Bartonella
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Bartonella. Prepared by: Ohood R. Sarsour. Introduction. Bartonella species (formerly known as Rochalimaea) Linked to a number of emerging zoonotic diseases B.quintana, B.bacilliformis, B.henselae

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Bartonella

Bartonella

Prepared by:

Ohood R. Sarsour


Introduction

Introduction

  • Bartonella species (formerly known as Rochalimaea)

  • Linked to a number of emerging zoonotic diseases

  • B.quintana, B.bacilliformis, B.henselae

    • Unique and common feature is ability to cause vasoproliferative lesions (process of pathological angiogenesis)

  • Infection affects function of endothelial cells resulting in cell invasion, suppression of apoptosis and induction of proliferation, resulting in vasoproliferative tumor growth


B henselae

B. henselae

  • Gram negative aerobic rods

  • Main reservoir is cats

    • Transferred to humans through scratches and bites (fleas/ticks??)

  • Resulting illness is Cat Scratch Disease (CSD)

  • About 40% of cats carry B.henselae

  • Cats are asymptomatic, although bacteria can be cultivated from their blood for up to 2 years

    • This persistent infection due to persistence in red blood cells


Epidemiology

Epidemiology

  • Cases of CSD occur worldwide

  • Higher incidence of Bartenellosis in warmer and more humid areas of the United States

    • More fleas and ticks

  • Children 2-24 and veterinarians make up 80-90% of human cases

  • 22 000 cases of CSD are diagnosed per year in the United States

    • Most cases occur in late fall and winter


Infections

Infections

  • CSD is a self-limiting disease characterized by lymphadenopathy and infection at the site of injury

  • Lasts 6-12 weeks in healthy individuals and can be accompanied by headaches, nausea, vomiting and fatigue

  • Severity of CSD depends on immune status of the host

  • Immunocompromised individuals can develop Bacillary angiomatosis (BA) and Parinaud’s oculoglandular syndrome (POS)


Bartonella

  • Diagnosis is difficult and is usually based on exposure to a cat, enlarged lymph nodes and lack of another appropriate cause


Virulence factors

Virulence Factors

  • VEGF (vascular endothelial growth factor)

    • Triggers angiomatosis and has a pathogenic role in vasoproliferative disorders (such as BA)

    • Highly mitogenic to endothelial cells

    • B.henselae induces host cell production of VEGF

    • This production and subsequent proliferation is necessary for angiogenesis and BA

    • This proliferation also promotes growth of B.henselae’s own cells


Bartonella

  • Pili

    • Expression of pili allows adhesion and invasion of host cells

    • Pili are also thought to be responsible for the induction of VEGF as pili- mutants have a significant decrease in production of VEGF


Bartonella

  • Type 4 secretion system (virB-D4)

    • Consists of a multiprotein channel that allows transportation of DNA or protein into the host cell

    • virB operon encodes 10 genes, 8 of which known to encode a T4SS

    • virD4 locus located just downstream

    • virB5 encodes a 17kD protein found in patients with CSD

      • Function not known but not found outside Bartonella species


Bartonella

  • Downstream region of virB encodes Bep proteins that are translocated into the endothelial cells

    • These proteins thought to mediate all virB-virD4-dependent changes of endothelial cell function

  • Recent studies have shown that a mutation in either virB or virD4 prevents intraerythrocytic infection as well as endothelial cell invasion


Bartonella

  • Type 4 Secretion System (Trw)

    • Second T4SS identified that is active during endothelial cell infection

    • Primary function to establish contact with erythrocytes through surface expressed T4SS pili


Bartonella

  • Deformin

    • Hydrophobic secreted protein

    • Affinity for albumin

    • Formation of pits and trenches on red blood cell membranes that aids in colonization and entry to the cell


Bartonella

  • Outer Membrane Proteins (OMPs)

    • Induce NFκB-dependent upregulation of E-selectin and ICAM-1

    • Leads to increased adhesion molecule expression

    • NFκB plays a role in initiation and regulation of the body’s proinflammatory response


Persistent infection

Persistent Infection

  • Endothelial cell interaction

    • Primary niche

    • Most information gathered using HUVEC cells

    • Bartonella species can enter endothelial cells by rearranging actin cytoskeleton

    • B.henselae can also enter using “invasome” mechanism

      • Bacterial aggregate formation on cell surface that is engulfed and internalized through an actin-dependent process


Bartonella

  • Intraerythrocytic persistence

    • Common theme of Bartonella is prolonged intraerythrocytic bacteremia associated with transmission by blood-sucking arthropods

    • Adherence mediated by pili and OMPs exposed on bacterial surface

    • Exact mechanism is not known but assumed to be bacterial-induced endocytosis

    • Assisted by deformin secretion


Bartonella

  • After invasion intracellular multiplication occurs

    • Limited by quorum sensing to prevent hemolysis

  • Bacteria survive for the duration of the cell life and remain in the blood stream for several weeks, facilitating transmission

  • Bacteria seeded into blood stream every 5 days

  • Unique persistence is an adaptation to mode of transmission

  • Intraerythrocytic bacteremia subsides due to strong IgG antibody response (in animal models)


Prevention and treatment

Prevention and Treatment

  • Proper cat care

    • Keeping cats indoors

    • Using flea products

    • Prevent roughhousing with kittens

    • Do not let cats like open wounds

    • Wash cat wounds out with warm water


Bartonella

  • Most healthy people recover without treatment in anywhere from 3 weeks to several months

  • Immunocompromised individuals may develop more serious complications and possibly death

  • If antibiotics are prescribed

    • Erythromycin, rifampin, doxycycline


Bartonella

  • Antibiotics can not reach intraerythrocytic bacteria but can prevent new waves of parasitism

  • A recent study has shown that cats treated for bacteremia caused by B.henselae were resistant to reinfection when challenged following recovery


B quintana

B.quintana

  • Facultative,intracellular,gram negative rod.

  • Catalase and oxidase reactions are negative.

  • The bacterium can be grown on axenic media

  • When grown on blood agar,rough colonies embedded in the agar obtained after 12to14 days

  • Humans are the reservoir of the bacterium,and the human body louse is its usual vector

  • The bacterium has atropism for endothelial cells,leading to angioproliferative lesions,observed in bacillary angiomatosis.


Transmission

Transmission

  • B.quintana is transmitted by the human body louse, which lives in clothes


Clinical manifestations

Clinical Manifestations

  • Trench Fever.

  • Chronic Bacteremia.

  • Endocarditis.

  • Bacillary Angiomatosis.

  • Lymphadenopathy.


Diagnosis

Diagnosis

  • Serologic tests

Western blot and cross-adsorption results in a patient

with Bartonella quintana endocarditis. A) Nonadsorbed. B)

Adsorbed with B. quintana. C) Adsorbed with B. henselae. Lane 1,

B. quintana; lane 2, B. henselae; lane 3, B. elizabethae; lane 4, B.

vinsonii subsp. Berkhoffi; lane 5, B. vinsonii subsp. Arupensis.

Before adsorption (A), antibodies are detected against all species

(1, 2, 3, 4, and 5). After adsorption with B. quintana antigen (B), all

antibodies disappear. After adsorption with B. henselae antigen

(C), antibodies against B. quintana (1) persist. This reaction shows

B. quintana infection.


Bartonella

  • Culture.

  • Molecular Biology.

  • Immunohistochmistry and Immunoflurescence.

. Immunohistochemical demonstration of Bartonella sp

Laser confocal microscopy showing the intraerythrocytic

location of Bartonella quintana.


Antimicrobial drug susceptibility of b quintana

Antimicrobial drug susceptibility of B. quintana

  • Evaluation of susceptibilities to antimicrobial drugs has been performed in both axenic media and cell culture.

  • Penicillines,cephalosporins,aminoglycosides,chloramphenicol,tetracyclines,rifampin,fluoroquinolones,and cortimonazole.

  • However only aminoglycosides have bactericidal effect.


Bartonella

Bartonella bacilliformis

Gram negative aerobic, pleomorphic, flagellated, motile, coccobacillary, 2-3 m large and 0,2 - 0,5 m wide and facultative intracellular bacterium.

For its isolation, special cultures are required containing complemental soy agar, proteases, peptones, some essential amino acids and blood. The optimum growing temperature is 19-29 ºC.


Bartonella

Suspected vectors:

Phlebotomine sand flies

  • Smaller than a mosquito, larger than a midge

  • Coloration varies from light brown (sandy or fawn) to gray or black

  • Require humid, not wet, conditions

  • Only female sand flies take a blood meal

  • Nocturnal feeding behavior

Lutzomyia verrucarum


Bartonella

Suspected Vectors:

Phlebotomine sand flies

  • Sand fies are weak fliers

  • Fly only at night unless disturbed in their daytime resting site

  • Sand flies transmit Bartonella bacilliformis from infected to uninfected hosts by bite

  • At least two species suspected in Peru: Lu. verrucarum and Lu. peruensis

Lutzomyia peruensis


Pathogenesis

Pathogenesis

  • Bartonella bacilliformis is transmitted by the bite of the suspected vector Lutzomyia spp

  • Following transmission, the bacterium infects red blood cells and endothelial cells

  • The physical damage and introduction of antigens in the membranes of the red cells stimulate the Reticuloendothelial System to produce an intense erythrophagocytosis by macrophages and histiocytic cells resulting in severe extra vascular hemolytic anemia


The disease

The disease

  • The clinical symptoms of bartonellosis are pleomorphic and some patients may be asymptomatic

  • The two classical clinical presentations are the acute phase and the chronic phase, corresponding to the two different host cell types invaded by the bacterium


Acute phase oroya fever or carrion s disease

Acute phase: Oroya fever or Carrion’s disease

  • The mean incubation time is 21 days (range 10 to 270 days)

  • The diagnostic tests in this phase are:

Values in porcentaje


The diagnosis

The diagnosis

The diagnosis in the acute phase can be done using the thin blood film with Giemsa stain.

It is possible to observe the bacillus inside the red blood cells.


Bartonella

Immunologic technics: Sonicated immunoblot

Lane A: Positive control pool

Lane Band C:Bartonella bacilliformis-positive serum taken from a patient in acute phase

Lane D: Negative control pool

20 kDa

18 kDa

17 kDa

14 kDa

A B C D


Bartonella

Molecular technics

M: DNA ladder (100 bp).

1:B. bacilliformis DNA from culture extracted by thermal lysis (100°C, 10 min.) using 16S 23S primers (positive control).

2: Whole blood extraction from an acute phase patient, using 16S 23S primers.

3: Whole blood extraction from an acute phase patient, using primers for Citrate Synthetase gene.

4: B. bacilliformis DNA from a culture extraction using primers for Citrate Synthetase gene.

M 1 2 3 4

Base pairs

1500 bp

600 bp


Chronic phase peruvian wart verruga peruana

Chronic Phase: Peruvian wart (Verruga Peruana)

Mularlesions


Chronic phase peruvian wart verruga peruana1

Chronic Phase: Peruvian wart (Verruga Peruana)

Miliary lesions


Chronic phase peruvian wart verruga peruana2

Chronic Phase: Peruvian wart (Verruga Peruana)

Miliary lesions with overwhelming infection


Chronic phase some numbers

Chronic phase: some numbers

  • The diagnostic tests in this phase are blood culture (13% of patients with verruga have bacteriemia), culture of the verrugous warts and Immunoblot with a sensitivity of 70% and specificity of 100%

  • The IFA has a sensitivity of 82% and specificity of 92%


Immunity and infection

Immunity and infection

  • One factor that complicates the clearance of the bacterium is that intra-erythrocytic Bartonella are protected from both humoral and cellular immune responses due to a lack of major histocompatibility complex (MHC) molecules on the surface of the mature erythrocytes

  • They are unable to present antigens of their invaders to the immune system


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