typhi ~0.1% of those infected with nontyphoidal salmonellae

potential for cross-contamination of foods by the infected handler

Typhoid Mary Mallone but more common in textbooks than in real life

Clinical Features Enteric Fever

incubation period 10 to 14 days septicaemic illness
myalgia and headache fever splenomegaly leukopenia abdominal pain Rose spots (macular rash on abdomen)

10% fatal positive blood, urine, and stool cultures Sequelae: intestinal haemorrhage and perforation

Clinical features Gastroenteritis

incubation period depends on dose symptoms usually begin within 6 to 48 hours
Nausea and Vomiting Diarrhoea Abdominal pain Myalgia and headache Fever

duration varies, usually 2 to 7 days seldom fatal, except in elderly or immunocompromised

Pathogenesis Gastroenteritis
Pathogenic salmonellae ingested in food survive passage through the gastric acid barrier invade intestinal mucosa invasion of epithelial cells stimulates the release of proinflammatory cytokines induces an inflammatory reaction causes diarrhoea and may lead to ulceration and destruction of the mucosa

Pathogenesis Enteric Fever

Bacteria invade mucosa or Peyer's patches of small intestine (?M cells), pass into mesenteric lymph nodes where they multiply and then enter the blood stream via the thoracic duct Primary bacteraemia cleared by RES, bacteria multiply in RES cells and destroy them Facultative intracellular parasites

Pathogenesis Enteric fever

Secondary bacteraemia occurs and results in spread to other organs.
Infection of the biliary tract.

Multiplication in biliary tract leads to seeding the intestine with large numbers of bacteria. Involvement of intestinal lymphoid tissue may lead to necrosis and ulceration. In untreated nonfatal cases, temperature drops in 3 to 4 weeks (onset on immunity?)

S. typhimurium in the mouse

S. typhimurium
causes gastroenteritis in humans causes typhoid-like disease in mice

infection can be established orally or systemically used as model of typhoid primary mechanisms of pathogenesis
invasion of the intestine survival and growth in macrophages

Invasion
membrane ruffling depends on Spi1 Type III secretion system effectors of invasion
SopE affects actin cytoskeleton SipA binds to actin, inhibits depolymerization SopB inositol phosphate phosphatase. SptP: PTPase, disrupts the actin cytoskeleton

Invasome
Bacterial surface appendage expressed when in contact with host cells

Survival in cells
Spi2 Type III secretion system
expressed in cells activated by acidic pH in phagosome mutants severely attenuated in mice currently under intense investigation

PhoP/PhoQ
Pags Prgs

Induction of apoptosis
Spi1-dependent SipB-mediated

Laboratory Diagnosis
Isolated from stool, blood and urine in enteric fever (blood cultures need to be taken!) Isolated from stool in gastroenteritis Appears as a non-lactose fermenter
on MacConkey agar or similar selective agar

Laboratory Diagnosis
Biochemical tests and serological tests must be done in parallel
Some other bacteria, e.g. Citrobacter, may have similar serological profiles Commercial kits commonly used, e.g. API20

Phage typing done for epidemiological purposes

E.g. to find source of outbreak Certain phage types predominate nationally
S. typhimurium PT4 S. enteritidis DT109

Treatment
Gastroenteritis
replace fluid loss by oral and intravenous routes antibiotics are not recommended for uncomplicated gastroenteritis
do not shorten illness prolong excretion.

antibiotic therapy reserved for the septicaemic and metastatic disease

Typhoid fever and enteric fevers should be treated with antibiotics

usually ciprofloxacin rise of resistance

Prevention
Remove source
Salmonella free life-stock Vaccinate chicks

Interrupt transmission
Good food hygiene
Cook food properly Keep raw and cooked foods apart

Public Health: clean water

Strengthen host
vaccination

Salmonella vaccines
Vaccination of travellers against typhoid recommended, but does not remove need for good hygiene Three licensed vaccines
Traditional heat-killed
very reactogenic

Vi subunit vaccine live oral vaccine, S. typhi Ty21A

Salmonellas can act as live attenuated carriers for other antigens

So far only experimental

No vaccines for gastroenteritis

Salmonella Genome Sequencing Projects

S. typhiumurium LT2 at WashU Multi-resistant S. typhi from Vietnam at Sanger Centre Will allow delineation of how Salmonella became a pathogen

Online bibliography
http://www.sanger.ac.uk/Projects/S_typhi/ http://genome.wustl.edu/gsc/bacterial/salmonella.shtml http://www.salmonella.org/ http://www.who.int/inf-fs/en/fact149.html http://www.bmj.com/cgi/content/full/313/7065/1094 http://vm.cfsan.fda.gov/~mow/chap1.html

http://129.109.112.248/microbook/ch021.htm