Yersiniosis: Yersinia Pathogenic Kinds and Variants

Yersiniosis

-‐ monkey of all diseases(clinical features same as other infectious/non-‐infectious
diseases)
-‐ although Y. pseudotuberculosis and Y. enterocolitica were identified as human pathology
early in 20th century, their significance as cause of human disease is not appreciated until
much more recently
-‐ Y. pseudotuberculosis and Y. enterocolitica are associated with human diseases in Europe,
particularly Northern parts
-‐ 2 possible explanations for this predominance:
1. more widespread appreciation by clinicians and microbiologists
2. more frequent exposure to environmental sources, eg: pork products
-‐ both organisms can cause diarrhea and extraintestinal diseases
-‐ while infection due to Y. pseudotuberculosis is more severe, it is less common than
Y. enterocolitica
-‐ Yersinia spp are gram negative bacilli which colonize a variety of vertebral hosts and are
only incidentally pathogens for humans
-‐ Only 3 of the 11 Yersinia spp are pathogenic for humans. Y. pestis causes plague, Y.
pseudotuberculosis and Y. enterocolitica cause yersiniosis

Yersinia Pathogenic Kinds and Variants
1. high pathogenic kinds(HPI ! ) : Y. pestis, Y. enterocolitica(biovar 1b),
Y. pseudotuberculosis(serogroup 1)
2. moderate pathogenic kinds(HPI ! ) : Y. pseudotuberculosis(serogroups 2, 4, 5),
Y. enterocolitica(biovars 2-‐5)
3. non-‐pathogenic kinds and variants : Y. enterocolitica(biovar 1a), Y. intermedia,
Y. frederiksenii, Y. aldovae, Y. rondei, Y. mollaretti,
Y. ruckeri

-‐ genus Yersinia represents a series of facultative, gram negative, anaerobic
coccobacilli(able to transform to L-‐form) of family Enterobacteriaceae
-‐ Y. pseudotuberculosis and Y. enterocolitica are subtyped based on biochemical reactivity,
biogroups and by surface antigenic determinants(connected with serogroups)
particularly the cell surface Ag, O-‐Ag
-‐ There is only 1 biogroup of Y. pseudotuberculosis which included 6 serological variants
and 6 biogroups of Y. enterocolitica which includes ~60 serological variants

Characteristics of Yersinia(Pathogenic Species) on Biogroups, Serovars, Geographical
Diffusion
Biogroups Serogroups Geographical Diffusion
Y. enterocolitica 1b O:8, O:4, O:20, O:21, pigs(O:8), environment
(increasingly O:18, O:13a, O:13b usually in USA
pathogenic) 2 O:9; O:5, 27 pigs, Russia, Europe, USA,
-‐ severe course Japan
3 O:1, 2, 3; O:5, 27 pigs
4 O:3 pigs, Russia, Europe, USA
5 O:2, 3 rabbits
Y. pseudotuberculosis 1 1-‐6

-‐ Y. enterocolitica subtype most commonly associated with human disease in both North
America and Europe is biogroup 4, O:3
-‐ subtyping is important epidemiologically since serotype distribution varies between
Europe, North America and Asia
-‐ subtyping can provide important clues to environmental source of infection

Virulence Factors
-‐ pathogenic Y. enterocolitica produces a variety of proteins which facilitate adherence of
the organism to the gut mucosa. Binding to intestinal epithelial cells and invasion of the
gut wall
-‐ both Y. enterocolitica and Y. pseudotuberculosis are localized in lymphoid tissue within
the gut wall and regional mesenteric lymph nodes
-‐ the organism elaborates additional proteins which allows it to evade host defense
mechanisms including phagocytosis and resistance to bactericidal action of serum
-‐ some of these essential proteins: invasion and attachment invasin locus are
chromosomally encoded
-‐ invasin: important virulence determinant for early stages of infection and is regulated by
the phase of growth of organism and temperature
-‐ Yersinia outer membrane proteins: important virulence factors are plasmid mediated.
These proteins are injected by the organism into cells which are believed to result in
destruction of cellular immune mechanisms.
-‐ Yersinia outer protein(one of plasmid encoded proteins) suppresses TNFα released by
macrophages in vitro and in vivo
-‐ expression of many virulence characteristics is temperature dependent
-‐ at 25°C, organism is motile and doesn’t express some virulence proteins
-‐ at 37°C, organism is non-‐motile but virulence factors are expressed
-‐ Y. enterocolitica also produces an enterotoxin but only at very low levels above 30°C. This
temperature dependence may be important for survival of organism outside host once
infection has occurred
-‐ Y. enterocolitica is also an iron-‐loving organism and it contains several pathways to
facilitate iron uptake which is essential for growth
-‐ V-‐ and W-‐Ag’s are absolute pathogenic factors for Yersinia

Pathogenic Factors of Y. enterocolitica and Their Function Ensuring Realization of
Infectious Process
Factors Function(s)
Urease neutralization of acid in stomach
Adhesin Yad A(suppressive factor for -‐ adhesion and colonization
immune) -‐ antiphagocytic activity
-‐ anticomplementary activity
-‐ introduction of inflammation in
lymphoid tissue
Protein Vir F activator of genes Yad A
Proteins of Outer Membrane(YOPs) -‐ antiphagocytic activity(YOPH),
-‐ YOPE and YOPH cytotoxicity
-‐ YOPB and YOPD -‐ immunosuppression
-‐ YOPN and YOPQ -‐ auxiliary for YOPE and YOPH
-‐ dissemination in tissues of organism
Protein(YscA-‐U), Lkr D system of secretion of YOPs
Catalase antiphagocytic activity
Proteins Htr A, Gsr A antiphagocytic activity
LPS anticomplementary activity
Factors Function(s)
Protein of Outer Membrane 103kDa -‐ adhesion
(invasin) -‐ penetration into cells of owner
-‐ introduction of inflammation in lymphoid
tissues
Protein of Outer Membrane 17kDa(Ail) -‐ adhesion
-‐ penetration into cells of owner
-‐ anticomplementary activity
Enterotoxin Yst stimulation of GMP in enterocytes(GMP
accumulation)
Protein RpoS auxiliary for Yst
Yersiniabactin(biovar 1b) carry Fe!! into microbial cells
Protein Flu A(biovar 1b) receptor for Yersiniabactin(carry Fe!! into
microbial cells)
Superoxide dismutase antiphagocytic activity

Epidemiology
-‐ reservoir: soil, vegetables, fruits, water, cattle(meat and milk products), pets,
gnawers(mice, rats, rabbits, etc.)
-‐ mechanism and ways of transmission: fecal-‐oral route, water-‐alimentary route
-‐ afflicted contingent: animals, humans of all ages, children in particular

Yersiniosis is observed in Spring. Why?
-‐ Yersinia spp live in low temperature(eg: fridge). During Autumn and Winter, vegetables
are stored in places which have low temperature. These places are usually infested with
rats and mice, so it’s a good place for growth of Yersinia. Which is why when vegetables
are consumed in Spring, an outbreak is observed.

Pathogenesis
-‐ after oral ingestion, organism invades intestinal epithelium using virulence factors. It
then localizes to lymphoid tissue of intestinal mucosa particularly Peyer’s patches and is
carried to regional lymph nodes within the mesentery.
-‐ These features of infection result in major clinical manifestation of acute Yersiniosis,
acute gastroenteritis, pseudoappendicular syndrome, mesenteric adenitis
-‐ The occurrence of various clinical syndromes is age-‐dependent
-‐ Yersinia septicemia can occur during acute infection particularly in infants and
immunocompromised persons/iron-‐overload states

Stages of Pathogenesis Mechanism of Pathogenesis Clinics
Entry to intestinal tract -‐ adhesion -‐ secretion of water and
particularly to descending -‐ production of enterotoxin electrolytes. Diarrhea is
part of small intestine -‐ thermolabile and cholera-‐like
(may think about food thermostable
poisoning)
-‐ penetration through the -‐ injury of the mucosal surface,
mucosal epithelium and inflammation, exudative
proliferation diarrhea. Hemorrhagic
-‐ production of cytotoxin enterocolitis like Shigella
-‐ kills cells dysenteriae

-‐ invasion in monocytes and -‐ symptom of endotoxicosis:
polynuclearis fever, weakness, headache,
-‐ complete phagocytosis algia in muscles and joints,
-‐ appearance of endotoxin = low appetite, bad sleep,
LPS tachycardia, arterial
-‐ hypotonia
Penetration and -‐ complete and incomplete -‐ symptom of endotoxicosis:
proliferation in regional phagocytosis ileitis, appendicitis,
lymph nodes -‐ appearance of granulomas mesenteritis(in children)
Generalization of -‐ septicemia -‐ increase of symptoms of
infection via blood -‐ endotoxinemia endotoxicosis: rash(around
Diffusion in different joints), hepatolienal
organs(in symptoms, injury of
immunosuppression) different organs
Immunopathology -‐ immunocomplex -‐ immune organic injuries
process pathology (thyroiditis, hepatitis,
-‐ autoimmune reaction erythema nodosum)
-‐ slow type hypersensitivity
(granuloma formation)

Main Clinical Syndromes of Yersiniosis
1. intoxication
2. catarrhal tonsillitis
3. diarrhea
4. hepatolienal symptom
5. rash symptom
6. arthropathy

Clinical Classification of Yersiniosis
Type of Disease Clinical Version Severity Duration
Local(GI form) -‐ gastroenterocolitis -‐ mild -‐ acute from 4-‐5 days to
-‐ terminal ileitis -‐ moderate 3 months
-‐ acute appendicitis -‐ severe -‐ recurrent from 3-‐6
-‐ mesenteritis months
(mesenteric -‐ chronic from 6
lymphadenitis) months to 3 years

Type of Disease Clinical Version Severity Duration
Generalized form -‐ hepatitis -‐ mild -‐ acute from 4-‐5 days to
-‐ meningitis -‐ moderate 3 months
-‐ pyelonephritis -‐ severe -‐ recurrent from 3-‐6
-‐ pneumonia months
-‐ mixed form -‐ chronic from 6
-‐ sepsis months to 3 years
-‐ Scarlet-‐fever-‐like
form
Secondary focal -‐ arthritis -‐ mild -‐ acute from 4-‐5 days to
form -‐ Reiter’s syndrome -‐ moderate 3 months
-‐ erythema -‐ severe -‐ recurrent from 3-‐6
nodosum months
-‐ myocarditis -‐ chronic from 6
-‐ thyroiditis months to 3 years
-‐ enterocolitis-‐like
Crohn’s disease

Scarlet-‐Fever-‐Like Form
-‐ catarrhal angina(tonsillitis)
-‐ red rash
-‐ “strawberry” tongue
-‐ desquamation of skin of extremities
-‐ intoxication syndrome
-‐ diarrhea
-‐ abdominal pain
-‐ ileitis
-‐ appendicitis

Clinical Manifestations
-‐ length of incubation period is inversely proportional to number of organisms ingested.
Generally 1-‐11 days
-‐ acute gastroenteritis from Yersinia is marked by diarrhea, abdominal pain, fever and less
frequently nausea and vomiting
-‐ gastroenteritis due to Yersinia infection can’t be distinguished by other causes of acute
diarrhea
-‐ bowel movements(5-‐10 times/day) at the peak of illness which is similar to many other
etiologies
-‐ when abdominal pain appears with Yersinia infection, usually localized at right lower
quadrant. Presence of this localization is a helpful diagnostic clue
-‐ in some sporadic cases, sore throat is reported by almost 20% patients
-‐ Y. enterocolitica was isolated from throat cultures, illustrating the propensity of
organisms to affect lymphoid tissue such as tonsils
-‐ since no other cause of acute bacterial diarrhea routinely produces pharyngitis, therefore
useful in suspecting diagnosis
-‐ mean duration of diarrhea is about 12-‐22 days. A period longer than this means illness is
caused by other bacterial diarrheal agents(Salmonellosis not more than 7 days)
-‐ prolonged fecal shedding of organism even after symptoms have subsided. 47% of
patients sheds organism up to 40 days. This feature is implication of person-‐to-‐person
transmissions and for childcare setting should be excluded/special precautions
-‐ in some patients with acute Yersinia infection, abdominal symptoms, systemic toxicity,
high fever, leukocytosis are far more prominent than diarrhea which can be minimal.
This presentation which occurs more commonly in older child and young adults may be
confused with acute appendicitis. Such patients undergo abdominal surgery for
appendicitis. In surgery, inflammation around appendix, terminal ileitis and
inflammation of mesenteric lymph nodes either alone/combination is found. The
appendix itself is normal/shows minimal inflammation
-‐ Yersinia can be cultured from the appendix and involved lymph nodes
-‐ Y. enterocolitica may infect the terminal ileum producing watery and sometimes bloody
stools
-‐ Y. enterocolitica primarily infects terminal colon and ileum but in children <5 years old it
usually manifests as watery diarrhea
-‐ in older children, bacteria of intestine invade mesenteric lymph nodes, causing focal
inflammation. Mesenteric adenitis does not cause diarrhea
-‐ many adults infected with Y. enterocolitica has reactive arthritis within 3 weeks after
onset of diarrhea. Reactive arthritis is probably an immunological phenomena because
organisms are not found in joint fluid
-‐ individuals affected most severely by arthritis often possess major histocompatible Ag:
HLA-‐B27

Outcome and Complications
-‐ despite severity of complications, overall mortality is low
-‐ a major feature of Yersiniosis is appearance of chronic sequelae
-‐ the most common are erythema nodosum, reactive arthritis, Reiter’s syndrome
-‐ myocarditis and liver failure are reported but are unusual
-‐ complications typically begin several weeks after onset and lasts for 3-‐5 months
-‐ complications appear to be more frequent in Northern Europeans especially those who
are HLA-‐B27 positive
-‐ several studies show evidence of Yersinia Ag’s in synovial fluid and in peripheral blood
cells in persons with reactive arthritis
-‐ a relationship between Yersinia seropositivity and thyroiditis has been reported
-‐ gastroenteritis complications: suppurative appendicitis, diffuse ulcerative ileitis and
colitis, intestinal perforation, peritonitis, toxic megacolon, mesenteric vein thrombosis,
cholangitis
-‐ non-‐gastroenteritis complications: hepatic sepsis, splenic sepsis, kidney sepsis,
endocarditis, meningitis, osteomyelitis, septic arthritis, suppurative lymphadenitis, skin
manifestation, septicemia

Clinical Manifestations of Yersiniosis
1. without risk factors:
-‐ enterocolitis, acute mesadenitis, terminal ileitis
2. with risk factors(DM, tumor, liver diseases, hemocatheretic anemia):
-‐ enterocolitis, acute mesadenitis, terminal ileitis, reactive arthritis, erythema nodosum,
hematosepsis, abscess of liver, kidney, spleen, ostemomyelitis, meningitis, empyema,
peritonitis, septic arthritis, thyroiditis, uveitis, myocarditis(seldom),
glomerulonephritis(seldom)

Diagnosis
1. microbiological culture:
-‐ standard for diagnosis
-‐ culture from stool is preferred for patients with intestinal symptoms. Result remains
positive 4 weeks after acute infection
-‐ other specimens that should be considered for culture are blood, throat swabs,
specimens from surgery(appendix, lymph nodes)
-‐ depending upon symptoms, joint fluid, pleural fluid, abscess material may also be
appropriate to obtain
2. PCR and immunofluorescence assay:
-‐ not widely available but developed
3. Serological test:
-‐ widely used for diagnosis
-‐ agglutination assay, ELISA and immunoblotting have been developed. These assays can
be used to detect IgG, IgM and IgA
-‐ IgM positive: supports diagnosis and acute Yersiniosis as there is 4 fold rise between
acute and convalescent titers drawn several weeks apart
-‐ test sensitivity and specificity are serotype dependent and assays can cross-‐react with
same bacteria and inflammation states
-‐ persons with chronic sequelae have oscillating Ab titers depending on activity of illness.
High titer: exacerbation; low titer: remission

Treatment
1. antibacterial therapy
Clinical Forms Indications Terms of Treatment
GI form
-‐ gastroenteritis -‐
-‐ terminal ileitis + till 10th day of normal
-‐ acute appendicitis + temperature
Generalized form +
Secondary focal form +/-‐

antibacterial drugs
Ciprofloxacin 500mg bid
Ofloxacin 400mg bid
Doxycycline 100mg bid
Trimetoprim & Sulfomethoxazole 0.960 bid
Gentamicin 0.240mg daily
Ceftriaxone 2.0g daily

2. detoxification therapy
3. anti-‐inflammatory therapy
4. anti-‐allergic therapy
5. probiotics

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