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Block 6: Microbio, ID, Derm, Heme-Onc > Viruses (Week 1) > Flashcards

Viruses (Week 1) Flashcards

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1
Q

3 things viruses cannot do on their own

A

1) Synthesize protein
2) Generate energy (no mitochondria)
3) Maintain ionic potential across membrane

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2
Q

Structure of a virus

A

1) Nucleic acid either RNA or DNA (ss or ds)
2) Protein capsid around nucleic acid
3) Some have envelope around capsid

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3
Q

Non-enveloped virus

A

MORE stable

Viral attachment proteins part of capsid

Transmitted fecal-oral

Ex: Hep A, poliovirus

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4
Q

Enveloped virus

A

LESS stable

Viral attachment glycoproteins on envelope (so if envelope destroyed by alcohol, attachment proteins gone too!)

Transmitted host-to-host (think skin to skin)

Ex: herpes, HIV

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5
Q

Why are enveloped viruses LESS stable than non-enveloped viruses?

A

Because envelope can easily be destroyed by alcohol, salt, etc, and the virus’ attachment proteins are on that envelope, once the envelope is gone, the virus has no way of entering/infecting a cell!

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6
Q

Viral life cycle (in general)

A

1) Enveloped virus uses its glycoproteins to attach to cellular receptor
2) Fusion of envelope with cellular membrane allows penetration of virus into cell
3) Production of empty capsids and nucleic acis
4) Empty capsids filled and pick up envelope and glycoproteins as they begin to egress
5) Viral production/completion and egress

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7
Q

What viral attachment proteins does influenza virus use?

A

Influenza virus has hemagglutinin (HA) on surface that binds to cell’s sialic acid protein to enter

Note: can surround HA with antibodies to prevent attachment/infection of cells with influenza

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8
Q

Types of human herpesviruses

A

1) Herpes simplex 1 (HSV-1)
2) Herpes simplex 2 (HSV-2)
3) Varicella zoster virus (VZV)
4) Cytomegalovirus (CMV)
5) Epstein-Barr Virus (EBV)
6) Human herpesvirus 6 (HHV-6)
7) Human herpesvirus 7 (HHV-7)
8) Human herpesvirus 8 (HHV-8)

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9
Q

Properties of all herpesviruses

A

1) Large double stranded DNA virus (125-240kb)
2) Enveloped virions
3) Establish life-long latent infections in host
4) Periodic reactivations from latent state
5) Diverse biology

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10
Q

HSV-1

A

Disease: fever blisters, ocular lesions, encephalitis

Site of latency: nerve ganglia

50-70% of adults seropositive

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11
Q

HSV-2

A

Disease: genital lesions, neonatal infections, meningitis

Site of latency: nerve ganglia

20-50% adults seropositive

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12
Q

VZV

A

Disease: chickenpox (primary), shingles (recurrence)

Site of latency: nerve ganglia

Sequence of events of CHICKENPOX: airborne transmission –> viremia, replication in organs, incubation of 2 weeks –> virus emerges from capillaries to skin

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13
Q

CMV

A

Disease: mononucleosis, congenital infections, immunocompromised gastritis, retinitis (AIDS pts), pneumonia (bone marrow transplant pts)

Site of latency: monocytes, neutrophils, vascular endothelia

Transmission: in utero (TORCHES), perinatally, postnatally (saliva, sexual)

Negative monospot (heterophil antibody) test

Cytopathic effect = owl’s eye (nuclear inclusions, factories making lots of viral DNA)

Treat with gancyclovir

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14
Q

HHV-6 and HHV-7

A

Disease: roseola in infants

Site of latency: T cells, monocytes, macrophages

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15
Q

EBV

A

Disease: infectious mononucleosis, Burkitt’s Lymphoma, nasopharyngeal carcinoma

Site of latency: B lymphocytes

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16
Q

HHV-8

A

Disease: Kaposi Sarcoma, tumors

Site of latency: virus infected tumors

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17
Q

Life cycle of HSV-1

A

Overall: get into cell, create proteins needed for DNA replication, do DNA replication, create proteins for virus to be packaged, package virus with new DNA inside and egress

1) Viral glycoproteins attach to receptors on cell membrane, allowing fusion and entry of virus into cytosol
2) Transcription (then translation) of 5 viral genes using the cell’s DNA-dependent RNA polymerase, and 2 of these genes activate early gene transcription
3) 2 important early genes are DNA polymerase and thymidine kinase, which activate viral DNA synthesis
4) Rolling circle of viral DNA replication (note: acyclovir blocks this step!)
5) After DNA synthesis, THEN late proteins (capsid, viral glycoproteins) made and form empty capsids to be filled with viral DNA
6) Viral glycoproteins from first cell fuse the surrounding cells so virus plows through cells (need CD8 cell-mediated immunity to kill virus!)

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18
Q

HSV-1 and HSV-2 in latency

A

HSV-1 enters through lips or eye and establishes latency in trigeminal ganglion

HSV-2 is latent in DRG

Latent DNA exists as episomal circles and no viral proteins transcribed, only RNA for LAT (intron)

Stimuli such as UV light may cause reactivation

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19
Q

Why don’t we kill HSV latently infected neurons?

A

No viral protein made in latency so no target on cell membrane to go after to kill latently infected neurons!

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20
Q

How are HSV transmitted?

A

Skin to skin contact when there is some abrasion or chapping (cannot penetrate intact skin)

Remember though, virus can be shed asymptomatically–no sores, but still little breaks in skin!

NOT hematogenous spread!

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21
Q

Tissue tropism of HSV

A

HSV-1 causes 95% of orofacial herpes and 10-30% of primary genital herpes (NOT recurrent); anything above the belt

HSV-2 causes primary and recurrent genital infections and rarely causes oral herpes

Note: when in its tropic area, will reactivate more but if not in tropic area will not reactivate

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22
Q

Disease syndromes caused by HSV-1

A

1) Gingiviostomatitis
2) Herpes Whitlow (finger)
3) Encephalitis
4) Keratitis (ulcers on cornea)
5) Eczema makes lesions worse

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23
Q

Do you usually have viremia (virus in the blood) with HSV?

A

Not sure?!

However, have viremia in 30% of primary vaginal infections

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24
Q

Genital herpes

A

HSV-2 (definitely if recurrent, and most likely primary too)

Lesions more prone to secondary bacterial infection by S. aureus, Streptococcus, Trichomonas and Candida albicans

60% of patients experience recurrences

Recurrences usually longer than oral HSV-1 lesions

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25
Q

Herpes simplex encephalitis

A

One of most serious complications of herpes simplex

1) Neonatal: entire brain almost liquefied; mortality almost 100%
2) Focal disease: temporal lobe most commonly affected; appears in kids and adults; could be from reactivation of virus; 70% mortality without treatment

Give IV acyclovir if HSE is suspected, before lab tests come back

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26
Q

Neonatal herpes simplex

A

Baby infected during passage through birth canal

Greatest risk when mother has primary infection (has sex and contracts HSV days before birth)

Have lower viral titer and have specific antibody if recurrent infection so smaller risk

Spectrum from mild skin infection to fatal disseminated infection

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27
Q

Disseminated herpes simplex

A

Widespread vesicular rash (like chickenpox)

Other organs involved (liver, spleen, lungs, CNS)

More likely in immunocompromised individuals

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28
Q

Zosteriform herpes simplex

A

Rare presentation of herpes simplex where HSV lesions appear in dermatomal distribution similar to herpes zoster

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29
Q

Antiviral drug mechanism of action

A

Examples of antiviral drugs: acyclovir, ganciclovir, famciclovir, valaciclovir

Viral thymidine kinase adds monophosphate onto 5’ OH –> cellular enzymes add 2 more to make triphosphate –> acyclovir incorporated into DNA –> however, acyclovir has no 3’ OH so DNA chain is terminated! –> also, viral DNA polymerase binds and is inhibited by acyclovir so can no longer be active

Note: acyclovir has to be phosphorylated by viral thymidine kinase to even be added to the DNA chain, so will only halt DNA synthesis in virally infected cells that HAVE viral thymidine kinase. In other cells that acyclovir enters, it won’t get phosphorylated (because cellular thymidine kinase will NOT phosphorylate it), so won’t be added to the DNA chain!

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30
Q

Use of acyclovir for HSV

A

Acyclovir taken daily suppresses oral and genital recurrence

IV acyclovir effective against encephalitis (HSE) and neonatal herpes

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31
Q

Lab Diagnosis of HSV

A

Immunofluorescence of skin scraping (distinguish HSV from VZV)

PCR (used to diagnose HSE)

Virus isolation (cultivate for 1-5 days; easy to do)

Serology not helpful because takes 1-2 weeks for antibodies to appear after infection

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32
Q

When do we use antiviral chemo-therapy?

A

Only if severe primary infection, dissemination, sight threatened, herpes simplex encephalitis (HSE)

Very expensive!

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33
Q

Asymptomatic shedding of HSV

A

Can transmit virus to another person (via skin to skin contact) even when no presence of lesions

Both HSV-1 and HSV-2

Only form of shedding in ~2/3 of patients

Accounts for most transmissions

Low viral titers

Not completely suppressed by acyclovir

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34
Q

Positive (+) stranded RNA viruses

A

Just like mRNA

When (+) RNA enters host cell, can immediately be translated by host’s ribosomes into protein

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35
Q

Negative (-) stranded RNA viruses

A

When (-) stranded RNA enters cell, must be transcribed into (+) strand RNA using RNA-dependent RNA polymerase

(only virus has RNA-dependent RNA polymerase–has to carry it in their capsid)

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36
Q

2 types of capsid

A

1) Icosahedral (20 triangles put together)
2) Helical (protein capsomers bound to RNA)

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37
Q

Why do people get blisters as a result of HSV infection?

A

HSV migrates out to skin via nerves –> HSV causes cell destruction (multinucleated giant cells and intranuclear inclusion bodies as a result of cell fusion) –> separation of epithelium causes blisters (vesicles)

Note: CMV and EBV have less of this cytopathic effect

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38
Q

How does varicella (chickenpox) cause infection?

A

Virus infects respiratory tract –> replicates for 2 week incubation period –> viremia (viral dissemination in bloodstream)

Note: VZV is unitue in being transmitted so readily through air

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39
Q

Is shingles contagious?

A

Yes someone with shingles can give the VZV to someone else

However, that person would get chickenpox, NOT shingles

“you get shingles from yourself” (by definition it is a reactivation)

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40
Q

Enterovirus

A

Subtype of picornavirus

Infect intestinal epithelial and lymphoid (tonsils, Peyer’s patches) cells

Spread fecal-oral route

1) Poliovirus
2) Coxsackie A viruses
3) Coxsackie B viruses
4) Echovirus

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41
Q

Complications of chickenpox (varicella)

A

1) Bacterial superinfection of lesions (mainly children)
2) Varicella pneumonia (more in adults)
3) Neonatal varicella (mother is seroNEGATIVE but baby gets it from a nurse)
4) Encephalitis
5) Reyes syndrome, a neuroencephalopathy (liver failure –> toxic buildup of bilirubin –> brain cells damaged); because of Aspirin

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42
Q

Varicella vaccine

A

Actively replicating, attenuated virus (33 mutations)

Prevents 70-90% of chickenpox and reduces severity in the rest

2 doses

Can still reactivate to cause shingles (because TK gene intact, and virus still replicating)

Vaccine is just a low enough dose of virus so you don’t get a rash

Probably fewer vaccinated children will get shingles becaus the vaccination seeds fewer neurons so lower chance of getting reactivated

Note: zoster vaccine given to people over 65 is SAME virus, just higher dose

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43
Q

Complications of Zoster (shingles)

A

1) Postherpetic neuralgia: affects 25-50% of zoster patients over 50
2) Ramsay Hung syndrome: pain and vesicles in external auditory canal; lose sense of taste in anterior 2/3 of tongue; ipsilateral facial palsy; involves geniculate ganglion of sensory branch of facial nerve

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44
Q

Why only a few vesicles in HSV and many in VZV?

A

HSV can only go from cell body to axon to dendrites to next neuron (linearly)

VZV can go horizontally through myelin sheath to many other nerves in the bundle

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45
Q

Prevention of varicella

A

1) Zoster immunoglobulin (ZIG) for passive immunization in children who need urgent protection
2) HNIG (human normal serum?) for passive immunization too because has many antibodies
3) Varicella vaccine

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46
Q

How does our body recognize virus?

A

1) TLR3 recognizes viral dsRNA; TLR7 recognizes viral ssRNA (Macrophages and neutrophils have highest levels of TLRs; Dendritic cells, NK cells, T cells and B cells have a few TLRs)
2) Our own RNA helicases recognize dsRNA, try to unwind it and in so doing, signal the presence of dsRNA (end up producing IFN-a, IFN-b, etc)

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47
Q

How do interferons fight viral infections?

A

1) IFN-a and IFN-b (Type I INFs) cleave host and viral mRNA to block translation into proteins (kill cell, but kill virus too)
2) IFN-a and IFN-b (Type I INFs) activate NK cells to kill viral infected cells
3) IFN-g (Type II IFN), secreted when IL-12 activates NK cells, activates macrophages which secrete cytokines to help T cells
4) All IFNs upregulate expression of MHC-I on cells so they’re more susceptible to T cell destruction
5) IFN-a and IFN-b induce strong Th1 response

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48
Q

Which T cells are needed for which types of infection?

A

1) CD4 Th2 needed for extracellular (bacteria)
2) CD4 Th1 needed for intracellular within phagosomes (bacteria)
4) CD8 needed for intracellular viruses and uses MHC-I which is on all cells (?)

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49
Q

What is the best APC for viral antigens?

A

Dendritic cell

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50
Q

4 steps to make a cytotoxic T cell

A

1) Virus infected dendritic cell activates TLR3, RIG-1 or MDA-5 (RNA helicases) for dsRNA or TLR7 for ssRNA
2) Activated DC presents viral peptides on MHC-I to naive CD8 T cells
3) IL-2 secreted by T cellls, increased affinity of IL-2 receptors on T cells, CD8 T cells differentiate into cytotoxic (killer) T cells
4) Cytotoxic (killer) T cells recognize viral infected cells by seeing viral peptides on MHC-I, secrete granzyme B (protease) and perforin to destroy cell membrane and cause lysis

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51
Q

Congenital CMV infection

A

Most common congenital viral infection, second most common cause of mental handicap (after Down’s)

May result in Cytomegalic Inclusion Disease (CNS, eye, ear, liver, lung, heart, blood sequelae)

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52
Q

CMV gastroenteritis/colitis

A

In immunocompromised individuals, get effects on esophagus, stomach, small intestine, colon (pain, dysphagia, nausea, vomiting, ulcers, diarrhea)

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53
Q

Infectious Mononucleosis

A

Caused by EBV

EBV infects B cells –> causes B cells to be transformed and proliferate and pass on copies of EBV DNA to progeny –> cytotoxic T cells react to abnormal B cells to kill them (this immune response is what causes disease symptoms) –> eventually T cells win (however, EBV can reactivate later just like all good herpesviruses can!)

Disease symptoms: fever, chills, sweats, headache, painful pharyngitis (sore throat), enlarged lymph nodes, enlarged spleen (prone to rupture!)

High WBC count with atypical lymphocytes (large activated T lymphocytes)

Positive Monospot test (heterophile antibody against EBV that cross reacts with and agglutinates sheep red blood cells)

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54
Q

EBV latency

A

10 EBNAs (Epstein-Barr nuclear antigens) and LMP (latent membrane protein) are made in latently infected B cell

EBNA-1 binds origin of replication of EBV genome and partitions circular DNA among B cell chromosomes as it divides

Other EBNA proteins immortalize B cell in return for B cell keeping many DNA circles around

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55
Q

What causes proliferation of mononuclear cells in Infectious Mononucleosis?

A

1) B cells transformed by EBV so are proliferating more than normal
2) EBNAs and LMP are foreign antigens inside B cell during latency, but are presented on MHC-I on surface of B cell BECAUSE they are foreign and this triggers a CD8 cytotoxic T cell response to those latently infected B cells

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56
Q

How do you tell the difference between EBV mononucleosis and CMV mononucleosis?

A

1) EBV will have positive monospot test (heterophile antibody positive) and CMV will not
2) EBV will have VCA (viral capsid antigen) antibodies and CMV will not

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57
Q

EBV and lymphoproliferative disorders

A

EBV found in cancer cells of Burkitt’s lymphoma which affects children in Africa –> since people in other places with EBV don’t get Burkitt’s lymphoma, thought that EBV is just a co-factor –> since EBV causes rapid uncontrolled B cell growth, may cause chromosomal arm translocation (c-myc with immunoglobulin enhancer on chrom 14, 22, 2) that has been associated with Burkitt’s lymphoma

Other lymphoproliferative diseases may also be secondary to EBV reactivation (Non-Hodgkin’s lymphoma, Hodgkin’s disease)

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58
Q

Picornaviruses

A

Non-enveloped, (+) stranded, IRES where translation begins, codes for long polyprotein that has viral proteases within it, fecal-oral transmission (ingestion of contaminated food and water)

1) Enterovirus: infect intestinal epithelial and lymphoid cells ( poliovirus, coxsackie A and B, echovirus, enterovirus
2) Rhinovirus: 185 serotypes
3) Heparnavirus: hepatitis A virus

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59
Q

Replication of retroviruses

A

1) 2 ssRNA molecules and reverse transcriptase contained in virions
2) ssRNA –> RNA-DNA hybrid –> remove RNA to make DNA-DNA –> dsDNA (cDNA) integrated into human chromosome using viral integrase enzyme
3) Viral genes transcribed using host cell RNA polymerase and LTRs as promoters

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60
Q

Poliovirus

A

Picornavirus

Viremia –> infection of anterior horn cells of spinal cord and motor cortex of brain

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61
Q

2 poliovirus vaccines

A

1) Live oral polio vaccine (OPV): Albert Sabin; attenuated; can revert/pick up virulence and cause paralysis; used only in areas where polio is endemic (NOT used in US)
2) Inactivated polio vaccine (IPV): Jonas Salk; injected, causes IgG antibody response to prevent viremia; only 94% effective; used in US

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62
Q

Coxsackievirus A

A

Picornavirus

Causes herpangina, hand-foot-and-mouth disease

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63
Q

Coxsackievirus B

A

Picornavirus

Causes pericarditis, myocarditis, pleurodyina

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64
Q

Enterovirus 70

A

Picornavirus

Causes paralytic disease and acute hemorrhagic conjunctivitis

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65
Q

Enterovirus 71

A

Picornavirus

Causes paralytic disease and hand-foot-and-mouth disease

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66
Q

Echovirus

A

Picornavirus

Causes paralytic disease, encephalitis, meningitis, myocarditis, GI disease

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67
Q

Rhinovirus

A

Picornavirus

Replicates in the nose; optimal replication temp is 33 degC; sensitive to low pH so doesn’t replicate in GI tract

Causes common cold

More than 100 different serotypes

Rhinovirus A and B found in nose; Rhinovirus C causes lower respiratory tract disease

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68
Q

Coronavirus

A

Not part of a bigger class, but enveloped and (+) strand RNA virus

Causes common cold (less frequently than rhinovirus)

Includes SARS virus

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69
Q

Arbovirus

A

Means that is transmitted by insects

Includes bunyavirus, togavirus, flavivirus

70
Q

Togavirus

A

1) Alpha viruses cause encephalitis (Western equine encephalitis; Eastern equine encephalitis; Venezuelan equine encephalitis)
2) Rubivirus causes rubella

71
Q

Rubivirus (rubella)

A

Togavirus

Only infects humans

Congenital rubella (TORCHES)

This virus causes rubella = German measles

Transmitted via respiratory tract

72
Q

Flavivirus

A

Not part of bigger class, enveloped, (+) strand RNA virus

Cause encephalitis (Japanese encephalitis, Russian encephalitis, St. Louis encephalitis), Yellow fever, Dengue fever, West Nile fever

73
Q

Retrovirus

A

(+) strand RNA viruses (2 RNAs per virion); enveloped, packages reverse transcriptase

Includes oncoviruses (HTLV-1, HTLV-2), leukemia (rous sarcoma virus in chickens), lentiviruses (HIV-1, HIV-2)

74
Q

Reovirus

A

dsRNA, non-enveloped, double-layered capsid (outer capsid digested in GI tract), 10-12 RNA segments (can get reassortment)

Rotavirus is a type of reovirus (?): causes infantile diarrhea; fecal-oral route

75
Q

3 strains of influenza virus

A

Influenza A: toggles between human and animals

Influenza B: only humans

Influenza C: not pathogenic

76
Q

Influenza A

A

Shuttled between humans and animals

Has 8 RNA segments of (-) sense ssRNA

77
Q

Life cycle of influenza virus

A

1) HA protein binds sialic acid receptor on cell surface
2) M2 ion channel imports H+ ions, denaturing HA protein and releasing capsid into cytoplasm
3) Enclosed RNA polymerases transcribe 8 RNA segments (in the nucleus)
4) HA protein cleaved before packaging
5) NA helps virus egress (cleaves sugars that still attach virus to membrane)

78
Q

How do we make subtypes of influenza A virus?

A

Use 3 HA subtypes (H1, H2, H3) and 2 NA subtypes (N1, N2)

Ex: H3N2

79
Q

Proteins contained on envelop of influenza virus

A

Hemagglutinin (HA)

Neuraminidase (NA)

80
Q

Why is it that human flu strains (influenza A or B) can only infect the lungs (not the stomach)?

A

Because the HA of human flu strains are only cleaved by a protease in the lung, so human influenza viruses can only infect cells in the lung (can’t affect cells anywhere else in the body!)

H5N1 is a non-human influenza virus that can be cleaved by furin, which is present in all tissues (pantropic!)

81
Q

Pandemic

A

Nobody on earth has seen this virus before

82
Q

Antigenic shift

A

Reassortment/trading of RNA segments between animal and human strains

Two influenza types co-infect same cell, undergo replication and capsid packaging, and RNA segments are mispackaged into a new virus!

Complete change in HA, NA or both

Humans have never been exposed to this HA or NA ever before!

83
Q

Orthomyxoviridae

A

Spherical virions

8 segments of (-) strand RNA put together with nucleocapsid protein into helical symmetry capsid

Around nucleocapsid is outer membrane with long glycoprotein spikes (either HA or NA)

84
Q

Hemagglutinin (HA)

A

Glycoprotein on envelope of influenza virus

Attaches to host sialic acid receptors (which are on RBCs and upper respiratory tract cell membranes

HA needed for adsorption

85
Q

Neuraminidase (NA)

A

Cleaves neuraminic acid which is in mucin and is part of host’s upper respiratory defense barrier –> exposes sialic acid binding sites beneath

Critical for release of newly formed virion from infected host cell (as virus buds out of host membrane, virion’s HA still attached to host’s sialic acid receptor, so NA cleaves this)

86
Q

Antigenic drifty our immune system

A

During viral replication, mutations occus in HA or NA

Small changes add up and resulting new strains aren’t attacked well by our immune system

87
Q

Can you get a pandemic a second time?

A

Yes, if the initially infected people have all died already

Ex: H1N1 in 1918 then again in 1977?

88
Q

Drugs for treatment and prophylaxis of influenza virus infections

A

1) Adamantanes (amantadine and rimantadine): M2 ion channel inhibitors inhibit acidification of inside of virion which is required for viral uncoating; effective only against influenza A
2) Neuraminidase inhibitors (zanamivir (Relenza, inhaled) and oseltamivir (Tamiflu, oral)): interfere with release/egress of progeny virus from infected host cell; effective against influenza A and B
3) Antibodies neutralize HA so can’t bind to sialic acid to enter the cell

89
Q

H5N1

A

“Avian flu” that started in Asia, is epidemic in birds and spread to a few people

H5 protein binds better to a2,3 sialic acid (in chickens) than to a2,6 sialic acid (in humans), but we worry that mutation in H5N1 will cause it to be able to bind a2,6 well and then will be able to grow to high titer and transmit from human to human

Very pathogenic for 3 reasons:

1) More invasive than human viruses because HA can be cleaved by furin which is in all tissues (can infect all tissues) = pantropic
2) Two genes of the virus are able to mask immune response and increase replication efficiency
3) Humans have no exposure to H5N1 so have no immunity to the H5 protein

90
Q

When someone is reinfected with similar or same strain of influenza, which antibodies are used to neutralize the response?

A

IgM against HA

IgG against HA

Nasal IgA against HA

91
Q

Which sialic acids do humans have?

A

Mostly alpha2,6

Only very few cells in the nose and lung have alpha2,3

92
Q

SARS virus

A

Coronavirus

Was transmitted from bats, due to antigenic drift (couldn’t have reassortment/antigenic shift because only has 1 RNA)

Clinical features: 2-10 day incubation, then fever, myalgia and chills, then dry cough and chest pain and SOB (no sore throat or rhinorrhoea), can progress to ARDS

93
Q

Classic flu-like symptoms

A

Fever, malaise, myalgia, sore throat, nonproductive cough

In children: high fever (watch for seizures, keep temp under 101), GI symptoms (due to cytokines, not stomach bug), otitis media, croup, myositis (inflammation of muscle)

94
Q

Complications of influenza

A

1) Viral pneumonia (primary)
2) Secondary bacterial pneumonia (usually Streptococcus pneumonia)
3) Reye’s syndrome if give kids Aspirin for fever (so give acetaminophen instead!)

95
Q

How do we make influenza vaccine?

A

Take one strain in human population (H1N1) and reassort it with Puerto Rico strain, then take another strain in human population (H3N2) and reassort it with Puerto Rico strain, and one more –> get 3 different flu strains into a vaccine strain by reassortment

96
Q

What can we use for the influenza vaccine?

A

1) Formalin-inactivated whole virus
2) Chemically disrupted virus (subvirion)
3) Purified antigens

97
Q

FluMist

A

Live attenuated influenza vaccine administered by intranasal spray

Cold mutant (grows better in colder temperatures)

Gives T cell immunity, mucosal immunity (IgA) and IgG immunity

Much more effective than inactivated flu vaccine that most people get

98
Q

Parainfluenza (PIV)

A

1 segment of RNA (so no reassortment)

ssRNA (-) sense

3 serotypes so no antigenic drift

No vaccine, highly infectious, respiratory transmission, cause pediatric infections

Complications: croup (inflammation of subglottal region –> difficulty breathing, high pitched inspiration and barking, spasmodic cough and stridor)

99
Q

Respiratory Syncytial Virus (RSV)

A

1 RNA segment

ssRNA (-) sense

Lower respiratory virus

Major cause of bronchiolitis, important cause of infant pneumonia

100
Q

Mumps

A

1 RNA segment

ssRNA (-) sense

Infects epithelial cells of nasal mucosa and upper resp tract

Parotid gland swelling

Complications: CNS involvement, infection of ovaries and testicles

101
Q

MMR vaccine

A

No link between MMR vaccine and autism!

Measles, Mumps, Rubella

Live attenuated virus

102
Q

Measles

A

1 RNA segment

ssRNA (-) strand

Infets epithelial cells of oropharynx and upper resp tract

Virus spreads to regional lymph nodes

Viremia

Prodromal phase of coryza, conjunctivitis, cough

Clinical syndrome: Koplik’s spots on buccal mucosa, head to toe rash

103
Q

Nipah virus

A

In Asia, in fruit bats (then to pigs then to humans)

Encephalitis (often fatal) in humans

104
Q

Human metapneumovirus (hMPV)

A

Causes rhinorrhea, congestion, cough, tachypnea, wheezing, rales

Patients more at risk are cancer pts, elderly, and adults with underlying medical conditions

105
Q

Rabies

A

Rhabdovirus

Can be asymptomatic or can show symptoms 60-365 days after bite

Symptoms: fever, nausea, vomiting, lethargy

Negri body is the inclusion body of rabies virus

106
Q

Bunyavirus

A

200 different versions of them

Most are arboviruses (from arthropods/insects)

Hantaan virus is not arthropod borne, and can infect lung or kidney

107
Q

Haantavirus

A

Bunyavirus

Aerosol inhalation of rodent excreta; infection initiated and remains in lung; no human to human transmission

Hantavirus pulmonary syndrome (HPS): fever, myalgia, abdominal pain, pulmonary edema, sometimes shock

Capillary leak syndromes: infection of endothelial cells, no cytotoxicity, T cells and cytokines create gaps between endothelial cells

Lung: HPS with pulm edema, shock and resp failure

Kidney: Hemorrhagic fever with renal syndrome (HFRS) with hypotension and shock, renal failure

108
Q

Filovirus

A

Marburg virus

Ebola virus: comes up in Africa

Modes of transmission: direct contact, droplets onto mucous membranes, fomites, body fluids, airborne

Symptoms: flu-like, bleeding (petechiae is bleeding from capillaries and eccymoses are large purple spots), rash, death by shock

109
Q

2 groups of viruses that require really high CD8 immunity

A

1) Paramyxoviruses
2) Herpesviruses

110
Q

What virus is most likely to cause pneumonia in children vs. adults vs. immunocompromised?

A

Children: RSV, PIV

Adult: influenza

Immunocompromised: CMV

111
Q

IgG vs. IgM

A

IgM: produced in primary (immediate) response to antigen)

IgG: main antibody in secondary (delayed) response to antigen; most abundant in blood

112
Q

Viruses that cause gastroenteritis

A

1) Calicivirus: norovirus (most common in US)
2) Reovirus: rotavirus (most common worldwide)
3) Other: adenovirus 40 and 41, sapoviruses, astroviruses, aichi virus-picornavirus

113
Q

Rotavirus

A

Reovirus

dsRNA, 11 RNA segments, non-enveloped

Most common cause of infantile diarrhea worldwide

Causes wintertime vomiting disease

Group A capsid most common in US

Treatment is IV hydration for diarrhea

Vaccines: Rotateq (bovine rotavirus x 5 human strains of rotavirus), Rotarix

114
Q

Norovirus (Norwalk agent, Norwalk virus)

A

Calicivirus

ssRNA, (+) sense, non-enveloped, fecal-oral

Outbreaks on ships, in schools, in older children and adults

115
Q

Viruses that cause hepatitis

A

Hep A, B, C, D, E

EBV, CMV, yellow fever virus

116
Q

Which hepatitis viruses produce only acute phase?

A

Hep A and E (AcutE)

They are both non-enveloped

117
Q

What happens during the chronic phase of hepatitis?

A

Chronic hepatic inflammation

Hepatic fibrosis, cirrhosis, liver failure

Increased risk of hepatocellular carcinoma

(note: only with Hep B, C, D, G)

118
Q

Hepatitis A virus

A

ssRNA, (+) sense

Non-enveloped (very stable capsid), icosohedral capsid

4 genotypes but only 1 serotype

Transmitted fecal-oral

119
Q

Pathogenesis of HepA virus

A

Enters portal bloodstream through intestinal epithelium

Replicates in hepatocytes and Kupffer cells

Released by exocytosis (not cell lysis!)

Goes into bile, intestine, excreted in feces (in blood transiently)

Shed virus for 10 days prior to symptoms

Note: immune response causes damage to hepatocytes (hepatitis), not cell lysis!

120
Q

Acute HepA infection

A

May be mild or asymptomatic, especially in children

Abrupt onset of disease in adults

“Self-limited” so cleared by immune system

Low mortality

121
Q

Diagnosis and treatment of Hep A

A

Antibody detection: IgM in acute infection (4-6 months) and IgG present for decades

Virus in feces by electrom microscopy

PCR

There is no antiviral treatment, just supportive care

122
Q

Hep A vaccine

A

Passive immunization: Hep A immune globulin (polyclonal anti-Hep A antibodies persist for 6 months) but not used much for pre-exposure prophylaxis, only sometimes if <2 weeks post-exposure

Active immunization: inactivated whole virus vaccine

123
Q

Hepatitis E virus

A

Calicivirus

ssRNA, non-enveloped, fecal-oral transmission

Similar to Hep A but higher rates in pregnancy (10-20%)

Vertical transmission (during birth)

No vaccine available

124
Q

Incubation periods for different hepatitis viruses

A

Hep A and E: 15-50 days

Hep B: 45-160 days

Hep C and G: 15-180 days

Hep D: 15-64 days

125
Q

Symptoms during acute infection of hepatitis

A

Prodrome: malaise, anorexia, fatigue, fever, nausea, vomiting, RUQ pain, if doesn’t progress to icteric phase, could never know that this was hepatitis!

Icteric phase: elevated serum bilirubin causes jaundice (>2.5mg/dL), acholic stools (light), dark urine, hepatomegaly, elevated ALT>AST, elevated alkaline phosphatase, decreased synthesis of albumin and clotting factors

126
Q

Symptoms during chronic infection of hepatitis

A

Chronic hepatic inflammation

May progress to hepatic fibrosis, cirrhosis, liver failure, increased risk of HCC

Most of global morbidity and mortality of viral hepatitis due to chronic infection (not acute)

127
Q

Hepatitis B

A

(partially) dsDNA, small circular, enveloped, unusually stable to solvents/heat/low pH

Huge amount of surface antigen (appears free in serum of infected patients)

Antibody response to HBsAg associated with viral clearance; core antigen (HBcAg) not detected in serum (but antibody can be measured!); e antigen (HBeAg) made from precore protein, detectable in serum and associated with chronic active hep B with increased production of virus and increased activity of infection

Transmission: blood and bodily fluids

128
Q

Pathogenesis of Hep B virus

A

Virions released by exocytosis, not cytolytic

Cell-mediated immune response (CD8) leads to injury and destruction of infected hepatocytes: infants have mild symptoms/asymptomatic because weak CD8 immune response, but adults have good immune response and some can even get such a huge immune response that get fulminant hepatitis and die from acute hep B infection

129
Q

Acute Hep B infection

A

Longer incubation period prior to symptoms

Insidious onset of symptoms rather than abrupt like Hep A

Can get immune complex disease related to HBsAg: rash, arthritis, fever, necrotizing vasculitis (polyarteritis nodosum), glomerulonephritis)

130
Q

Diagnosis of Hep B

A

NOT based on clinical symptoms

Serologic tests

DNA assay (PCR)

131
Q

Chronic Hep B infection

A

Occurs in 5-10% of acute infection

Happens when cell mediated immune response doesn’t clear all virally infected cells

10% go on to develop cirrhosis of liver failure

Always see HBsAg, but only in early phase see HBeAg

If see anti HBe, means have cleared HBeAg, and that is associated with better prognosis

Will see anti-HBc antibodies early on–good way to detect infection

132
Q

Phases of chronic Hep B

A

1) Replicative, immune tolerance: high levels of replication, HBeAg, HBV DNA, little/no evidence of active liver disease
2) Replicative, immune clearance: spontaneous clearance of HBeAg with HBeAb, may be minimally symptomatic or severe with acute liver failure
3) Low or non-replication (“chronic persistent”): no HBeAg but have HBeAb, may have HBsAg but less HBV DNA (via PCR), no HBsAb; less likely to develop cirrhosis of HCC

133
Q

Hep B vaccine

A

Recombinant HBsAg

Series of 3 injections

All newborns are required to get Hep B vaccine

134
Q

Hepatitis D virus

A

Defective virus

ssRNA, small circular

Single Hep D antigen

Need lipid envelope from HBV in order to package so can only get Hep D if you have or are getting Hep B too!

Replicates very efficiently in hepatocytes

Increases risk of fulminant hepatitis, cirrhosis

No vaccine

Unlike other hepatitis viruses, Hep D KILLS liver cells!

135
Q

Hepatitis C virus

A

(+) RNA virus

Prolonged cell-associated state where virus in hepatocytes but not replicating much, low level chronic cell-mediated host immune response (person can be infected but never know that they have it)

Some patients get hepatic fibrosis and cirrhosis

Transmission via blood (not sexually)

Diagnosis: RNA in serum, HCV antibody positive (but this is not associated with viral clearance like Hep B is!)

No vaccine

136
Q

Hepatitis G virus

A

Flavivirus (distantly related to yellow fever and dengue fever viruses)

30% homology to hep C, but probably does not even cause hepatitis!

May have protective effect in HIV

Transmission is parenteral (blood, body fluids)

137
Q

Serology for acute hepatitis infection

A

sAg +

sAb -

eAg +

eAb -

cAb +

138
Q

How do you know if someone has had a natural hepatitis infection?

A

Will always have antibody to core protein (cAb +)

139
Q

Human papillomavirus

A

Papovavirus

dsDNA, non-enveloped

Causes benign cutaneous warts (feet, hands, face, also oral, laryngeal, genital)

Malignant potential: HPV-16, 18 (for genital carcinoma)

140
Q

Functions of early genes of HPV

A

E1: DNA replication

E2: downregulates transcription of E6 and E7

E5: on cell membrane; can stimulate transforming action of EGF

E6: in oncogenic HPV (16, 18), binds p53 tumor suppressor protein and degrades it

E7: binds Rb tumor suppressor protein so can no longer bind/inactivate E2F and now E2F is free to activate transcription

141
Q

Koliocytes

A

HPV-producing cells

Have dark stained nuclei with halo (no cytoplasmic staining) with pyknotic nuclei

Appear in granular layer?

Do colposcopy, and if see red or white cells, that is abnormal

142
Q

If you have negative HPV test (no HPV DNA, so no/undetectable HPV infected cells), does that mean you don’t have HPV?

A

Not necessarily

All HPV infected cells present antigenic proteins on MHC-I to attract CD8 cells, so can get spontaneous loss of HPV-positive cells between pap smears

143
Q

How does HPV cause invasive cervical cancer?

A

1) Integration with E2 causes increased synthesis of E6 and E7
2) E6 inactivates p53 and E7 inactivates Rb
3) Cell division, DNA damage, aneuploidy
4) Invasive cervical cancer

(CIN1 then 4-7 years later CIN3 then 15 years later invasive cervical cancer)

144
Q

Treatment for HPV

A

Imiquimod (induces IFN-a, cytokines)

Also cryotherapy, loop or cone section, podophylin

145
Q

Gardasil

A

Quadrivalent vaccine against HPV: strains 16, 18 (likely to cause cervical cancer), 6, 11 (likely to cause genital warts)

Contains virus-like particles of empty DNA surrounded by L1 protein

Almost 100% effective in women, and also some protection against other strains

Effective in males to prevent genial warts

146
Q

Polyomavirus

A

Papovavirus

SV40 (monkeys)

Polyoma virus (mouse)

BK (ubiquitous)

JC (causes PML in immunocompromised)

147
Q

Transmissible spongiform encephalopathies (TSE)

A

These are all prions

1) Scrapie (sheep)
2) Mad cow disease
3) Creutzfeld-Jakob disease (CJD)

148
Q

How do prions form?

A

1) Mutations cause misfolded proteins = prions
2) Prions can interact with normal proteins to turn them into prions

149
Q

Categories of CJD

A

1) Sporadic (85%)
2) Hereditary (5-10%)
3) Acquired: transmitted by exposure to brain or nervous system tissue usually through medical procedures

150
Q

Parvovirus (B19)

A

ssDNA, non-enveloped

Replicates in erythroid precursor cells

Causes Fifth disease/erythema infectiosum (slapped face rash on cheeks and fever), aplastic crisis (suppression of erythropoiesis), hydrops fetalis, arthralgia and arthritis

Respiratory transmission

Two phases of infection: (1) fever, malaise, myalgia, viremia for 1-2 weeks; (2) drop in hemoglobin, rash caused by immune complexes and infection of epidermal cells

No therapy, no vaccine

151
Q

Five childhood exanthems or rashes

A

1) Measles (paramyxovirus)
2) Rubella (togavirus)
3) Roseola (herpesvirus 6 and 7)
4) Varicella (varicella zoster, a herpesvirus)
5) Fifth disease (B19 parovirus)

152
Q

Poxvirus

A

dsDNA, enveloped, largest virus

Variola (smallpox), vaccinia (vaccine strain; combo btwn variola and cowpox), molluscum contagiosum

Replicates in cytoplasm!!

Carries many enzymes in virion

Respiratory transmission (very contagious)

153
Q

Adenovirus

A

Different serotypes cause many different symptoms

dsDNA, non-enveloped

Cause 10% of respiratory infections in children

154
Q

For what diseases would you give passive immunization after exposure?

A

Varicella

CMV

Hep A

Hep B

Rabies

155
Q

For which diseases do you give active immunization?

A

MMR

Influenza

Rotavirus

Hep A and B

Varicella

HPV

156
Q

For which diseases do we give antiviral therapy?

A

Influenza, RSV

HSV-1, HSV-2, VZV, CMV, EBV

Hep B, Hep C

Papillomavirus

Retrovirus (HIV-1, HIV-2, HTLV-1)

157
Q

Neuraminidase inhibitors

A

Both Zanamivir and Oseltamivir are structural analogues of sialic acid

Oseltamivir has good oral bioavailability due to ester moiety

158
Q

Drugs for ophthalmic infections caused by herpes viruses

A

Cidofovir: nucleotide analogue; treat CMV (delay progression of CMV retinitis in AIDS), herpesviruses; nephrotoxicity, neutropenia and metabolic acidosis

Fomivirsen: 21 nucleotide antisense oligonucleotide for intravitreal injection; suppress reactivation of CMV retinitis; iritis, vitritis, other complications

Trifluridine (trifluorothymidine): topical treatment for herpetic keratitis

159
Q

Foscarnet

A

Treat acyclovir-resistant HSV, ganciclovir-resistant CMV

Block cleavage of pyrophosphates –> interfere with viral DNA synthesis

Side effects: renal tubular dysfunction, electrolyte abnormalities, anemia, diarrhea, genital ulcers (lots of toxicity, so this is second line drug!)

160
Q

Drugs for Hep B

A

INF-a-2b

Peginterferon a-2a

Lamivudine

Entecavir

Telbivudine

Adefovir

Tenofovir

161
Q

Lamivudine

A

3’ thiacytidine

Interferes with viral DNA polymerase and reverse transcriptases

Side effects: uncommon at doses used to treat Hep B (if treating HIV with larger dose: pancreatitis, lactic acidosis, hepatomegaly, steatosis, headache, fatigue, nausea)

Resistance develops in 25% of patients within a year

162
Q

Entecavir

A

Deoxyguanosine nucleoside analogue –> inhibits HBV DNA polymerase

Well absorbed, little metabolized

Side effects: well-tolerated; headache, fatigue, dizziness, abdominal pain, fever, diarrhea, cough, myalgia

163
Q

Telbivudine

A

Thymidine analogue –> inhibits HBV DNA polymerase

Well absorbed, little metabolized

Better than lamivudine!! (less resistance)

Side effects: well-tolerated but similar to lamivudine; lactic acidosis, myopathy, creatine kinase elevations

164
Q

Adefovir

A

Acyclic adenosine monophosphate nucleotide analogue –> interferes with DNA polymerase and reverse transcriptase

Side effects: at doses used to treat Hep B get severe exacerbations of hepatitis in 25% after cessation

Resistance: several percent per year

165
Q

Drugs for Hep C

A

Ribavarin with INF-a-2b

Pegylated IFN (plus ribavarin)

166
Q

Telaprevir and Boceprevir

A

Hep C protease inhibitors

Combined with pegylated IFN

Side effects: anemia, neutropenia, nausea, diarrhea, taste disturbance

167
Q

Imiquimod

A

Treat papillomavirus (anogenital and common warts)

Immunomodulator, likely stimulates TRL-7

Topical 3x per week

Only 50% success

Side effects: irritation, itching, flaking

168
Q

Treatments for papillomavirus

A

Imiquimod

Polofilox 0.5% (mechanism unclear)

Surgical, cryotherapy

169
Q

Non-FDA approved uses for antivirals

A

Ribavirin for RNA viruses (measles, SARS-CoV, hantavirus)

Cidofovir for DNA viruses (papovaviruses, variola)

170
Q

Do we give everyone antivirals?

A

No, mostly immunocompromised patients

171
Q

Agglutination

A

Clumping of particles

Occurs when antibody can crosslink two things

Hemagglutination: virus antigen attaches to RBC

Block 6: Microbio, ID, Derm, Heme-Onc (10 decks)

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