Lecture 15: Lyme Disease, Relapsing Fever

Lyme Disease & Relapsing Fevers

Extracellular, parasitic Borrelia bacteria

Spirochaetota

gram-negative, corkscrew-shaped bacteria

Long

Thin peptidoglycan and lack LPS → Gram stain poorly & less immunogenic

Obligate, fastidious, and motile bacterial parasites

Linear genome & plasmids encode few biosynthetic proteins

Promote antigenic variation

Microaerophilic

SLOW grower

7–11 periplasmic flagella

Arthropod vectors (Ectoparasites)

Borrelia burgdorferi/mayonii

Lyme Disease or Lyme Borreliosis

Arthropod vector: Blacklegged ticks

Reservoir: Small mammals (white-footed mouse) & birds- Wild & domestic animals

Worldwide

N America, Europe (central & western), & Asia

In US - NE, mid-Atlantic, and upper Midwest regions

Rarely fatal

Borrelia burgdorferi/mayonii Virulence Factors

Outer Surface Protein:

Tick: OspA, binds bacteria to tick midgut

Mammals: OspC, binds bacteria to tick salivary glands

Required to establish mammalian infection

Adherence to host cells via Decorin-binding proteins A & B (DbpA & DbpB)

Protease HtrA digest extracellular matrix (ECM) proteins

Lipoprotein VlsE exhibits antigenic variation → avoidance of antibody mediated killing

Complement Regulator-Acquiring Surface Proteins (CRASPs), bind Factor H & Factor H-like proteins to inactivate C3B and prevent complement cascade

OspC antiphagocytic properties and competes with C2, limiting activity of complement cascade

Lyme Disease Clinical Manifestations

Progressive disease with 3 main stages:

Early, localized disease (< 1 mos after tick bite):

Rash: Erythema Migrans (EM)

Red macule or papule, expands to form large, oval patch with flat erythematous border and center may become clear (“Bull’s eye”)

Nonspecific flu-like illness (Fever, fatigue, headache, myalgia)

Early, disseminated disease (Weeks to months after infection):

Lymphohematogenous spread → Spirochetemia with lymphadenopathy

EMs; arthralgia & arthritis (large joints); neurological manifestations with meningitis; facial nerve palsy & painful radiculopathy; and cardiac disease with conduction defects & myopericarditis

Late disease (months to years after infection): Lyme arthritis and neuropathy

Chronic Lyme disease

Lingering symptoms after treatment

Post-Treatment Lyme Disease Syndrome (PTLDS)

Nonspecific symptoms that persist for months to years

Fatigue, pain, and cognitive issues

Lyme Disease Diagnosis

Two-Tiered Serology:

ELISA – highly sensitive

Antigen = whole cell or VlsE C6 peptide

Immunoblot: Detects Borrelia-specific IgG/IgM antibodies

IgM: valid only ≤ 30 days after symptom onset

IgG: valid ≥ 30 days after onset

PCR (Synovial fluid > CSF; EM biopsy): ≤7 days of illness

Detects Borrelia DNA

Lyme Disease Treatment

Early, localized & disseminated stages:

Doxycycline (DOC)

Children and pregnant– amoxicillin and cefuroxime

Early disseminated & late stages: IV and oral antibiotics

Followed by oral Doxycycline

Borreliella mayonii

Lyme Disease

Upper Midwest US- Minnesota & Wisconsin

Nausea & vomiting

Respiratory or GI symptoms

Higher conc. of bacteria in blood

Widespread, diffuse macular rashes

Real-Time PCR amplifies plasminogen binding protein gene, oppA1

Epidemic and Endemic Relapsing Fevers

One or more episodes of fever, headache, and muscle pain that lasts several days and is separated by roughly a week of no fever/symptoms

Progressive disease with 4 main stages:

Incubation (~7–9 days)

Primary spirochetemia (1–6 days): Acute onset of symptoms – high fever, chills, headache, tachycardia, arthralgia, myalgia

Followed by CRISIS:

Chills (15–30 min) – Rigors; increase temp and pulse

Flush (hours) - Profuse diaphoresis; falling temp & hypotension

Latent Phase (~7–9 days): Afebrile episode – Spirochetes disseminate, replicate, & undergo antigenic variation

Secondary spirochetemia: Symptoms return

Followed by CRISIS

With each relapse the duration, severity, and latent phase time decreases

Infection is controlled when antigenic repertoire no longer escapes immune response

Epidemic and Endemic Relapsing Fevers Virulence

Due to antigenic variation

Linear plasmids coding for Variable Membrane Proteins (VMPs)

Variable large (Vlp) & Variable small (Vsp) proteins

Gene conversion → new variation of VMP on bacterial surface

Epidemic and Endemic Relapsing Fevers Diagnosis

Blood smears: Giemsa or Wright stain; Darkfield microscopy

Perform during febrile episodes (spirochetemia peaks)

PCR (blood or CSF):

Distinguishes Borrelia spp.

Peripheral blood – highest sensitivity during fever

CSF for neuroinvasive disease

Serology (ELISA, IFA, immunoblot)

Culture: Barbour-Stoenner–Kelly medium (BSK) or mouse inoculation

Epidemic and Endemic Relapsing Fevers Treatment

Endemic RF:

Doxycycline (DOC)

Children and pregnant– Erythromycin or penicillin

Epidemic RF: Single dose oral or intramuscular antibiotic

Doxycycline, azithromycin, or penicillin

Severe disease - IV penicillin followed by oral Doxycycline

Borrelia recurrentis

Epidemic Louse-Borne Relapsing Fever (LBRF)

Arthropod vector: Human body louse (Pediculus humanus)

Transmitted via crushing vector on skin or conjunctivae

Reservoir: Humans

Africa – Sudan & Ethiopia

Outbreaks associated with overcrowding and poor hygiene (refugee camps)

Absent in the US

High mortality

Borrelia hermsii and turicatae

Endemic Tick-Borne Relapsing Fever (TBRF)

Arthropod vector: Soft-bodied ticks (Ornithodoros)

ALL life stages (transovarial passage)

Nocturnal & resilient

Reservoir: Small rodents, birds, + ticks

Worldwide

In US – Western states and Texas

Low mortality

Borrelia miyamotoi

Hard Tick Relapsing Fever (HTRF)

Arthropod vector: Blacklegged ticks

ALL life stages (transovarial passage)

Reservoir: Small mammals (rodents), birds, ruminants (deer), and ticks

Worldwide

In US – Upper MW, NE, and mid-Atlantic states

Only single fever episode

Avg. symptom manifestation is ~2 weeks (range 3 days to 6 weeks)

Jarisch-Herxheimer Reaction (JHR)

Acute, self-limited inflammatory response that develops within 24 hours of initiating antibiotic therapy for spirochete infections

Patient’s response to antigens produced during spirochete die-off

Massive release of cytokines (e.g., TNF-alpha, IL-6, and IL-8)

Remits within 24–48 hours