• STRUCTURE: ss (+) RNA, lipid envelope, "crown-like," more than twice as large as Picornaviridae.

• DIAGNOSIS: It isn't cultured, but must distinguish it from bacterial otitis media or pharyngitis. Culture for Strep-A.

• IMMUNITY: Acquired immunity is poor; reinfection with same strain occurs.

• MANIFESTATIONS:

  • Common Cold: 10-15% of cases, peaking in winter / spring months.

• STRUCTURE: Small, spherical, non-enveloped, ss (+) RNA, infectious.

  • Structure similar to Picornaviruses.

  • "Calix" = "cup" -- cup-shaped depressions on capsid.

• REPLICATION: Cytoplasmic, like Picornaviruses. They do produce subgenomic mRNA for capsid proteins.

• HEPATITIS-E:

  • TRANSMISSION: Fecal-oral, often found in contaminated water. Found primarily in other countries -- India and central Asia.

  • MANIFESTATIONS: Acute infection similar to HAV.

    • High fatality rate among pregnant women, and high perinatal fatality.

• NORWALK AGENT: Little village in Ohio.

  • MANIFESTATIONS: Major cause of gastroenteritis. Short-incubation period.

    • Infection more common in adults.

  • TRANSMISSION: Fecal-oral.

  • TREATMENT: None.

  • IMMUNITY: Induced immunity is poor.

• STRUCTURE: ss (+) RNA, cap and tail, diploid (two copies), enveloped.

  • The two copies of RNA are base-paired to each other, and are hooked to an accessory tRNA which is essential for replication.

  • Reverse Transcriptase: RNA-Dependent DNA Polymerase. It is encoded by Pol gene and has three different functions.

    • RNA-Dependent DNA Polymerase (make ds-DNA out of RNA)

    • RNAse-H: This activity degrades the RNA portion of the RNA:DNA hybrid during replication. Located on the same protein as the RT action.

    • Integrase: This activity cleaves host and viral DNA in preparation for integration of virus into host genome. Separate protein cleaved from the pol transcript.

  • Long Terminal Repeats (LTR'S): Genome contains LTR's at each end, which have some sequences in them unique to each virus.

    • R: Redundant sequences at both ends of genome.

    • U5: Unique sequence at 5' end.

    • U3: Unique sequence at 3' end.

  • THREE RETROVIRAL GENES: These genes are required by all retroviruses for successful replication.

    • Gag: Group-Antigen. Encodes a structural precursor protein.

    • Pol: Polymerase. Encodes the Reverse Transcriptase.

    • Env: Envelope-protein. Encodes glycoproteins that become a part of the viral envelope.

• ONCOVIRUS PARTICLES: Retroviruses become proviruses and can cause transformation by several mechanisms. They can induce host-genome mutation (insertional mutagenesis), and they can act as transposable elements.

  • Four major types recognized.

    • A-Type: Non-infectious

    • B-Type: Budding through plasma membrane with eccentric core. MMTV.

    • C-Type: Most Common. Budding through plasma membrane with central core. Includes HTLV, RSV (Rous-Sarcoma), MuV.

    • D-Type: Some primate viruses.

  • Two Categories:

    • Acute: v-onc+ viruses have genes homologous to host proto-oncogenes. They are defective in that they can't replicate -- replication-deficient transformation-competent v-onc+ viruses.

    • Chronic: Not in themselves v-onc+ genes, but rather they cause transformation long after infection by insertional mutagenesis. Usually cause leukemia.

  • Specific Viral Oncogenes: v-onc genes.

    • arc: Role in Rous Sarcoma. It encodes a Tyrosine Kinase.

    • erbB: Encodes a receptor for Epidermal Growth Factor (EGF-R).

    • sis: Encodes PDGF.

    • ras: Encodes GTPase activity. v-ras (oncogene) differs from c-ras (protooncogene) by one codon.

    • myc: In Burkitt's Lymphoma, it is involved with an Ig gene in a 8:14 translocation.

    • abl: Involved in 9:22 translocation with bcr to form the Philadelphia chromosome, in Chronic Myelocytic Leukemia (CML).

    • erbA: A thyroid-hormone receptor in birds. It blocks the differentiation of proliferating erythroid precursor cells.

  • Tumor-Suppressor Genes:

    • Retinoblastoma (Rb) Gene

    • Wilms Tumor Gene

    • p53

• REPLICATION: Via reverse transcriptase

  • Cytoplasmic Stage: Particle is not immediately uncoated. RNA genome utilizes Reverse Transcriptase to make a double-stranded copy of DNA (RNA ------> cDNA ------> dsDNA). Then the RNA is degraded.

    • It utilizes a hydrogen-bonded host-cell tRNA as a primer.

  • Nuclear Stage: ds-DNA copy enters nucleus. It becomes integrated as a provirus, with the aid of the nuclease activity of Reverse Transcriptase. If integration fails, then the virus can't survive. Thus it's a potential drug target.

    • Transcription then ensues and viral mRNA is made. The unspliced transcripts serve as progeny genome.

    • Gag, Pol, and Env proteins are translated, glycosylated, and incorporated with the genome as a new virion particle is formed.

• Endogenous Proviruses: Human have a few silent endogenous proviruses: EREV1, and ERV3. They are both defective and produce no symptoms.

• HUMAN T-LYMPHOMA VIRUS (HTLV-1): (ONCOVIRINAE)

  • STRUCTURE: Type-C Oncovirus particle.

  • MANIFESTATIONS: Adult T-Cell Leukemia / Lymphoma (ATL). The virus infects CD4+ T-Cells, causing proliferation.

    • tax/rex gene is the single viral gene that is implicated in oncogenesis. HTLV virus is integrated into the infected cell as a provirus (no replication occurs). The mechanism of transformation is unknown, but they think it is acute and that the virus has v-onc+ genes.

    • Symptoms: Skin manifestations, hypercalcemia, leukocytosis, hepatosplenomegaly.

    • Bad prognosis.

• Rous Sarcoma Virus (RSV): (Oncovirinae). Causes sarcoma in birds.

• HUMAN IMMUNODEFICIENCY VIRUS (HIV): (LENTIVIRINAE)

  • SUBTYPES:

    • HIV-1: Human HIV.

    • HIV-2: More closely related to SIV and infects monkeys.

  • STRUCTURE:

    • Gag, Pol, and Env proteins.

    • Accessory Proteins:

      • vpu protein is required for maturation and budding.

      • tat (transactivator of transcription): Activates transcription of the major viral mRNA's.

    • Glycoproteins: Encoded by the Env genes. gp160 is the precursor glycoprotein, which is then cut in two:

      • gp120: Also called the 'Secretory Subunit." High antigenic variability.

        • High degree of antigenic shift. We make antibodies to gp120, but it is always changing its antigenic specificity.

          • Has V1-V5 Variable Regions. V3 is responsible for M-Tropism. The CD4 binding domain lies in between V4 and V5.

        • It is responsible for the binding of the virus to CD4⁺ receptors.

      • gp41: Transmembrane component. Less antigenic variability.

        • Responsible for the fusion of viral and cell membranes.

        • Also confers the tropism on the cell -- L-Tropic or M-Tropic.

      • Protease Inhibitors inhibit this cleavage.

    • Structural Proteins: Capsid proteins encoded by the Gag gene.

      • P55 is cleaved by protease into 5 substituents, including P24.

      • These structural proteins are required for viral replication.

      • Protease Inhibitors inhibit this cleavage.

  • VIRUS-TROPISM: Conferred by gp41 glycoprotein.

    • L-Tropic: Attracted to lymphocytes (CD4⁺ cells)

      • Infection of T_H cells accounts for depressed CD4 count.

    • M-Tropic: Attracted to macrophages or cells in macrophage lineage.

      • Infection of Alveolar Macrophages: accounts for HIV interstitial pneumonia.

      • Infection of CNS microglial cells: accounts for neurological symptoms and HIV encephalopathy.

  • DIAGNOSTIC TESTS:

    • ELISA Test: Detects antibodies to P24. It is highly sensitive but not specific. If positive, must confirm with a Western Blot.

    • Western Blot: Required confirmatory test. Highly specific. Must reveal antibodies to two viral proteins to be confirmatory.

    • Immunofluorescence, Flow Cytometry: Can be used to detect P24 viral antigen and thereby monitor disease and measure viral burden.

  • MANIFESTATIONS:

    • Primary Infection: A mononucleosis-like infection of fever, pharyngitis, lymphadenopathy. Leukopenia is present, but CD4 count returns to normal after initial infection.

    • Asymptomatic Phase: Can last from 1 to 15 years.

      • The virus continues to replicate throughout -- so it is not proper to call it a latent infection.

      • About 5% of CD4 cells are infected at any point in time.

    • AIDS / AIDS-Related Complex (ARC): Happens when CD4 count gets below 500, and then below 200.

      • What makes AIDS emerge?

        • Antigenic stimulation of the infected CD4 cell may cause it to undergo apoptosis, thereby setting off the symptomatic phase of the disease.

        • May need to wait for cytopathic variants of HIV to arise, by random mutations.

      • OPPORTUNISTIC INFECTIONS: Fungal, mycobacterial, viral, and parasitic infections that require CMI. They show up at 500 CD4-count, and then others show up at 200 CD4-count.

      • MALIGNANCIES: Kaposi Sarcoma, B-Cell Lymphomas in brain, invasive cervical cancer in women.

        • Kaposi Sarcoma: Probably sexually transmitted, and caused by HHV-8.

      • HIV Neurological Disease: Cognitive symptoms, behavioral symptoms, motor symptoms, due to infection of microglial cells by M-Tropic viruses.

      • HIV-Associated Nephropathy: 10-40% of infected patients. Renal failure and mesangial hyperplasia, due to infection of mesangial cells (nephritic macrophages) by M-Tropic viruses.

      • HIV Interstitial Pneumonia: Due to infection of alveolar macrophages. It is a giant-cell pneumonia.

  • TREATMENT:

    • Nucleoside-Analog Inhibitors of Reverse Transcriptase: AZT. It inhibits Reverse Transcriptase.

      • SIDE-EFFECTS: Bone marrow toxicity, nausea, myalgia, headache.

      • PROBLEM: Reverse Transcriptase acquires resistance by mutation. Resistance arises more rapidly in patients with advanced disease.

      • ddC and ddI are other analogs that are useful in combination with AZT. They also ameliorate side-effects.

    • Non-Nucleoside Inhibitors of Reverse Transcriptase:

    • Protease Inhibitors: They inhibit the cleavage of structural protein P55 into P24, thereby inhibiting replication. Promising drug.

      • The protease is an Aspartate Protease, thus any drug blocking that mechanism has promise.

  • VACCINES: Three types have been tried, all disappointing.

    • Humoral Immunity against gp120: it was unsuccessful.

    • Whole killed virus

    • Live attenuated virus: low success-rate and too risky.

• HUMAN FOAMY VIRUS (HFV): (SPUMAVIRINAE). Causes foamy vacuolation of many different cell types. Apparently benign.

• Inflammation of leptomeninges (arachnoid and pia mater) including subarachnoid space and CSF

• C/S are F, H/A, stiff neck, and behavior changes

• CSF changes in meningitis

  • Bacterial

    • Neutrophilic pleocytosis (pleocytosis = increase in cells)

    • Elevated protein

    • Reduced sugar

  • Viral

    • Lymphocytic pleocytosis (may have PMN pleocytosis early on)

    • Protein less elevated than bacterial, sugar normal

• Bacterial

  • Also called acute meningitis or purulent meningitis

  • Caused by

    • Neonates: E. coli, Streptococcus agalactaciae (Group B strep), and Listeria

    • Kids: H. influenzae (incidence decreased due to vaccine)

    • Young adults: N. meningitidis

    • Older adults: S. pneumoniae, Listeria

    • Open head trauma: staph, strep, other flora

  • Subdural empyema

    • Spread of infection from skull or sinus to subdural space

    • May be bacterial (often fungal)

    • Can produce mass effect

    • Thrombophlebitis of bridging veins may result in brain infarction

    • Resolution from dural side

• Viral

  • Also called lymphocytic or aseptic meningitis

  • Can be caused by numerous viruses, but enteroviruses are very common causes in summertime (1/3 of cases have unknown cause)

  • Has to be treated symptomatically, since a/b don’t work

• Chronic

  • Usually fungal or TB

  • Cryptococcus meningitis – form of fungal meningitis in AIDS and other immunocompromised patients

• TB meningitis

  • Chronic meningitis usually localized to the base of the brain

  • If gets into brain (encephalitis) will form discrete tuberculomas in the brain matter

    • 25% of intracranial masses in South America and India

    • Adult lesions are supratentorial, kids’ lesions are infratentorial

• Hematogenous spread from distant site

• Local extension from sinus or ear

• Direct implantation following puncture

• Peripheral nerve spread (e.g., herpes, rabies)

• Can be viral, bacterial, fungal, or parasitic

• If there are abscesses it’s usually due to bacteria

• Viral encephalitis

  • CMV and herpes are the 2 most common causes

  • Arboviruses (arthropod borne) can also cause encephalitis

    • Transmitted by biting insects

    • Local outbreaks associated with mosquitoes (birds are reservoirs)

    • Viruses: St. Louis, Eastern equine, Western equine, Venezualan equine, California, Japanese, and West Nile virus

  • Mumps, measles, rubella, and chickenpox can cause encephalitis

  • Herpes encephalitis

    • Most common cause of viral encephalitis

    • HSV-1 causes an acute encephalitis that usually involves the temporal lobes

    • HSV-2 is a problem in babies born to infected moms; can cause meningitis in older persons

    • Can occur without active infection elsewhere

  • CMV

    • Seen in the immunocompromised and fetuses

    • Starts as ependymitis and spreads through the CSF

    • Can cause focal, necrotizing lesions of brain tissue that may lead to periventricular calcification

    • Also causes meningitis and spinal radiculitis

  • Poliomyelitis

    • An enterovirus that secondarily involves nervous tissue

    • Initially a meningitis

    • Involvement of only anterior horn motor neurons; produces a flaccid paralysis (death by respiratory paralysis or myocarditis)

    • Pretty much gone now due to vaccine

  • Rabies

    • If untreated, causes a fulminant encephalitis that is always fatal

    • M/O get to CNS by peripheral nerves

    • See local paresthesias at site of wound and malaise, H/A, and F (classic)

    • Selectively involves basal cerebral nuclei, midbrain, and floor of 4^th ventricle

    • Negri bodies: intracytoplasmic inclusions of virion aggregates

    • 2 forms

      • Furious: volatile, violent, emotional behavior with lucid states and hydrophobia; usually die from arrhythmias

      • Paralytic (dumb): ascending flaccid paralysis; die of respiratory arrest

  • Subacute sclerosing panencephalitis

    • Kids and young adults who had measles

    • Personality change followed by involuntary movements; progressive over years

    • Defective viral particles lack M protein of viral coat and spread more slowly

• 
  

  • Toxoplasmosis

    • See behavior changes and lots of small abscesses on MRI

    • Almost always treated for in AIDS patients

    • Lots of small abscesses throughout the brain

  • HIV encephalitis

    • Direct infection of brain by HIV (crosses the BBB in macrophages)

    • Seen in 20-30% of AIDS patients

    • See multinucleated giant cells, especially perivascularly

  • AIDS dementia complex

    • Clinical syndrome due to direct CNS infection of brain (still crosses BBB in macrophages)

    • HIV not in neurons, but in microglia (which migrated in as tissue macrophages?) and astrocytes

    • Mechanism unknown because there’s not too much neuronal damage

    • May see some gliosis and vacuolization of the white matter

  • Vacuolar myelopathy

    • Degenerative disease of the spinal cord seen in 20-30% of AIDS patients

    • Maybe due to direct infection of spinal cord by HIV

    • Looks like subacute combined degeneration seen with vitamin B₁₂ deficiency (affects the posterior and lateral columns of the spinal cord), but it’s not associated with deficiency

  • Meningitis (often cryptococcal)

  • Progressive multifocal leukoencephalopathy – is an opportunistic brain infection in AIDS patients caused by JC virus which infects the oligodendrocytes and causes MS-like c/s

• Usually from staph, strep, or anaerobes (fungi in immunocompromised)

• Think toxoplasmosis if seen in AIDS patient

• Can be a complication of

  • Acute bacterial endocarditis

  • Cyanotic congenital heart disease (R to L shunt prevents filtration of m/o by lungs)

  • Bronchiectasis

• This is one of the few times collagen will be seen in the brain (seen in abscess wall)

• Symptoms are those of a mass lesion

• Generally seen in the immunocompromised and are hematogenous (except Mucor mycosis, which comes in directly from the nose)

• Cryptococcus meningitis is most common infection

  • M/O are encapsulated and appear as such

  • Multiple abscesses in the brain and granulomatous response

• Candida infection can produce meningitis or encephalitis

• Malaria

  • Vasculature prominent from congestion with malaria m/o

  • Looks like petechiae all over brain (from pigment in m/o from RBC ingestion)

• Trypanosomiasis

• Amoeba

  • Most infections are from Naeglaria species via direct infection (swim in amoeba-infested water, they enter the nose, and go to the frontal lobes through the cribiform plate); m/o look like foamy macrophages

  • Entamoeba histolytica can infect the brain by hematogenous spread from an infection elsewhere in the body (won’t be just in the frontal lobes)

• Cysticercosis

  • From eating eggs of pork tapeworm

  • Infection can be in any organ (look for numerous small radiopaque lesions)

  • Have a cystic appearance because the m/o is rather cystic

• Echinococcosis – mostly causes liver problems

• Meningovascular

  • Most common form

  • See plasma cells in the meninges

  • Special stains will show spirochetes

• Parenchymal (gummas) – more of a granulomatous reaction

• General paresis

  • Spirochetes invade the brain (and can be seen with special stains) and cause gliosis and other reactive changes

  • Fe deposits are common and there is a progressive neuronal loss

• Tabes dorsalis

  • Looks similar to vacuolar myelopathy of AIDS

  • Involves posterior columns of the spinal cord

  • Will not see spirochetes with special stain

  • Present with sensory disturbances, shooting pains, loss of proprioception and ataxia

• CJD

  • Most common prion disease in humans; typically seen in older people

  • Starts with subtle behavior changes followed by rapid progressive dementia (most rapidly progressive of human prion diseases – uniformly fatal within a year of c/s onset)

  • Startle myoclonus is common in later stages

  • Transmitted by exposure to eye and neural tissue products, but there are familial and sporadic forms

• vCJD (new vCJD)

  • Seen in younger patients

  • Associated with consumption of BSE beef

  • More protracted than is classic CJD

• Kuru – cannibals in Papua/New Guinea

• Scrapie

• Mink encephalopathy

• BSE

• Gerstmann-Straussler-Schenker syndrome – presents with progressive ataxia

• Familial fatal insomnia – characterized by sleep disturbances leading to dementia

• Kuru plaques can be seen in all of the prion diseases (these are amyloid plaques)

• Pathogenesis of prion diseases in general

  • Prion protein (PrP) is a normal protein that we all make

  • Some folks have a PrP that is prone to change from its alpha helix to a beta pleated sheet; when this happens, it encourages other PrP around it to change conformation as well (now called PrP_SC)…lots of PrP_SC cause spongiform changes – this explains how prion disease can be acquired and spontaneous

  • If you don’t make PrP you are immune from prion diseases

  • PrP_SC is very resistant to proteases, heat, and steam (autoclaving)

• Collateral circulation
• Duration of ischemia
• Magnitude of flow reduction
• Rapidity of flow reduction (slower processes like atherosclerosis allow more time for collaterals to form)

• Thrombotic infarcts

  • Usually from atherosclerosis but can be due to vasculitis

  • Usually non-hemorrhagic (pale)

• Embolic infarcts

  • Usually from mural thrombi from heart or carotid atherosclerotic plaques

  • The MCA is most often involved and they are usually hemorrhagic

• Venous infarcts

  • From thrombosis of the superior sagittal sinus

  • Very rare and very hemorrhagic

• Selective vulnerability

  • Some neurons are more susceptible to ischemia (Purkinje cells are very vulnerable)

  • Not due to reduction of blood flow

  • Can see a ribbon-like area of necrosis since certain areas of the cerebral cortex are more vulnerable (called laminar infarcts)

• Watershed infarcts

  • Infarcts at borders between arterial supply regions

  • These low perfusion areas are at higher risk of injury even with mild hypoxia

• Respirator brain – autolytic softening of brain in veggies on respirators

• After first 12 hours see red dead neurons

• Up to 48 hours see neutrophils

• Within days the neutrophils are replaced by macrophages stuffed with neuronal debris and may have hemosiderin in them if the infarct was hemorrhagic

• 1 – 2 weeks see gliosis (not fibrosis)

• May resolve as a cystic cavity

• HTN vascular disease accounts for > ½ of intraparenchymal hemorrhages

• Usually affects deep gray matter (like basal ganglia and thalamus)

• Charcot-Brouchard microaneurysms: “leaky” microscopic outpouchings of vessels due to HTN

• Lacunar infarcts

  • Cystic spaces in deep gray matter

  • The hypertensive blood vessel creates a space that gets left behind

• Hypertensive encephalopathy

  • Associated with very high BP

  • See H/A, seizures, and confusion

• Multi-infarct dementia

  • Multiple infarcts over time wipe out enough gray matter to wipe out cognitive abilities

  • Presents as a progressive dementia

• Binswanger’s disease: dementia and white matter loss from multiple infarcts

• Epidural hematoma – almost always from trauma

• Subdural hematoma – usually from trauma

• Subarachnoid hemorrhage – usually not from trauma

  • Bleeding between arachnoid and pia mater

  • Usually from ruptured berry aneurysm at branch points of Circle of Willis; also from trauma, bleeding d/o, AVM, or rupture of intraparenchymal hemorrhage into ventricles

  • Berry aneurysms are more common in those with HTN (or at least more prone to rupture) and are associated with ADPKC

• AVM

  • Irregular tangle of vessels with an AV shunt, usually in the cerebrum

  • May see seizures and subarachnoid and/or intraparenchymal hemorrhage

• Cavernous hemangioma

  • Collection of dilated vessels without an AV shunt

  • Usually in cerebellum or pons

• Capillary telangiectasia

  • Microscopic foci of dilated vessels separated by normal brain tissue; no AV shunt

  • Usually in pons

• Multiple Sclerosis – most common

  • Mostly in whites in northern latitudes, 20-40 YOA, female > male

  • Autoimmune or postviral

  • Formation of plaques in white matter that exhibit demyelination, inflammation, and gliosis

    • Gitter cells will be present

    • Plaques are separated from one another and come and go with time (get better during periods of remission)

    • Axons seem to be spared

  • Intermittent but progressive disease

    • Early C/S: paresthesias, incoordination, and mild sensory and motor symptoms of extremities

    • Late C/S: ataxia, paraplegia, and mental dysfunction

  • Variants

    • Neuromyelitis optica (Devic’s disease)

      • Demyelinating disease of spinal cord and optic tract

      • Permanent damage to axons

    • Acute MS – more accelerated form in younger patients

    • Balo concentric sclerosis – fuhgedaboudit

• Progressive multifocal leukoencephalopathy

  • Caused by JC virus (a papovirus); may rarely come from SV40

  • Opportunistic – seen in AIDS and other immunocompromised patients

  • Oligodendrocytes are affected and show intranuclear inclusions

  • Causes focal demyelinating plaques that mimic those seen in MS (plaques tend to be larger and more separated, giving a “moth-eaten” appearance)

  • See also a bizarre reactive gliosis (very atypical-looking astrocytes that aren’t infected with the virus)

  • Progressive neurologic signs and symptoms, no effective treatment

• Perivenous encephalomyelitis

  • Severe disease centered around blood vessels

  • Probably from immune-mediated reactions

  • Acute disseminated encephalomyelitis

    • Perivenous demyelination

    • Rapidly progressive and can be fatal (most patients do recover and may have neurological sequellae)

    • Usually follows a viral infection and may be an immune reaction against myelin

  • Acute necrotizing hemorrhagic encephalomyelitis

    • Similar to ADE with acute vasculitis

    • May be related to immune complex deposition; poorly understood

• STRUCTURE: ss (-) RNA, segmented, helical nucleocapsid, enveloped.
  Cell envelope is acquired by budding through plasma membrane.
  • Hemagglutinin (HA) on viral envelope attaches to sialic acid receptor on host cells. One source of antigenic types.
    
  • There are 15 subtypes of HA. H1, H2, H3 exist in humans.
  • Neuraminidase (NA) is released from infected cells. Another source of antigenic types.
  • There are 9 subtypes of NA. Only N1, N2 are found in humans.

• REPLICATION: In host nucleus. Cap-snatching transcription. Viral RNA's utilize portions of host-cell RNA to make their own 5' Cap in the host cell nucleus.

• ANTIGENIC VARIATION:
  Antigenic Shift: Major source of antigenic variation, due to re-assortment of the RNA genome segments. It leads to changes of subtype of the envelope glycoproteins.
• Antigenic Drift: Minor changes in antigenic variation, due to point mutations in the genome.

• INFLUENZA VIRUS-A: 8 segments.
  • DISTRIBUTION: Found in humans, aquatic birds, swine, horses, seals, whales.
  • EPIDEMIOLOGY: This is the major player in flu epidemics, because of its antigenic variation. Highly contagious, spread by person-to-person contact.
  • MANIFESTATIONS: It targets the epithelial cells of the respiratory tract, upper and lower.
  • Epithelial cells become ciliastatic as a result of infection, which can predispose to more serious bacterial infections.
  • Incubation Period: 1-4 days.
  • Symptoms: Soar throat, fever, chills, myalgia, headache.
  • Normally Self-Limiting infection, lasting 3-7 days. Cough may last 1-2 weeks.

• INFLUENZA VIRUS-B: 8 segments
• DISTRIBUTION: Found only in humans
• EPIDEMIOLOGY: Less serious infection than Type-A. Generally found in children or adolescents.
• Influenza-B does not undergo reassortments or antigenic shift.
• INFLUENZA VIRUS-C: 7 segments.

• DISTRIBUTION: Found in humans and swine.
• EPIDEMIOLOGY: Rarely causes diseases. Ubiquitous, and we all generally have antibodies by early childhood.

• In the past they've used inactivated whole viruses.
• This year they are using a trivalent subunit vaccine consisting of purified viral HA antigen: (1) Type-A H1N1 and (2) H3N2, and Type-B antigen.
• Vaccine administered during the fall. Breakouts are in winter.

• STRUCTURE: ss (-) RNA, enveloped.

  • Fusion Protein (F): Responsible for forming syncytia, multi-nucleated cells.

  • Hemagglutinin-Neuraminidase (HN): Single protein.

  • Has a Transcriptase, RNA-dependent RNA-Polymerase.

• REPLICATION: Entirely cytoplasmic.

  • Primary Transcription occurs, and the RNA genome is replicated.

  • Syncytia (via F-Protein) allow for cell-to-cell infections. Virion doesn't need to go outside of cell to infect neighboring cells.

• DETECTION: You can use hemadsorption (hemagglutination) to detect the cells, as they have the HN-Protein on their surface.

• GENERAL PATHOGENESIS:

  • Infection by respiratory tract. Mucosal IgA is more important than serum IgG in preventing infection.

  • Infection occur in late winter, early spring.

• PARAINFLUENZA VIRUS: (PARAMYXOVIRUS).

  • STRUCTURE: Four human serotypes. Types 1 and 3 are within the Paramyxovirus family, while types 2 and 4 are within the Rubivirus family.

    • Sendai Virus = Parainfluenza Type 1.

  • DIAGNOSIS: Culture. Detect by FA. Respiratory Panel available commercially can identify seven common respiratory viral pathogens.

  • MANIFESTATIONS: Infection often occurs in autumn.

    • Croup (Types 1 & 2): Laryngotracheobronchitis in young children is the Croup. Fever, cough, and respiratory distress due to bronchial obstruction.

      • Barking cough is seen.

      • Crop = obstruction of larynx in young children.

    • Type-3: Bronchiolitis in infants. Severity correlates to IgE levels, indicating an immunopathogenesis for the disease.

    • Parainfluenza may also be the cause of the common cold.

    • Only short-term immunity is acquired.

• MUMPS VIRUS: (PARAMYXOVIRUS).

  • STRUCTURE: Only one major serotype.

  • DIAGNOSIS: Culture, demonstrate hemadsorption, look for syncytia.

    • Will see multinucleated cells on cell culture.

  • MANIFESTATIONS: Generalized infection, with incubation period of 1-3 weeks.

    • Lifelong immunity is acquired.

    • Symptoms: Parotitis (parotid gland inflammation), Orchitis.

      • Infants may be subclinical due to maternal antibodies.

    • Complications:

      • Use to be most common cause of viral meningitis -- seen in the Winter and Spring (not Summer and Fall like Coxsackie A Virus).

      • May see pancreatitis or encephalitis.

• MEASLES VIRUS: (MORBILLIVIRUS).

  • STRUCTURE: Only one major serotype.

  • Related Diseases: Distemper in dogs, Rinderpest in cattle are also a part of this family.

  • DIAGNOSIS: Culture, serology.

    • Koplik's Spots on buccal mucosa.

    • Will see multinucleated cells on cell culture

  • MANIFESTATIONS: Generalized infection, with incubation period of 1-3 weeks.

    • Lifelong immunity is acquired.

    • Symptoms:

      • Early Symptoms: Fever, cough, coryza, conjunctivitis.

      • Late Symptoms: maculopapular rash.

      • Flat macules that coalesce to form large blotches, and fade in 5-6 days. Rash spreads from head, down to rest of body.

    • Severe Complications: Otitis media, viral or bacteria pneumonia which is possibly fatal.

      • Post-Infectious Encephalomyelitis: 1:1000 cases. 15% fatality rate. Appears to be an autoimmune pathogenesis. This is the most important complication.

      • Subacute Sclerosing Panencephalitis (SSPE): 1:1 million cases. Follows the acute measles by several years.

        • Patients afflicted with this lack antibodies against the measles-virus M-Protein. The virus is being produced without an envelope in these cases, and that results in this fatal complication.

      • Pneumonia occurs especially in developing countries where malnutrition is common. It can be fatal.

  • TREATMENT: Vitamin-A for infants. Passive immunity.

  • MMR VACCINE: Live-attenuated vaccine.

    • Primary dose at 12-15 months.

    • Booster shot in elementary school.

    • Vaccine should not be given to immunodeficient children -- except for HIV children, for which it is recommended.

• RESPIRATORY SYNCYTIAL VIRUS (RSV): (PNEUMOVIRUS)

  • STRUCTURE: Has a G-Protein and F-Protein, but lacks NA and HA activity.

  • DIAGNOSIS: FA, Respiratory Panel of viruses.

    • Will see multinucleated cells on cell culture.

  • MANIFESTATIONS: Acute infection, with incubation period of 3-5 days.

    • Only short-term immunity is acquired.

    • Serious respiratory infection in neonates (0 - 6 months). Only mild disease in older folks.

  • TREATMENT: Ribavirin, aerosolized, may have limited effectiveness, for hospitalized babies.

  • VACCINE: Passive immunization is available for infants at high risk.

• Newcastle Disease Virus (NDV): Avian virus, can produce conjunctivitis in humans.

• VESICULAR STOMATITIS VIRUS (VSV): Arbovirus causes disease in cattle and horses. Can cause mild disease in humans. Has been utilized as a model virus in research.

• STRUCTURE: ss (-) RNA, helical capsid, enveloped, bullet-shaped.

  • Transcriptase, RNA-dependent RNA Polymerase is present.

• REPLICATION: Cytoplasmic.

  • Primary transcription ------> genome replication ------> more transcription and translation occur post-replication.

  • Nucleocapsids bud through host cell-membrane to form new particles.

• EPIDEMIOLOGY:

  • Racoons are the most common animal carrier today.

  • Bats are most common carrier in U.S. to actually result in infection.

  • Also skunks, wild mammals, and unvaccinated domestic mammals.

• DIAGNOSIS: Look for Negri bodies in the animal tissue.

• MANIFESTATIONS:

  • PATHOGENESIS:

    • Virus replicates in striated muscle at site of bite. Then it travels up nerve endings to spinal cord and brain.

    • Virus hooks to Acetylcholine receptors at neuromuscular junction.

  • Symptoms: Fatal encephalitis. Hypertonic muscle contraction, convulsions, coma, death.

    • Hydrophobia happens as swallowing would precipitate a spasm of throat muscles.

• TREATMENT: No treatment known.

  • PREVENTION: Post-exposure immunization, both passive and active, should be given prophylactically in cases of possible infection.

    • Human Rabies Immune Globulin (HRIG) administered on same day as first vaccine dose, but at a different site.

    • Human Diploid Cell Vaccine (HDCV) is the new active vaccine (inactivated virus), grown in human diploid fibroblast cells. Given in 6 doses.

• STRUCTURE: Non-enveloped, double-stranded segmented (-) RNA, in 10-12 segments. Contains concentric inner and outer capsids.
• VP4: Viral glycoprotein neutralization antigen.
• VP7: Viral glycoprotein neutralization antigen, derived from host-cell ER.
• RNA-dependent RNA-Polymerase can make messenger RNA's out of the double-stranded viral genome.
• Rigid capsule makes fecal-oral transmission possible.
• REPLICATION: The inner capsid always remains intact.
• The outer capsid is removed upon entry into the cell.
• Inside the capsid, the RNA-dependent RNA-polymerase makes subgenomic (+) mRNA's. These mRNA's are transported into host-cell cytoplasm and translated into proteins.
• Inside the capsid, the (-) RNA's are used as templates to make new ds-RNA genomes, which are then released outside the capsid.
• The new genomes are assembled along with the viral proteins to make new infectious particles.
• EPIDEMIOLOGY: Fecal-oral transmission.
• Infection occurs in 6 months to 2 years old. Neonates, older children, and adults are usually asymptomatic. Breast-milk IgA probably provides protection for neonates.
• Prevalent in winter, but throughout year in tropical climates. Unexplained west-to-east trend in seen in its incidence: Nov ------> Feb as you go from West ------> East in United States.
• REOVIRUS: (ORTHOREOVIRUS)
• STRUCTURE: 3 serotypes.
• MANIFESTATIONS: Commonly infects, but asymptomatic, hence they are orphan viruses.
• ROTAVIRUS: Group-A Rotavirus has 4 serotypes, based on the VP7 antigen.
• MANIFESTATIONS: Gastroenteritis, which can be life threatening. It is the major cause worldwide, in infants and young children.
• MECH is believed to be decreased absorption at brush border, but not sure.
• IMMUNITY: Serotype-specific, and incomplete.
• DIAGNOSIS: ELISA of stool samples
• TREATMENT: IV-fluid replacement. Oral rehydration therapy.
• VACCINE: In clinical trials are re-assortment-viruses containing genomes that encode VP4 or VP7. These are human viruses that infect the cell and reassort with the segmented genome of the rotavirus, rendering it non-pathogenic.
• ORBIVIRUS: All are arboviruses. Most are asymptomatic. 10 segments.
• COLORADO TICK FEVER VIRUS:
• MANIFESTATIONS: Standard common viremia symptoms: fever, myalgia, rash, vomiting. May see maculopapular rash.
• STRUCTURE: Has 12 segments, not 10.

• EPIDEMIOLOGY: Insect spread.
• Mosquito-born viruses: prevalent in summer generally.
• Tick-born viruses: Prevalent year-around.
• MANIFESTATIONS: Usually asymptomatic, but may be severe disease. 4-7 incubation period for clinical symptoms.
• Initial Infection: Viruses will replicate in vascular endothelial cells, in subclinical infection.
• VIREMIA: Most common mild disease. Fever, arthralgia, rash, nausea, vomiting.
• Dengue Fever: Most common cause
• Sindbis virus
• Colorado Tick Fever
• HEMORRHAGIC FEVER: Extensive hemorrhages from almost any epithelial surface. Can lead to CV collapse and death. Fatality rate ranges from 2% - 50%.
• Dengue Virus: Dengue Shock Syndrome
• Yellow Fever: Hemorrhagic fever with hepatitis.
• ENCEPHALITIS:
• From highest to lowest lethality:
• Eastern Equine Encephalitis
• St. Louis Encephalitis
• Western Equine Encephalitis
• California
• Symptoms:
• Starts with Meningitis -- fever, headache, vomiting, stiff neck.
• Followed by lethargy, confusion, paralysis, and coma and death in most serious cases.
• May see neuropsychiatric sequelae in non-fatal cases, such as mental retardation, paralysis.

• IMMUNITY: Acquired and lifelong.
• DIAGNOSIS: Must use serology. Acute:convalescent titers, or IgM.

• STRUCTURE: ss (+) RNA, spherical, enveloped, infectious.

• REPLICATION: Polymerase is at the 5' end and structural proteins are at the 3' end.

  • First, the 5' end of the genome is translated, making some non-structural proteins and RNA-Dependent RNA Polymerase.

  • RNA-Dependent Polymerase then makes a minus-strand out of the plus strand, and then uses that to make more plus-strands.

  • Then the 3' end is translated, forming structural proteins that are packaged together with the new RNA strands.

• ALPHAVIRUS: All are arboviruses, transmitted by insect-vector.

  • STRUCTURE: All share serological reactivity, i.e. cross-reactive for some internal viral antigens.

  • EASTERN EQUINE ENCEPHALITIS VIRUS (EEEV):

    • The deadliest of the encephalitis viruses.

    • The rarest of the encephalitis viruses.

    • Fatality: 30-50%

  • WESTERN EQUINE ENCEPHALITIS VIRUS (WEEV): The next deadliest.

    • TRANSMISSION: Horse-mosquito. Man is dead-end host.

    • Fatality: 3-5%

  • VENEZUELAN EQUINE ENCEPHALITIS (VEEV):

  • SINDBIS VIRUS:

    • MANIFESTATIONS: Standard common viremia symptoms: fever, myalgia, rash, vomiting. May see maculopapular rash.

• RUBIVIRUS: RUBELLA -- not an Arbovirus (no arthropod vector)
• STRUCTURE: ss (+) RNA, enveloped.
• DIAGNOSIS: Immunofluorescence on cultured viruses in mammalian cell lines. MANIFESTATIONS: German Measles. Usually a trivial disease
• Incubation Period: 2-3 weeks. Disease most prevalent in Spring.
• Rubella is non-Cytocidal, as compared to the Arboviruses.
• Symptoms:
• Lymphadenopathy and mild conjunctivitis.
• Maculopapular "Rubelliform" Rash that forms small discrete blotches, that do not coalesce, and disappear in 3-5 days.
• Complications: Arthritis and, rarely, post-encephalitis.
• MANIFESTATIONS: Congenital Rubella Syndrome (TORCH). Very few cases seen today, but an outbreak happened recently when people were lax about vaccines.
• Do a Rubella titer for women of child-bearing age.
• Greatest risk when maternal infection is early in pregnancy (first trimester).
• Effects: Blindness, deafness, congenital heart defects, and brain defect are all possible. Rarely fatal (no spontaneous abortion).
• DIAGNOSIS: Look for Anti-Rubella IgM in fetal cord-blood.

• PESTIVIRUS:

:

• STRUCTURE: ss (+) RNA, enveloped

  • Used to be classified with Togaviruses, but now is reclassified, because:

    • Nucleic acid sequences for Yellow Fever virus genome are different.

    • The virus does not utilize a subgenomic mRNA.

    • Alpha viruses bud mainly from the surface plasma membrane, whereas the Flaviviruses bud mainly into internal membranous structures (Golgi).

• ST. LOUIS ENCEPHALITIS VIRUS: It has been the major cause of arboviral-born encephalitis over the last three decades.

  • TRANSMISSION:

    • Urban cycle of man-mosquito-man.

    • Natural cycle of bird-mosquito-bird.

• JAPANESE ENCEPHALITIS VIRUS:

  • VACCINE: Vaccine available before travel to endemic area. Inactivated, purified vaccine given in three subcutaneous doses.

• YELLOW FEVER VIRUS:

  • TRANSMISSION: Monkey-insect-monkey cycle, with occasional transmission to man.

    • Can also have an Urban man-mosquito-man cycle.

  • MANIFESTATIONS: Hemorrhagic Fever with hepatitis. Yellow = jaundice.

  • VACCINE: Live attenuated vaccine is available, recommended before travel.

• DENGUE FEVER VIRUS:

  • TRANSMISSION: Can have an Urban man-mosquito-man cycle.

  • SUBTYPES: Divided into Types 1-4.

  • MANIFESTATIONS: Dengue fever is the most common and (usually) least serious arboviral infection.

    • Fever-arthralgia-rash: Common symptoms of viremia -- Fever, chills, headache, myalgia, rash, nausea, vomiting.

    • Dengue Shock Syndrome: A form of hemorrhagic fever. Thought to be a hypersensitivity reaction with reinfection of a second subtype of Dengue virus.

      • Mechanism involves immune enhancement and extended tissue tropism -- i.e. infecting cells which are not normally infected.

      • Macrophages get infected by the virus whereas they normally are not infected.

• HEPATITIS-C:

  • TRANSMISSION: Primary mode of transmission is parenteral route (blood). In the past has been associated with transfusions.

  • MANIFESTATIONS: Most often leads to chronic hepatitis.

• STRUCTURE: ss (-) RNA, segmented, 3 segments. Enveloped. Spherical, helical nucleocapsid. There may be some ambisense (+/-) characteristics.
• RNA-Dependent RNA-Polymerase is present.
• DIAGNOSIS: Serology -- no culture.
• BUNYAVIRUSES: Arboviruses
• CALIFORNIA ENCEPHALITIS VIRUS:
• Fatality: less than 1%
• LA CROSSE VIRUS:
• PHLEBOVIRUSES:
• RIFT VALLEY FEVER VIRUS:
• HANTAVIRUSES: Rodent-born viruses, not arboviruses. Transmitted by rodent urine and respiratory secretions.
• HANTAAN VIRUS: First discovered member of this family. From 1950's Korea (Korean War).
• MANIFESTATIONS: Korean Hemorrhagic Fever with Renal Syndrome (HFRS). Incubation period 2 - 4 weeks.
• MUERTO CANYON VIRUS: Relative of Hantaavirus discovered in 1993 epidemic in New Mexico, U.S.
• MANIFESTATIONS: Hantavirus Pulmonary Syndrome (HPS). ARDS-like syndrome with 70% fatality.
• TRANSMISSION: Deer Mouse was newly discovered and found to be the vector. Direct contact with rodents or rodent-products required.
• TREATMENT: Respiratory therapy. Ribavirin was once shown effective, but requires special permission to use.
• SEOUL VIRUS:

• STRUCTURE: ss (-) RNA, enveloped, long "filum."
• Previously categorized with Rhabdoviridae, since reclassified.
• MARBURG and EBOLA VIRUSES:
• TRANSMISSION: Endemic to monkeys, and assumed to have a natural reservoir.
• MANIFESTATIONS: Hemorrhagic Fevers. Hepatitis is prominent.

• STRUCTURE: ss (-) RNA, segmented, lipid-envelope and helical capsid.
• Some ambisense (+/-) properties, like Bunyaviruses.
• Viral RNA-dependent RNA-polymerase.
• Name derives from a picture of sand on EM, which is cellular ribosomes accidentally packaged into the viral particles.
• TRANSMISSION: Natural rodent reservoir. Transmitted by rodent respiratory secretions and urine.
• LYMPHOCYTIC CHORIOMENINGITIS VIRUS: Causes meningitis.
• LASSA FEVER VIRUS:
• TRANSMISSION: Western Africa. Can be via rodent or human-to-human.
• MANIFESTATIONS: Hemorrhagic fever with hepatitis.
• MACHUPO VIRUS: Bolivian Hemorrhagic Fever. Epidemic in 1962-64 which resembles in many ways the Muerto Canyon epidemic of 1993. Rat population probably increased prior to the epidemic.
• JUNIN VIRUS

• Patients have normal functioning and then begin losing certain neurons (either a specific kind or neurons in a specific pathway) and are not due to trauma or toxic insult

• Either attack cortical neurons (progressive dementia) or subcortical neurons (movement d/o)

• Pathogenic, not a part of normal aging

• Cortical atrophy similar to AD

• Atrophy differs from AD in location (localized in frontal and temporal lobes and is called “wafer atrophy” or “knife edge atrophy”)

• Clinical picture similar to AD

• Brain looks atrophic (thin gyri and widened sulci) – often see hydrocephalus ex vacuo

• Characteristic microscopic findings

  • Neurofibrillary tangles

    • Microtubular elements within neurons form a rigid structure

    • After the neuron dies these remain as evidence of the disease

    • Look like candle flames and are often called “flame cells”

  • Senile (AKA neuritic) plaques – extracellular material that’s mostly amyloid

  • Hirano bodies – intracytoplasmic crystalloid things

  • Granulovacuolar degeneration

  • Cerebral amyloid angiopathy

    • Amyloid deposits in blood vessels throughout the brain

    • Can become leaky and lead to intraparenchymal hemorrhage

  • None of the above are specific for AD, as all may be seen in a “normal” brain of an elderly person…what matters most is the number of these things seen (especially plaques)

• Diagnosis of AD

  • Can make presumptive diagnosis because of typical clinical course, but definitive diagnosis can only be made upon autopsy

  • Diagnosis made by counting number of plaques per filed and relating that to patient’s age

    • Diagnosis not based on number of tangles

    • Also not based on number of diffuse plaques (which are different than senile plaques)

  • Very difficult to tell early (low-grade) AD from normal aging

• Pathogenesis

  • Amyloid definitely plays a role based on the importance of amyloid precursor protein

    • APP is a normal, membrane-bound protein that is endocytosed and digestion (after digestion it is known as amyloid beta protein which is the bad one; it is the protein present in the amyloid angiopathy and neuritic plaques)

    • A mutation in the APP gene leads to early onset AD, which accounts for some of the familial cases of AD (familial only responsible for 5-10% of cases)

    • APP gene found on chromosome 21, so Down’s patients who live long enough will develop a progressive decline in mental function and will have pathologic features consistent with AD

  • Presensilins

    • Coded for on chromosomes 1 and 14

    • Somehow enhance the production of amyloid protein

    • Mutations increase risk for early AD onset

  • Apolipoprotein E4

    • Coded for on chromosome 19

    • Mutations lead to increased risk of early AD onset

  • Aluminum toxicity may play a role

  • Tau protein

    • Normal microtubular protein

    • One of the main proteins present in the neurofibrillary tangles

• CERAD designates certain brain foci as standard sections for AD diagnosis

  • Hippocampus and entorhinal cortex

  • Superior and medial gyri of the temporal lobe

  • Middle frontal gyrus of the frontal lobe

  • Inferior parietal lobe

  • Anterior cingulate gyrus (cortical Lewy bodies)

  • Midbrain

• May get Parkinsonism from drugs, toxins, a byproduct of heroine synthesis (MPTP), and influenza encephalitis

• Movement d/o characterized by

  • Shuffling gate

  • Stooped over posture

  • Rigidity

  • Expressionless (“mask-like”) face

  • Tremor

• Typical onset at 50 YOA

• Pathogenesis

  • Degeneration of pigmented (dopaminergic) neurons in the substantia nigra of the midbrain

  • These neurons project to the striatum; the lack of dopaminergic input to the striatum causes the movement problems

• Lewy bodies

  • Big, round eosinophilic intracytoplasmic inclusions in neurons of the substantia nigra

  • Not specific for Parkinson’s

  • Alpha-sinuclien is the major component

• Dementia seen in about 10% of patients; some patients have dementia without movement problems – this is called diffuse Lewy body disease

• Postencephalic Parkinsonism

  • Mostly seen after flu epidemic of 1914-1918

  • Starts months to years after initial encephalitis

  • Has been associated (rarely) with western equine, measles, and Japanese B viruses

  • Neuronal degeneration in the substantia nigra with the formation of tangles, not Lewy bodies

• Striatonigral degeneration

  • C/S almost the same as Parkinson’s disease, but resistant to L-Dopa therapy

  • Loss of pigmented neurons of substantia nigra and loss of target cells in the striatum, but no Lewy bodies