Hdm Test 4, Vector-Borne Bacterial Infections

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Lyme disease -- summary

Back 1

*Borrelia burgdorferi = cultivable spirochete
*EM rash, Chronic infection in host (stage 1, 2, 3)
*Pathogenesis not well understood
*Immune evasion- antigenic variation and phase variation, binding of host proteins
*Stage 1 and 2 disease responds well to treatment
*Diagnosis by serology, better tests needed
*OspA vaccine

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Lyme disease -- agent and vectors

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Agent: Borrelia burgdorferi
Vectors: Ixodes scapularis, Ixodes pacificus
(black legged ticks)

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Lyme disease -- vertebrate hosts

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rodents

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Lyme disease -- discovery

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named after Lyme, Connecticut
In the 1970s- unusually high number of children with rheumatoid arthritis living in/around Lyme, CT; many of the children also had an erythema migrans (EM) rash
Epidemiological studies= disease was most likely caused by an arthropod vector transmitted pathogen. In the early 1980s- spirochete in the genus Borrelia transmitted by ticks. The new spirochete was named Borrelia burgdorferi to honor its discoverer

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Lyme disease -- epidemiology

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Borrelia burgdorferi- linked to several other acute and chronic diseases described in Europe
Lyme disease is now recognized as the most common vector-borne disease of people in North America and Europe

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Tick-Borrelia interactions

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during the 3 blood meals of a tick’s life time, infection is acquired during the 1st (larval) blood meal and transmission can occur during the 2nd (nymphal) and 3rd (adult) blood meals
the entire life cycle of a single tick occurs over 2 years and transmission mainly occurs during the warmer months of the year when ticks are active

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During which stage of the tick life cycle are most humans infected with Lyme disease?

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higher incidence of transmission from infected feeding nymphs

lower incidence of transmission from infected adult tick

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How long does it take for tick to transmit Borrelia into human host?
(Grace period)

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2 days of feeding

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Why is Lyme disease emerging in the USA?

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-- Massive increase in forested areas --> increase in deer populations --> increased tick populations
-- Large increase in human population
-- Housing developments in wooded area
-- People spend more time involved in recreational activities outdoors

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Borrelia burgdorferi -- characteristics

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- Gram negative
- Can culture in complex media
- No LPS
- Outer and inner membranes have many proteins (~10% genome)

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How does B. burgdorferi cause disease in host?
- virulence factors
- pathogenesis

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- extracellular organism
- no virulence factors
- direct attack by pathogen + host immune response = Lyme disease
- no LPS, but lipoproteins activate TLR2 -- >inflammation

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How does B. burgdorferi persist in host?

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-- antigenic variation (DNA recombination) --> VlsE
-- phase variation (protein expression) --> OspC, Erps
-- sequestration inside cells (?) or in immunologically privileged site
-- antigenically inert or cystic forms of spirochetes

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Lyme disease -- treatment

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doxycycline
blocks spread of localized infection (stage 1)
can also block persistent infection and long-term survival (stage 3)

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What can happen if Lyme disease is not treated?

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persistent infection despite strong immune response
skin to blood to nervous system/joints/tendons/heart
other: additional EM rashes, eyes, liver

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Lyme disease -- diagnosis

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Serology (ELISA, Western Blot): current method of testing; useful but problems of specificity and sensitivity
culture (from EM rash): high specificity but low sensitivity
PCR, urine antigen, immune complex methods: still experimental

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Lyme disease -- prevention

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most effective preventive measure: minimize exposure to ticks.
Recombinant protein vaccine (Lymerix, OspA), only recommended for use in high risk populations; company discontinued production of vaccine

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Chronic Lyme disease controversy

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Some people who have adequately treated infection continue to suffer from symptoms (treatment resistant Lyme disease) --> Autoimmune etiology suspected

Lyme diagnosis should be based on validated lab tests; disease responds well to short-term antibiotic therapy

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“Southern Tick Associated Rash Illness”
(STARI, Masters Disease) -- transmission

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agent of disease is unknown
vector: Amblyomma americanum (Lone Star tick)

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STARI -- clinical presentation

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rash: bull's eye, central clearing, outer ring (similar to rash with Lyme disease)

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STARI -- discovery

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-- rash like erythema migrans
-- exposure to Amblyomma americanum (Lone star ticks) **Not competent vectors of B. burgdorferi**
-- no evident exposure to Ixodes scapularis/pacificus (black legged ticks
-- no lab evidence of B. burgdorferi

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Evidence for novel tick-borne pathogen in the Southeast (STARI)

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-- Transmitted by Lone Star Ticks
-- Not cultivable from EM rash
-- Patients do not develop antibodies against Lyme disease spirochete

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Tick-borne infectious diseases in the US (5 main)

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- Lyme disease
- Rocky Mountain Spotted Fever
- Human Monocytic Ehrlichiosis
- Human Granulocytic Ehrlichiosis (Anaplasmosis)
- Babesiosis
others: Relapsing Fever, Powassan Virus (TBE), Tularemia, Colorado tick fever

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Rocky Mountain Spotted Fever -- agent and vector

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agent: Rickettsia rickettsii
vectors:
Dermacentor variabilis (American dog tick)
Dermacentor andersoni (Rock mountain wood tick)

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Rocky Mountain Spotted Fever -- vertebrate hosts

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small mammals

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One differentiating characteristic between R. ricketsii and B. burgdorferi

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R. ricketsii: vertical transmission in ticks (adult can lay infected eggs)
B. burgdorferi: NO vertical transmission in ticks (adult will lay UNinfected eggs)

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what is the grace period for R. rickettsii?

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10-24 hours
lives in salivary glands of ticks

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Rickettsia ricketsii -- characteristics

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Obligate intracellular bacterium
Divide in the cytoplasm of infected cells
Small coccobacilli
Gram negative-like cell envelope
Cannot culture without cells

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Rickettsia ricketsii -- pathophysiology, virulence factors

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-- Energy parasites- utilize host carbon sources and host ATP
-- Utilizes host actin for motility and neighboring cell invasion
-- Allows spread from cell to cell without encountering extracellular environment

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Rickettsia ricketsii -- pathophysiology

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-- Main target: vascular endothelial cell
-- Alters and damages endothelial cell membranes
-- Platelets bind to altered cells and set up cascade of events ---> DIC
-- Endothelial damage --> blood leakage out of blood vessels ---> shock

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Rickettsia ricketsii -- prodromal clinical symptoms,

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occur within 1-2 weeks
chills, fever, headache, rash
rash = erythematous, maculopapular, petechial,
typically on extremities, then on trunk
(rash not always present)

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Rickettsia ricketsii -- clinical symptoms, pathophysiology

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fulminant vasculitis, especially of endothelial cells (also the vascular smooth muscle cells of kidney, heart, skin, brain and subcutaneous tissues)
**vascular endothelial cell damage is proportional to the number of rickettsiae parasitizing them

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Rickettsia ricketsii -- mortality

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with treatment, case fatality is about 25%
older people are more susceptible to severe RMSF.

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Rickettsia rickettsii -- infection of vascular endothelial cells --> disseminated intravascular coagulation (DIC)

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- Occlusion of small vessels --> microthrombi and microhemorrhage = loss of blood cells (petechiae) and fluid (edema) --> shock
- Lack of O2 perfusion of vital organs may cause anoxic brain injury and acute renal failure
- Pulmonary edema and vasculitis in many organs
- Death can result from vasomotor weakness, shock, renal failure and respiratory or cardiac arrest.

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Rickettsia rickettsii -- immunopathological mechanism

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there is no evidence for a rickettsial toxin nor immunopathological mechanism

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Rickettsia rickettsii -- diagnosis

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*Culture is difficult and dangerous; Immunofluorescent antibody tests can detect organism in tissue biopsies
*Most practical method is serodiagnosis: IFA and latex agglutination test (good specificity and sensitivity), but early in disease course when treatment decisions need to be made, the person may not have had enough time to mount an antibody response.
Treatment decisions should be based on clinical findings and not serological test results.

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Rickettsia rickettsii -- treatment

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[Treatment decisions should be based on clinical findings and not serological test results]
Tetracycline antibiotics are effective against R. rickettsii.

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Ehrlichia and Anaplasma -- characteristics

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obligate intracellular
small gram-negative-like
grouped with Rickettsiae

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difference between Ehrlichia and Rickettsiae

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Grouped with Rickettsiae but different in that:
Ehrlichia replicate within vacuoles while most Rickettsiae grow free in cytoplasm

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the agent of human granulocytic ehrlichiosis

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now known as Anaplasma phagocytophila

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Ehrlichiosis -- disease

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characterized by fever, malaise, myalgia, headache, rash, rigors, diaphoresis
*Many asymptomatic or very mild cases while others can get very sick
*Death is rare

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Ixodes (black-legged ticks) transmits:

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-- Borrelia burgdorferi
-- Anaplasma phagocytophilum
-- Babesia microti
-- Tick-borne encephalitis virus (Powassan virus)
*co-infections can occur!*

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Amblyomma (Lone Star ticks) transmits:

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Ehrlichia chafeensis and STARI

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Dermacentor (Dog tick) transmits:

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Rickettsia rickettsii
and Ehrlichia chafeensis

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Human Monocytic Ehrlichiosis (HME) -- agent and vector

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Agent: Ehrlichia chaffeensis
Vectors: Amblyomma americanum, Dermacentor variabilis

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Human Monocytic Ehrlichiosis (HME) -- vertebrate hosts

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deer

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Anaplasmosis -- agent and vector

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Agent: Anaplasma phagocytophilum
Vectors: Ixodes scapularis, Ixodes pacificus

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Anaplasmosis -- vertebrate hosts

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rodents, maybe others

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Anaplasmosis -- miscellaneous

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infects neutrophils

population at risk is the same as those at risk for Lyme Disease

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RMSF and Ehrlichiosis summary

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**RMSF caused by Rickettsia rickettsii, obligate intracellular bacterium
**Transmitted by Dermacentor; NC= most cases in US
**Involvement of host actin in motility and cell-to-cell movement
**Main target: vascular endothelium
**Disease has very rapid progression and can lead to shock and death

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two types of Ehrlichiosis

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HME (Ehrlichia chaffeensis) and HGE (Anaplasma phagocytophilum)