6. Neisseria meningitidis, Streptococcal Meningitis, Toxoplasmosis and Lyme disease

meningitis

inflammation of the menges

(dura, arachnoid, pia)

effects of meningitis

10-15% fatality

20% of recovered patients have permanent damage:
– neurological damage
– hearing loss
– defects in spatial learning

Presence of _____ is a common feature to almost all meningitis-causing bacteria

capsule

Many meningitis-causing bacteria are members of

the normal microbiota
– N. meningitidis, H. influenza, S. pneumoniae, E. coli

Neisseria meningitidis

2nd most common cause of community- acquired meningitis in adults

Commonly found in nasopharynx of heathy people

Gram-negative diplococci (Meningococcus)

Covered w/ polysaccharide capsule

capsule

Protects from antibody-mediated phagocytosis

if antibody is directed against a surface protein

Protects from complement-mediated killing

also basis for vaccine-induced antibody recognition

Meningococcal Meningitis

Caused by Neisseria meningitidis

Occurs primarily in young children-teenagers

Can progress very rapidly; life-threatening

Untreated: ~100% fatal 

~10% fatal when treated with antibiotics

Symptoms of meningococcal meingitis 

Mild cold, sudden onset of severe headache, fever, neck and back pain, nausea, vomiting

“petechiae” may occur in skin from blood vessel hemorrhages

Can develop shock and die within 24 hrs due to release of endotoxin

cell wall LPS of Gram- bacteria (LOS for Neisseria)

Usually slower, with time for treatment

Low incidence of long-term effects (deafness, arthritis)

Meningococcal Pathogenesis

Infection by airborne droplets: person-person

Upper respiratory tract

incubation period 1-7 days

Attach to host cells via pili

Invade respiratory epithelium + gain access to bloodstream → release of endotoxin can lead to shock

Travel from blood to meninges and spinal fluid → crosses blood-brain barrier; grows quickly
Immune cell infiltration → Inflammation of meninges → death of tissue and increases pressure in the brain

Blood-Brain Barrier

characterized by tight intercellular adhesion junctions to prevent crossing of
the barrier

N. meningitidis Crossing the BBB

1. After attachment, microcolonies of N. meningitidis trigger cell signaling in endothelial cells

2. the reorganization of proteins maintaining the tight junctions to the area under the microcolony.

3. This loosens the tight junction and allows paracellular passage between cells of endothelial wall

Some evidence for transcytosis/invasion through endothelial cells as well

N. meningitidis virulence factors

Pili

Porin proteins

Opa proteins

Release membrane blebs containing LOS

IgA protease

Pili

mediate attachment to Attach to non-ciliated columnar epithelium of nasopharynx and brain microvascular endothelial cells (BMECs)

Porin proteins

facilitate attachment to cells

Opa proteins

facilitate attachment and confer resistance to serum proteins

Release membrane blebs containing LOS

shorter form called LOS not LPS (lipo-oligosaccharide, LOS)
– decoy for antibodies to Neisseria?

IgA protease

cleaves IgA antibodies to inactive them

some strains make beta-lactamases

Meningococcal Diagnosis

Gram stain: CSF (meningitis) or blood (septicemia)

Culture is also possible, but difficult

Immunity to Meningococcus

Antibodies are important for protection

Neonates are protected for 6 months by maternal antibodies

Complement is important for clearing infections

LOS can trigger inflammation leading to vascular damage, petechiae

Epidemiology and Vaccine

N. meningitidis is more likely to cause large outbreaks of
meningitis than Haemophilus influenzae or Streptococcus
pneumonia

Most N. meningitidis infections are restricted to nose and throat, then cleared

5-15% healthy people carry organism, transient carriers

Can be spread by asymptomatic carriers

Vaccine given in teen years and/or where an outbreak is occurring

Short term immunity, not effective on children <2yr

Often give prophylactic antibiotics during an outbreak

New vaccine approved in 2005, recommended for high school and
college age adolescents, MenACWY

Protects against 4 different capsule antigens (serotypes)

MenB vaccine introduced 2015

N. meningitidis treatment

Antibiotic of choice: ceftriaxone, first choice

can switch to penicillin if susceptible

Does not clear N. meningitidis from asymptomatic carriers

Alternatives: chloramphenicol

Chemoprophylaxis of exposed pt contacts

July 2016: Meningitis in Camp Councilor at Lifetime Fitness Gym Daycare

July 5-11, 2016 up to 213 children and 39 adult employees exposed to infected councilor

Those potentially exposed, recommended to be assessed by Dr. and put on prophylactic antibiotics

Councilor was 21-year old Central Michigan University student

Councilor dies of meningococcal meningitis on July 14

Meningococcemia signs + symptoms

Septicemia

Thrombosis of small blood vessels

Small petechial skin lesions on trunk & lower limbs

Can coalesce to form hemorrhagic bullae

Shock, disseminated intravascular coagulation (DIC)

Adrenal gland destruction: Waterhouse-Friderichsen syndrome

Starts with mild disease symptoms: low-grade fever, arthritis, petechial rash

Often fatal

Responds well to antibiotics

Septicemia

blood infection

not necessarily spread to brain

Group B Streptococci

Streptococcus agalactiae

Significant cause of septicemia, pneumonia, and meningitis in neonates

~10,000-15,000 episodes of invasive GBS disease each year in newborns in US-prior to preventive more recent measures

now more like 1500/year

Can also cause skin and soft-tissue infections, leading to sepsis

Guidelines to Prevent GBS Disease in Newborns

All pregnant women screened at 35-37 wks gestation for anogenital GBS infection

Antibiotics (penicillin) should be administered i.v. during labor (intrapartum) if:
– mother is a GBS carrier
– less than 37 weeks gestation
– membrane ruptures >18 hrs prior to delivery
– temperature of 100.4o F (38.0o C)
– previous delivery of infant with GBS disease

Late Onset Case of GBS Bacteremia in a Newborn (2016, Oregon)

Mom at 37 wks gestation was GBS-negative

Shortly afterbirth, infant developed respiratory distress and transferred to NICU

Blood culture + for GBS, CSF negative

Treated for 11 days with ampicillin

5-days later, re-admitted, again colonized with same strain of GBS

CSF still sterile, expressed breast milk did not contain GBS

What is source of infection?

Mom had been eating capsules derived from her placental tissue that had
been prepared by a commercial vendor

Vendor protocol is to clean and then dehydrate material with heat (46-71˚C) prior to making capsules which are then stored at room temperature

No standards exist for proper processing of placenta for consumption

Capsules were found to be contaminated with viable GBS genetically identical to re-infecting strain

Mom instructed to stop eating capsules and infant treated successfully for 14 days with antibiotics (ampicillin and gentamicin)

Streptococcus pneumoniae

Normal microbiota of nasopharynx

Important opportunistic pathogen

pneumonia, meningitis, sinusitis, otitis media (ear infection)

most common cause of bacterial meningitis in adults

Streptococcus pneumoniae

how does s. pneumoniae cause meningitis

Can damage BBB cells with a toxin called pneumolysin or facilitate invasion of BBB endothelial cells with LTA (Gram+ specific)

Hallmark on gram straining or CSF examination for s. pneumoniae meningitis

Gram + Diplococci

More in respiratory module

Toxoplasmosis

Caused by Toxoplasma gondii passed in feces

Cats infected by predation

Stable in soil/water for months

Either indirect through intermediate host or direct via food/water

Vertical transmission during pregnancy

incidence of Toxoplasma Infections

Acute Infection

oocysts from cat feces or tissue cysts in infected meat

infection initiates in intestine then disseminates throughout body

acute phase lasts 1-3 wks, usually asymptomatic or flu-like: fever lymphadenopathy headache myalgia

Latent Infection

Cytokines are critical for preventing reactivation of chronic infection

Periodic spontaneous cyst rupture stokes immune memory

Cysts often present in the brain

Toxoplasma Crossing the BBB

infect brain endothelial cells and grow inside cell

Eventually rupture out of cells and gain access to underlying brain tissue

Meta-analysis of 50 studies indicates a link between Toxoplasma gondii infection and

schizophrenia

bipolar disorder

Reactivation (Recrudescence)

bradyzoite (cyst) → tachyzoite (rapidly growing)

in immunodeficient or immunosuppressed individuals

Congenital Infection

Occurs only from primary infection during pregnancy

3-5% of babies from primary infected mothers have congenital effects

Transplacental transmission

Sequelae of congenital infection

retinochoroiditis (iinflammation at back of eye)

microopthalmia

mental retardation

hydrocephaly

spontaneous abortion (miscarriage)

Ocular Toxoplasmosis

Reactivation or acute → Retinochoroiditis

Unilateral or bilateral vision impairment

Retinal lesions visible via opthalmoscopy

Local inflammation contributes to pathology

Recurrences common

Congenitally acquired infections can manifest at birth or reemerge later in life

oxoplasmosis treatments

many patients do not require treatment

pyrimethamine + sulfadiazine

OR

trimethoprim + sulfamethoxazole (bactrim)

OR 

corticosteroids

pyrimethamine + sulfadiazine

both inhibit folic acid synthesis

often only required for immunocompromised patients

may require lifelong therapy at lowered dose if HIV+ and poorly controlled

trimethoprim + sulfamethoxazole (bactrim)

alternative medication (also inhibits folic acid production)

corticosteroids

for cerebral edema and ocular infections

Borrelia

Causative agent of Lyme Disease

in US Borrelia burgdorferi

B. burgdorferi grows in midgut of unfed tick.

Feeding induces migration to salivary glands in tick

Lyme Disease

Tick-borne disease transmitted from white-footed mice and white-tailed deer to man

Mouse host more relevant to human disease

symptoms of lyme disease

bells palsy (unilateral facial paralysis)

facial numbness

acute toothache radiating towards eyes and ears

Lyme Disease incubation period

3-30 days

Lyme Disease Stage I

Erythema migrans rash develops at site of tick bite

Starts at site of tick bite (2/3 of patients have rash). 5-50cm rash

Can culture organism from outer edge of rash

Early signs and symptoms: malaise, severe fatigue, headache, fever, chills, musculoskeletal pains, myalgias, lymphadenopathy (last for avg. of 4 wks)

Lyme Disease Pathogenesis

Spirochete enters skin and radiates out

Initial immune reaction suppressed by organism, allowing bacteria to multiply

B. burgdorferi enters blood and spreads throughout the body, flu-like symptoms

After a few weeks immune system holds infection in check

Early treatment with antibiotics can be effective

Lyme Disease Stage II

2-8 weeks after first signs of symptoms

Seen in 10-20% of pts; lasts days to months

Fatigue, headache, fever, malaise

Neurological symptoms: 10-20% of untreated pts severe headache, peripheral nerve neuropathy, facial nerve palsy, fatigue, difficulty concentrating

Cardiac dysfunction: 5%, atriventricular conduction block, myopericarditis, congestive heart failure

may require a pace-maker

Lyme Disease Stage III

Hallmark of Lyme Disease

begins ~6 months or years after skin rash, initial symptoms

60% develop this if untreated

Characterized by arthritis

Large joints generally involved

Chronic skin condition (acrodermatitis chronica atrophicans; more common in Europe)

Chronic disease

Lyme Disease - Prevention

Avoidance of ticks and their natural habitats

Protective clothing: long pants tucked into socks

Use of insect repellents

Check for ticks when return home

A recombinant vaccine was available

Withdrawn from market in 2002

accused of causing autoimmunity

FDA found no evidence of such

Withdrawn due to low demand for vaccine and potential lawsuits

Lyme Disease - Diagnosis

Diagnosis is clinical

Organism is hard to culture, but can use:
– Serology
– Polymerase chain reaction (PCR)

Lyme Disease - Treatment

Depends on stage

Erythema migrans - doxycycline drug of choice; alternative: amoxicillin or cefuroxime

Treatment lessens likelihood of late manifestations but arthritis, may still occur

Carditis, Neurologic, Arthritis - Ceftriaxone

B. burgdorferi-tick life-cycle

Tick eggs/larvae laid by females in spring are infected by feeding on
infected mice in summer/fall

Larvae develop into nymphs over winter

Nymph stage can transmit B. burgdorferi to dogs & humans

Most infections occur in late spring/early summer

90% of human cases from nymph stage

Adults ticks usually feed on deer, but can bite humans

How to remove a tick…

Grasp tick w/ fine tweezers/forceps as close to skin as possible

Pull straight and smoothly away from skin

Do NOT jerk or twist

Do NOT coat tick with anything or use heat to coax tick out

Infection of humans requires >48hrs of feeding

Using CRISPR to Make Mice Immune to Borrelia Infection

“Mice Against Ticks” project

Engineering white-footed mice to express antibodies protective against Lyme disease without requiring usual immune response

Antibody-encoding gene is introduced into mouse genome using CRISPR