CNS Infections, protozoal, fungal

Describe Prions

• AKA?

• Differenty Types?

• Transmission

• Describe the healthy protein version

  • Genetics?

  • Expressed in?

  • Function?

• Describe the changes that makes the protein pathologic

Prions

• Transmissable Spongiform Encephalopathies (TSE)

  • Creutzfeld-Jakobs Disease (CJD)

  • Bovine Spongiform Encephalopathy (BSE)

  • Kuru (humans), scrapie (sheep)

  • Chronic wasting disease (CWD)

• Transmission 

  • ingestion of contaminated meat

• PrPc (healthy protein)

  • PRNP gene on chromosome 20

  • Expressed in:

    • neuronal cells, Ganglia, Peripheral Nerve Cells

    •  tonsils, kidneys, heart, lungs, & spleen

  • Function (suggested):

    • Maintenance of neuronal integrity in the brain

    • Possible role in Cu metabolism & cellular response to oxidative stress

• Pathologic PrPc

  • PrPc -> PrPsc

    • α-helical >  β-sheets

1. What happens in Prion Disease

2. Symptoms

3. Describe Kuro

   1. Geography

   2. Epidemology

What happens in Prion Disease

• Vacuolization of neuronal cytoplasm

  • -> sponge-like appearance of brain parenchyma

---

Symptoms

• Personality changes

• Depression

• Lack of coordination

  • Jerky movements

• Insomnia, confusion, memory problems

• Later stages

  • Severe mental impairment

  • Inability to move or speak

---

Kuru

• Geography:

  • Restricted to the highlands of New Guinea

    • Fore (for-ay) Tribe

• Epidemology:

  • epidemic levels in the 1950’s and 60’s

  • Practiced ritualistic cannibalism

    • Relatives prepared and ate the tissues (including the brain) of deceased family members

    • Brain tissue is highly infectious

  • Transmission was through eating or contact through open sores or wounds

Describe T. Gondii

• Stats

• 3 infectious stages

• Life Cycle

• Normal vs immunocompromised response

STATs

• Most common parasitic infection of the CNS

• Worldwide zoonosis

  • In US, 20-40% of population seropositive for T. gondii

  • In Europe, as much as 90% are seropositive (esp. France)

    • Cultural habits of eating raw or undercooked meat

---

3 infectious stages

• Tachyzoites

  • Rapidly multiply in any cell

  • Seen in acute stages of infection

• Bradyzoites 

  • tissue cysts

    • neural and muscular tissues, brain, eyes, skeletal and cardiac muscles

  • Multiply slowly – in chronic stages

• Sporozoites

  • Found in oocysts 

  • Shed in feces

---

Life Cycle

organisms ingested -> Tachyzoites released -> GI Cells -> Multiply, rupture, Infect contiguous cells -> lymphatics -> body dissemination -> Tachyzoites proliferate -> necrotic foci surrounded by cellular response

---

Normal vs Immunocompromised:

• Normal: 

  • Immune response neutralizes and removes tachyzoites

• Compromised

  • -> necrotizing encephalitis

Sporulated and unsporulated oocysts of T Gondi

Cysts in brain tissue

Tachyzoites

List the symptoms of T. Gondii

• Immunocompetent

• Compromised

• Congenital

Symptoms:

• Immuno Competent (asymptomatic 80-90%)

  • Fever, malaise, night sweats, sore throat

  • Retroperitoneal & mesenteric lymphadenopathy

  • Chorioretin

• Immunocompromised (CNS disease in 50%)

  • Encephalitis, 

  • meningoencephalitis, 

  • mass lesions

  • Hemiparesis, 

  • seizures, 

  • mental status changes

  • Myocarditis, 

  • pneumonitis 

• Congenital (Severe if maternal infection occurs early in preg )

  • CSF pleocytosis & elevated protein levels

  • Microcephaly

  • Survivors:

    • Mental retardation

    • Visual defects

    • Seizures

What causes Cerebral malaria and the consequences

Cerebral malaria

• Deadliest complication of P. falciparum

---

Consequences:

• Encephalitic syndrome

  • Ataxia, 

  • seizures, 

  • hemiplegia, 

  • coma, 

  • Death

• residual neurological damage after successful antiparasite

  • Long term cognitive deficits

    • Memory, learning, and language impairments

• Visuospatial and motor deficits

• Psychiatric disorders

Describe Plasmodium falciparum

• Symptoms

• Key Feature

Symptoms

• Gradual onset

  • Disoriented (or violent), severe headaches, coma

• Abrupt onset

  • Can then suddenly lapse into a coma after asymptomatic

---

Key feature:

• RBC rosette-forming P. falciparum

  • Parasitized RBC surrounded by 3 Normal RBCs

    • mediated by knobs seen on parasitized RBC

1. Describe the pathogenesis of cerebral malaria

2. Most serious Complication? Stats?

Pathogenesis

• Sequestration of parasitized RBCs ->

  • increased brain volume

  • Compensatory vasodilation

  • In Cerebrum, cerebellum, and medulla oblongata

---

Most serious complication: Death 

• 10% of all P. falciparum-infected patients

• 80% of all fatal malarial cases

Describe Naegleria fowleri

• Disease Caused

• Characteristics

• Locations

Naegleria fowleri

• Disease Caused:

  • Primary amebic meningoencephalitis (PAM)

    • mortality rate = 95%

• N. fowleri Characteristics

  • Thermophilic, free-living amoeba

• N. fowleri Locations:

  • Waterways contaminated by thermal discharge of powerplants, heated swimming pools, hot springs (up to 45degC)

  • Inhabits fresh water ponds, lakes, rivers

  • Higher temperatures, low precipitation = decreased water depths -> proliferation of amoeba

Naegleria fowleri

• Transmission/ Period between contact of Naegleria fowleri and onset of symptoms?

• Symptoms

  • Early

  • Acute

  • Other?

• Prognosis

PAM

Transmission:

• amebic-contaminated water -> Nose (inhalation, aspiration, or aerosol) -> phagocytose olfactory epi. Cells -> olfactory mucosa -> Olf. Nerve 

Period between contact of Naegleria fowleri and onset of symptoms

• 2-3 days to as long as 7-15 days

---

• Early symptoms

  • Upper, respiratory distress

  • Headache, lethargy

  • Olfactory problems

• Acute phase

  • Sore throat

  • Stuffy, blocked, or discharging nose

  • Severe headaches

• Other symptoms 

  • Pyrexia, vomiting, stiffness of neck

  • Mental confusion, coma 

    • 3-5 days before death

  • Cardiorespiratory arrest and pulmonary edema = causes of death

NOTE: Symptoms indistinguishable from bacterial meningitis

---

Prognosis

• Only 5 survivors of PAM have been reported,

  • 3% of reported cases 

• High mortality rate

  • Difficulty in diagnosis

  • Poor to marginal response of patients to therapy

1. Why N. Fowleri likes to be in CSF/Brain?

2. N. Fowleri Pathological Abilities?

3. Laboratory diagnosis

Why N. Fowleri likes to be in CSF/Brain?

• Allows rapid growth 

  • B/c it has mitochondria -> High O2 in CSF and Brain Tissue

---

N. Fowleri Pathological Abilities

• highly phagocytic

  • RBCs/brain tissue

  • Severe hemorrhagic necrosis of brain

• Produces amebostome (food cup)

  • Secretes lysosomal hydrolases and phospholipases into it

• Produces/Secretes heat stabile hemolytic proteins, heat-labile cytolysin, phospholipase A, cysteine protease

  • Kill cells that come in contact 

---

Laboratory diagnosis

• Spinal Tap

  • Elevated protein

  • Normal or slightly reduced glucose levels

  • WBC high (400-26000/μL)

  • RBC high

  • CSF is hemorrhagic

  • Gram stain results in no bacteria

  • Wet mount positive for motile trophozoites

NOTE:

• Early diagnosis is mandatory due to rapid course of infection following incubation of 1-2 weeks

• Near immediate chemotherapy is essential for survival

Naegleria fowleri

What are some possible treatments of N. Fowleri

• Human African Trypanosomiasis (HAT)

• African Sleeping Sickness

Describe Trypanosomiasis

• Causative Agents? What is the difference between the two?

• What are kinetoplastids?

Trypanosomiasis

Causative Agent:

• Trypanosoma brucei gambiense

  • West African trypanosomiasis

  • Exclusively human reservoir

  • Slow-progressing that can be self-limiting or develop into a chronic disease involving the CNS and lymphatic system

• Trypanosoma brucei rhodesiense

  • East African (or Rhodesian) trypanosomiasis

  • Zoonotic disease (animal reservoir)

  • Rapidly progressing disease

---

Kinetoplastids: Mitochondrial DNA

Describe (African Sleeping Sickness)

• Disease Progression

• NS impairment

  • Time line

  • MOA

  • Symptoms

Disease progression

1. 1-2 week incubation period

   • Trypanosomal chancre (?)

2. Acute blood stage infection

   • Fever, headaches

3. Invasion of lymphatics

   • Enlarged lymph nodes

   • Weight loss, weakness, rash, itching

   • Continued, intermittent febrile attacks

4. Relapses occur

   • antigenic variation of trypanosomal surface

     • Life cycle exhibits different morphologies

---

Nervous system impairment

• Timeline

  • Trypanosoma gambiense: 6-12 months after initial 

  • Trypanosoma rhodesiense: within weeks with

• MOA:

  • Crosses BBB -> meningoencephalitis 

• Symptoms:

  • Apathy, fatigue, confusion, motor changes 

    • (tics, slurred speech)

  • Changes in sleep patterns

  • Extreme fatigue during day, extreme agitation during night

  • coma or death

What are Kinetoplastids?

Describe Taenia solium

• Life cycle

• Symptoms

• how does it avoid immune system

Taenia solium

Life Cycle:

eggs ingested -> hatch in stomach -> brain via blood stream -> crosses BBB (unknown) -> attach to brain tissues of cavities of brain fluid -> dev. Cyst-like structures (Neurocysticercosis)

---

Symptoms:

• Seizures

  • When larvae attach to brain tissues

  • Larval presence = brain activity uncontrolled

• Altered mental states

• Headaches, nausea, dizziness

  • When larvae blocks flow of brain fluid

---

Avoidance of the immune system

• Enters BBB

  • Brain not easily accessible to immune cells

• Cysts -> degrade Abs

  • Possible nutrient source

• production of protein signals -> inhibit phagocytosis

Cryptococcus neoformans

Describe Cryptococcus neoformans 

• Features

• Major Env. Sources

• Clinical Form

• Virulence factora

• Features:

  • Encapsulated yeast-like fungus w/ prominent capsule 

  • capable of forming mycelia

• Major environmental sources

  • Soil contaminated with pigeon droppings

  • Decaying wood in hollows of living trees

---

Clinical Form:

• Meningoencephalitis

  • Neurotropic in nature

• Virulence Factors

  • Polysaccharide capsule

  • Ability to grow at 37 degC

  • Production of phenol oxidase enzyme

    • Prevents formation of toxic hydroxy radicals

    • Protects organism against oxidative stress

describe cryptococcosis

• Locations

• Diagnostic

• Complications

• Pathogenesis

Cryptococcosis

• Locations:

  • Wound or cutaneous

  • Pulmonary

  • Cryptococcal meningitis

    • dissemination from pulmonary infection

• Diagnostic

  • Copious amounts of capsular material are produced

    • Detected in blood or CSF

• Complications

  • Pts affected

    • Those w/ cell-mediated deficiencies

      • AIDS

      • Organ transplant recipients

• Pathogenesis:

  • CNS infections involve both brain and meninges

    • Cryptococcal antigen in CSF -> changes osmolality -> changes flow/absorption -> Increase intracranial pressure

      • Headaches

      • Vision loss

      • Early death

Cryptococcosis

Coccidioides immitis

Coccidioides immitis

1. Describe Coccidioidomycosis

   • What is it?

   • Transmission

2. Describe the Coccidioides spp.

   • Two Types

   • STATs

   • Geography

3. Describe the pathology

Coccidioidomycosis

• What is it?

  • True, systemic mycosis

  • Acquired by inhalation

• Transmission:

  • Dry arthroconidia carried by dust storms 

  • Related to activities involving tillage of soil

    • Agriculture

    • Telephone post digging

    • Archaeology

---

Coccidioides spp.

• Two Types:

  • Coccidoides immitus

  • Coccidoides posadasii

• STATs

  • Most virulent of human mycotic agents

• Geography:

  • Narrow region

    • San Joaquin Valley, California

    • Maricopa and Pima counties of Arizona

    • Southwestern Texas

  • regions that are characterized by low

  • rainfall, semiarid conditions

NOTE: Dimorphic fungus

---

Pathology

• Mold form -> infectious athroconidia -> maturation -> airborne spores -> inhalation -> in lungs, forms multinucleated spherules -> ruptures, releases endospores -> new spherules

List the symptoms of Valley fever

• Immunocompetent

• Immuno compromised

Valley Fever

Symptoms:

• Immunocompetent

  • Asymptomatic

  • Self-limiting; some antifungals may be needed

  • Confers specific immunity to reinfection

• Immuno compromised

  • Pneumonia

  • Ruptured lung nodules

  • Disseminated disease

  • bone, heart and CNS (meningitis) infection

List the Consequences of CNS dissemination of coccidioidomycosis

Consequences of CNS dissemination of coccidioidomycosis

• Chronic granulomatous meningitis

  • Basilar meninges

• Cerebral and cerebellar abscesses

• Clinical symptoms

  • Headaches, nausea, vomiting

  • Altered mental status