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Flashcards in DNA & RNA Viruses Deck (226):
1

What are viruses made of?

1) Viruses are particles composed of an internal core containing either DNA or RNA (not both) covered by a protective protein coat
2) Some have outer lipomembrane protein (envelope) external to coat
3) Do not have nucleus, cytoplasm, mitochondria or ribosomes

2

How do viruses reproduce?

Within cells (they are obligate intracellular parasites) because they cannot generate energy or synthesis proteins

3

The difference between a virus replicating and a prokaryotic or eukaryotic cell replicating

Viruses do not undergo binary fission or mitosis. One virus can replicate to produce hundreds of progeny viruses, whereas one cell divides to produce only two daughter cells

4

Comparison of viruses and cells:
1) Type of nucleic acid
2) Proteins
3) Lipoprotein membrane
4) Ribosomes
5) Mitochondria
6) Enzymes
7) Multiplication by binary fission or mitosis

1) Type of nucleic acid:
Viruses: DNA or RNA but not both
Cells: DNA & RNA
2) Proteins:
Viruses: few
Cells: many
3) Lipoprotein membrane:
Viruses: Envelope present in some viruses
Cells: Cell membrane present in all cells
4) Ribosomes:
Viruses: Absent
Cells: Present
5) Mitochondria:
Viruses: Absent
Cells: Present in eukaryotic cells
6) Enzymes:
Viruses: None or few
Cells: many
7) Multiplication by binary fission or mitosis
Viruses: No
Cells: Yes

5

The shape of virus particles is determined by the arrangement of?

The repeating subunits that form the protein coat (capsid) of the virus

6

The viral nucleic acid (genome) is located internally and can be?

Either single or double stranded DNA or single or double stranded RNA

7

Only viruses have genetic material composed of?

Single or double stranded DNA or single stranded or double stranded RNA. The nucleic acid can either be linear or circular. DNA is always a single molecule; RNA can exist as either a single molecule or in several pieces (for example both influenza virus and Rotavirus have a segmented RNA genome)

8

The nucleic acid of viruses is surrounded by?

* A capsid (protein coat) made up of subunits called capsomers
* Capsomers consists of one or several proteins

9

The structure composed of the nucleic acid genome & the capsid proteins is called?

Nucleocapsid

10

Viral nucleocapsids have 2 forms of symmetry

1) Icosahedral- capsomers arranged in 20 triangles that form a symmetric figure
2) Helical- capsomers arranged in hollow coil that appears rod-shaped. Rigid or flexible.
* All human viruses that have a helical nucleocapsid are enclosed by an outer membrane (envelope)
* Viruses that have a icosahedral nucleocapsid can be enveloped or naked

11

What is the advantage of building the virus particle from identical protein subunits? It is twofold

1) Reduces need for genetic information
2) Promotes self assembly

12

Viral proteins serve several important functions

1) Outer capsid proteins protect genetic material & mediate attachment of virus to specific receptors on host cell surface. (This interaction is the major determinant of species & organ specificity)
2) Important antigens- induce neutralizing antibody & activate cytotoxic T cells to kill virus infected cells
3) Also target of antibodies
4) Some are structural others are enzymes
5) Some have DNA or RNA polymerase attached to genome
6) Some contain regulatory proteins in the virion in a structure called the tegument, these proteins include transcription and translation factors that control either viral or cellular processes

13

How are viral proteins a target for antibodies?

Antibodies bind to these proteins & prevent (neutralize) the virus from entering the cell and replicating
* The outer proteins induce these immune responses following both the natural infection & immunization

14

Some viruses produce proteins that act as "super-antigens"

Viruses known to produce superantigens include two members of the herpes virus family, Epstein-Barr virus and cytomegalovirus, & the retrovirus mouse mammary tumor virus

15

The herpesvirus family contains 6 important human pathogens

1) Herpes simplex virus types 1 & 2
2) Varicella-zoster virus
3) Cytomegalovirus
4) Epstein-Barr virus
5) Human herpes virus 8 (cause of Kaposi's sarcoma)

16

All herpes viruses are structurally similar

* Each has icosahedral core surrounded by lipoprotein envelope
* Genome linear double stranded DNA
* Virion does not contain a polymerase
* Large (2nd in size to poxviruses)

17

How do herpes viruses replicate?

* In nucleus
* Form intranuclear inclusions
* Only viruses that obtain envelope by budding from nuclear membrane
* Virions posses a tegument which contains regulatory proteins (transcription/translation factors) which play a role in viral replication

18

Herpes viruses are noted for their ability to cause latent infections, meaning?

* Acute disease is followed by an asymptomatic period during with the virus remains in a quiescent (latent) state
* When patient exposed to an inciting agent or immunosupression occurs, reactivation of virus replication & disease can occur

19

Shortly after HSV infects neurons what happens?

A set of latency-associated transcripts are synthesized (these noncoding, regulatory RNAs suppress viral replication)
* process by which latency is terminated & reactivation of viral replication occurs is unclear, but various triggers such as sunlight, fever, & stress are known

20

CMV established latency by?

Producing microRNAs that inhibit the translation of mRNA's required for viral replication.
*Genome encodes a protein and an RNA that have the ability inhibit apoptosis in infected cells, this allows infected cell to survive

21

Three of the herpes viruses cause a vesicular rash

Herpes simplex virus types 1 & 2 and varicella-zoster virus. Both in primary infections and in reactivations. Primary infections are usually more severe than reactivations

22

Four herpes viruses induce the formation of multinucleate giant cells

Herpes simplex virus types 1 & 2, varicella-zoster virus, & cytomegalovirus

23

The herpes virus family can be subdivided into three categories based on the type of cell most often infected & the site of latency

1) The alpha herpes viruses, consisting of herpes simplex viruses type 1 & 2, & varicella-zoster virus infect epithelial cells primarily & cause latent infection in neurons
2) The beta herpes viruses, cytomegalovirus & human herpes virus 6, infect & become latent in a variety of tissues
3) The gamma herpes viruses, Epstein-Barr virus & human herpes 8 (kaposi's sarcoma associated virus) infect & become latent in primarily in lymphoid cells

24

Certain herpes viruses are suspected of causing cancer

In humans, e.g Epstein-Barr virus is associated with lymphoma and nasopharyngeal carcinoma, & human herpes virus 8 is associated with Kaposi's sarcoma. Several herpes viruses cause cancer in animals

25

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are distinguished by two main criteria

Antigenicity and location of lesions.
* Lesions caused by HSV-1 are above the waist
* Lesions caused by HSV-2 are below the waist

26

Herpes simplex virus 1 (HSV-1) causes?

Acute gingivostomatitis, recurrent herpes labialis (cold sores), keratoconjunctivitis (keratitis), and encephalitis

27

Herpes simplex virus 2 (HSV-2) causes?

Herpes genitalis (genital herpes), neonatal herpes, & aseptic meningitis

28

Infection by HSV-1 and HSV-2 is a common cause of?

Erythema multiforme

29

Important properties of HSV-1 and HSV-2

* Structurally and morphologically indistinguishable
* Can be differentiated by restriction of endonuclease patterns of their genome DNA & by type-specific monocleonal antisera
* Humans natural host of both viruses

30

The replication cycle of HSV-1 begins when? Same cycle for Varicella-zoster

1) HSV-1 binds first to heparin sulfate on the cell surface and then to a second receptor nectin.
2) Following fusion of the viral envelope w/the cell membrane, the nucleocapsid & the tegumented proteins are released into cytoplasm.
3) Viral nucleocapsid transported to nucleus where it docks to a nuclear pore & the genome DNA enters nucleus along with tegument protein (VP16)
4) Linear DNA becomes circular
5) VP16 interacts w/cellular transcription factors to activate transcription of viral immediate early genes (IE) by host cell RNA polymerase
6) IE mRNA is translated into IE proteins that regulate the synthesis of early proteins (DNA polymerase) that replicates genome & thymidine kinase (these two proteins are important because they are involved in the action of acyclovir (most important drug effective against HSV

31

Early protein synthesis by HSV can be subdivided into two categories

"Immediate early" and "early"
Immediate early proteins are those whose mRNA synthesis is activated by a protein brought in by the incoming parental vision.
* No new viral protein synthesis is required for the production of five "immediate early" proteins. The "early" proteins do require the synthesis of new viral regulatory proteins to activate the transcription of their mRNAs

32

For HSV-1 and 2, the viral DNA polymerase replicates the genome DNA, at which time early protein synthesis is shut off and late protein synthesis begins. These late structural proteins are?

Transported to the nucleus, where virion assembly occurs

33

In latently infected cells, such as HSV-infected neurons, circular HSV DNA resides in the nucleus and is not integrated into cellular DNA. Transcription of HSV DNA is limited to?

A few latency associated transcripts (LATS). These noncoding regulatory RNAs suppress viral replication. Reactivation of viral replication can occur at a later time when the genes encoding LATS are excised.

34

How is HSV-1 transmitted?

Primarily in saliva, as a result they occur mainly on the face.
However, oral-genital sexual practices can result in infections of the genitals
* Transmission occurs most often when active lesions are present, asymptomatic shedding of both HSV-1 & 2 does occur and plays an important role in transmission

35

How is HSV-2 transmitted?

By sexual contact, as a result lesions occur in the genital area. However oral-genital sexual practices can result in lesions in the oral cavity (occurs in 10-20% of cases).
* Transmission occurs most often when active lesions are present, asymptomatic shedding of both HSV-1 & 2 does occur and plays an important role in transmission

36

The number of HSV-2 infections has _________ in recent years, whereas HSV-1 infections have. Roughly ___% of people in the US are infected with HSV-1 and ___% have recurrent herpes labialsis

HSV-2 has increased
HSV-1 has not
80%
40%

37

Most primary infections by HSV-1 occurs in?

Childhood, as evidenced by the early appearance of antibody. In contrast, antibody to HSV-2 does not appear until the age of sexual activity

38

Pathogenesis of HSV

* Virus replicates in skin or mucous membrane at initial site of infection, then migrates up neuron by retrograde axonial flow & becomes latent in the sensory ganglion cells. (HSV-1 becomes latent in trigeminal ganglion, HSV-2 becomes latent in lumbar & sacral ganglion)
* During latency, most viral DNA is located in cytoplasm rather than integrated into nuclear DNA
* Virus can be reactivated from latent state by variety of inducers: sunlight, hormonal changes, trauma, stress, & fever, at which time it migrates down the neuron & replicates in the skin, causing lesions

39

Typical skin lesions of HSV is a?

* Vesicle that contains serous fluid filled with virus particles and cell debris. When the vesicle ruptures, the virus is liberated and can be transmitted to others.
* Multinucleated giant cells are typically found at the base of herpesvirus lesions

40

Immunity for HSV

* Type specific, some cross protection exists
* Immunity incomplete, both reinfection & reactivation occur in presence of circulating IgG
* Cell-mediated immunity important in limiting herpesviruses

41

HSV-1 Gingivostomatitis occurs?

* Primarily in children & characterized by fever, irritability, and vesicular lesions in mouth.
* Primary disease more severe and lasts longer than recurrences.
* Lesions heal spontaneously in 2-3 weeks
* Many children have asymptomatic primary infections

42

HSV-1 Herpes labialis (fever blisters or cold sores) is the?

* Milder recurrent form
* Characterized by crops of vesicles (mucocutanous junction of lips or nose
* Recurrences reappear at same time

43

HSV-1 Keratoconjunctivitis is? (2 points)

* Characterized by corneal ulcers & lesions of conjunctivae epithelium
* Recurrences can lead to scarring & blindness

44

HSV-1 Encephalitis is? (8 points)

* Characterized by necrotic lesion in one temporal lobe
* Fever, headache, vomiting, seizures, and altered mental status
* Onset may be acute or protracted over several days
* Disease occurs as a result of either primary infection or recurrence
* MRI imaging reveals lesion
* Exam of spinal fluid shows increase lymphocytes, elevation protein amount, normal glucose amount
* High mortality rate
* Severe neurologic sequelae in those who survive

45

HSV-1 Herpetic whitlow is a?

Pustular lesion of the skin of the finger or hand. Can occur in medical personnel as result of contact w/patients lesions

46

HSV-1 Herpes gladiatorum is?

* Occurs in wrestlers & others who have close body contacts
* Caused primarily by HSV-1
* Characterized by vesicular lesions on head, neck, & trunk

47

HSV-1 Disseminated infections are?

Such as esophagitis & pneumonia, occur in immunocompressed patients with depressed T-cell function

48

HSV-2 Genital herpes is?

* Characterized by painful vesicular lesions of the male/female genitals/anal area
* Lesions more severe & protracted in primary disease than in recurrences
* Primary infections are associated with fever, & inguinal adenopathy
* Asymptomatic infections occur in men (prostate or urethra) & women (cervix). Can be source of infection of other individuals
* Many infections asymptomatic

49

HSV-2 Neonatal herpes is?

* Originates from contact w/vesicular lesions w/in birth canal (some cases no visible lesions)
* Shed onto birth canal (asymptomatic shedding) can infect child during birth
* Varies from severe to mild local lesions to asymptomatic infections
* May be prevented by performing C section
* Both HSV-1 & 2 can cause severe neonatal infections that are acquired after birth from carriers handling the child
* Neither virus causes congenital abnormalities

50

Serious neonatal infection is more likely to occur when the mother is experiencing a primary herpes infection than a recurrent infection for two reasons

1) Amount of virus produced during primary infection is greater than recurrent
2) Mothers who have been previously infected can pass IgG across placenta, which can protect neonate from serious disseminated infection

51

Aseptic meningitis caused by HSV-2 is?

A mild self-limiting disease with few sequelae

52

Both HSV-1 & 2 are associated with erythema multiforme. This rash appears as a central red area surround by a ring (target or bulls eye lesion). Lesions are typically?

Mascular or papular & occur symmetrically on the trunk, hands, and feet.
* Rash though to be immune-mediated reaction to presence of HSV antigens
* Acyclovir useful in preventing recurrent episodes by reducing amount of HSV antigens
* Many drugs commonly cause erythema multiforme

53

Erythema multiforme major, also known as Stevens Johnson syndrome, is characterized by?

Fever, erosive oral lesions, and extensive desquamating skin lesions. M. pneumonia is most commonly caused by this.

54

What suggests a herpes virus infection?

The presence of multinucleated giant cells

55

Treatment for HSV-1 & 2

1) Acyclovir (acycloguanosine, Zovirax) treatment for encephalitis and system disease caused by HSV-1
* also useful for primary & recurrent genital herpes
* neonatal infections caused by HSV-2
* mutans of HSV-1 resistant have been isolated from patients
2) HSV-1 eye infections other nucleoside analogs used topically
3) No drug treatment of primary infection prevents recurrences, drugs have no effect on latent state, but prophylactic, long term administration of acyclovir, valacyclovir, or famcicylovir can suppress clinical recurrences

56

What does Acyclovir do for HSV-1 & 2?

It shortens the duration of lesions & reduces extent of shedding of the virus

57

Prevention of HSV-1 & 2

* Avoid contact w/vesicular lesion or ulcer
* C-section for women who are at term & who have genital lesions or positive viral cultures
* Circumcision reduces risk of infection

58

Comparison of diseases caused by HSV-1 & 2:
Skin
Mouth
Eye
Central nervous system
Neonate
Dissemination to viscera in immunocompressed patients

Skin:
HSV-1: Vesicular lesions above waist
HSV-2: Vesicular lesions below waist (genitals)
Mouth:
HSV-1: Gingivostomatitis
HSV-2: Rare
Eye:
HSV-1: Keratoconjunctivitis
HSV-2: Rare
Central nervous system:
HSV-1: Encephalitis (temporal lobe)
HSV-2: Meningitis
Neonate:
HSV-1: Rare
HSV-2: Skin lesions, encephalitis, disseminating infections
Dissemination to viscera in immunocompressed patients:
HSV-1: Yes
HSV-2: Rare

59

What disease(s) does varicella-zoster virus cause?

Varicella (chickenpox) is the primary disease; zoster (shingles) is the recurrent form

60

Important properties of Varicella-zoster virus (VZV)

* Structurally & morphologically similar to others herpes viruses but is antigenically different.
* Has single serotype
* Same virus causes both varicella & zoster
* humans natural host

61

Replicative cycle of Varicella-zoster virus (VZV)

Similar to that of HSV

62

Transmission for Varicella-zoster virus

* Transmitted by respiratory droplets & by direct contact w/lesions
* Varicella is a highly contagious disease of childhood, more than 90% of people in US have antibody by age 10
* Varicella occurs worldwide
* Widespread use of vaccine has reduced number of cases
* Infectious VSV in zoster vesicles. This can be transmitted by direct contact to children & can cause varicella
* Appearance of either varicella or zoster in a hospital is major infection control problem because virus can be transmitted to immunocompressed patients & cause life-threatening disseminated infection

63

Pathogenesis & immunity for Varicella-zoster virus

* Infects mucosa of upper respiratory tract, then spreads via blood to the skin where vesicular rash occurs
* Multinucleated giant cells w/intranuclear inclusions are seen in base of lesions
* Virus infects sensory neurons & carried by retrograde axonal flow into cells of the dorsal root ganglion where virus becomes latent
* In latently infected cells VZV DNA is located in the nucleus & is not integrated into cellular DNA, later in life, at times of reduced cell-mediated immunity or local trauma, virus is activated & causes the vesicular skin lesions & nerve pain of zoster
* Immunity following varicella is lifelong, a person gets it once but zoster can occur despite immunity, zoster usually occurs once. Frequency of zoster increases w/advancing age

64

Clinical findings for varicella

* After incubation period (14-21 days), brief prodromal symptoms of fever & malaise occur
* Papulovesicular rash appears in crops on trunk & spreads to head & elsewhere
* Rash evolves from papules to vesicles then pustules & then crusts
* Itching symptom (vesicle present)
* Mild in children, severe in adults
* Varicella pneumonia & encephalitis are major rare complications (seen most in adults)
* Reye's syndrome (encephalopathy & liver degeneration) associated w/VSV & influenza B virus infection (seen in children given aspirin)

65

Clinical findings for zoster virus

* Occurrence of painful vesicles along course of a sensory nerve of the head or trunk
* Pain can last for weeks
* Postzoster neuralgia can be debilitating
* Immunocompressed patients, life-threatening disseminated infections (pneumonia) can occur

66

Lab diagnosis for varicella-zoster

* Most made clinically, lab tests also available
* Presumption diagnosis made by using Tzanck smear
* Multinucleated giant cells seen in VZV as well as HSV lesions
* Definitive diagnosis made by isolation of virus in cell culture & identification w/specific antiserum
* Rise in antibody titer can be used to diagnose varicella but less useful in zoster

67

Treatment for varicella-zoster virus

* No antiviral therapy necessary in immunocompetent children
* Immunocompetent adults with either moderate or severe cases are treated w/acyclovir which reduces duration & severity of symptoms
* Immunocompressed children & adults w/chicken pox, zoster, or disseminated disease should be treated w/acyclovir
* Disease caused by acyclovir resistant strains of VZV treated w/foscarnet
* No drugs can cure latent state & none have any effect on postzoster neurglia

68

Prevention for Varicella-zoster virus

1) 2 vaccines against VZV:
* One designed to prevent varicella, other designed to prevent zoster
* Both contain live attenuated VZV, but zoster vaccine contains 14x more virus than varicella
2) Zoster vaccine effective in preventing zoster symptoms, but doesn't eradicate latent state of VZV
3) Varicella vaccine recommended for children between 1-12yrs
4) Zoster vaccine recommended for older than 60yrs & who have had varicella
5) Because the vaccines contain live virus they should not be given to immunosuppressed people or pregnant
6) Acyclovir useful in preventing varicella & disseminated zoster in immunocompromised people exposed to virus
7) Varicella-zoster immune globulin (VZIG), which contains higher titer of antibody to virus also used

69

What diseases does cytomegalovirus cause?

* Cytomegalic inclusion disease (especially congenital abnormalities) in neonates
* Most common cause of congenital abnormalities in US
* Important cause of pneumonia & other diseases in immunocompromised patients (recipients of bone marrow,, solid organ transplants)
* Causes heterophilnegative mononucleosis in immunocompetent individuals

70

Important properties of cytomegalovirus

* Structurally & morphologically similar to herpesviruses but is antigenically different
* Single serotype
* Humans natural host
* Animal strains do not infect humans
* Giant cells are formed

71

Replicative cycle of cytomegalovirus

* Similar to that of HSV & VZV
* Unique feature: some immediate early proteins are translated from mRNAs brought into infected cell by parental virion rather than being translated from mRNAs synthesized in the newly infected cell

72

Transmission for cytomegalovirus

* Transmitted by variety of modes
* Early in life transmitted across placenta, w/in birth canal, breast milk
* In young children: saliva
* Sexually
* Present in both semen & cervical secretions
* Blood transfusions & organ transplants
* Occurs worldwide
* More than 80% adults have antibodies against virus

73

For cytomegalovirus, infection of the fetus can cause cytomegalic inclusion disease, characterized by multinucleated giant cells with prominent intranuclear inclusions. Describe this disease

* Many organs affected & widespread congenital abnormalities result
* Infection of fetus occurs when primary infection occurs in pregnant women (when she has no antibodies that will neutralized the virus before it can infect the fetus)
* Fetus won't be infected if mom has antibody
* Congenital abnormalities are common when a fetus is infected during 1st trimester than later gestation, because the 1st trimester is when development of organs occurs & the death of any precursor cells can result in congenital defects

74

Describe the infections in children and adults for cytomegalovirus

* Usually asymptomatic (except immunocompromised)
* CMV enters latent state in leukocytes & reactivated when cell mediated immunity is decreased
* Can persist in kidneys for years
* Reactivation from latent state in cervical cells can result in infection of newborn during passage through birth canal

75

Cytomegalovirus has a specific mechanism of immune evasion that allows it to maintain the latent state for long periods. Explain

Assembly of the MHC class-I viral peptide complex is unstable, viral antigens not display on cell surface & killing by cytotoxic T cells does not occur. Encodes several microRNAs, one of which binds to and prevents translation of the cells mRNA for class-I MHC protein. This prevents viral proteins from being displayed on the infected cell surface & killing by cytotoxic T cells does not occur

76

Cytomegalovirus infection causes an immunosuppressive effect by inhibiting T-cells. Host defenses against CMV infection include?

Both circulating antibody and cell-mediated immunity. Cellular immunity is more important because its suppression can lead to systemic disease

77

Approximately 20% of infants infected with cytomegalovirus during gestation show clinically apparent manifestations of cytomegalic inclusion disease such as?

* Microcephaly, seizures, deafness, juandice, & purpura
* Hepatospleomegaly is common
* Cytomegalic inclusion disease one of leading causes of mental retardation in US
* Infected infants continue to excrete CMV, especially in urine, for several years

78

In immunocompetent adults cytomegalovirus can cause heterophilnegative mononucleosis, which is?

Characterized by fever, lethargy, & presence of abnormal lymphocytes in peripheral blood smears

79

Systemic cytomegalovirus infections, especially pneumonoitis & hepatitis occurs?

In a high proportion of immunosupressed patients (those with renal & bone marrow transplants). In AIDS patients CMV commonly infects the intestinal tract & cause intractable colitis w/diarrhea. Also causes retinitis in AIDS patients which can lead to blindness

80

Treatment for cytomegalovirus

* Ganciclovir (cytovene) moderately effective in treatment of retinitis & pneumonia in patients w/AIDS. Valganciclovir which can be taken orally, also effective
* Resistance to ganciclovir & valganciclovir have emerged due to mutations in UL97 gene that encodes phosphokinase
* Drug susceptibility testing can be done
* Foscarnet also effective but causes more side effects
* Unlike HSV, & VZV, CMV is resistant to acyclovir
* Vistide also useful for treatment in CMV retinitis

81

Prevention for cytomegalovirus

* No vaccine
* Ganciclovir can suppress progressive retinitis in AIDS pateints
* Infants w/cytomegalic inclusion disease who are shedding virus in their urine should be kept isolated from other infants
* Blood for transfusion to newborns should be CMV antibody-negative
* If possible, only organs from CMV antibody-negative recipients
* High titer immune-globulin preparation (CytoGam) is used to prevent disseminated infections in organ transplant patients

82

What diseases does Epstein Barr virus cause?

Infectious mononucleosis. Associated w/Burkitt's lymphoma, other B cell lymphomas, & nasopharyngeal carcinoma. Also causes hairy leukoplakia

83

Important properties of Epstein Barr virus

* Structurally and morphologically similar to other herpesvirues but is antigenically different
* Most important antigen is viral capsid antigen (VCA), used most often in diagnostic tests
* Early antigens (EA) are produced prior to viral DNA synthesis & nuclear antigen (EBNA), which is located in the nucleus bound to chromosomes, sometimes diagnostically helpful
* Also detected antigens are; lymphocyte-determined membrane antigen & viral membrane antigen
* Neutralizing activity directed against the viral membrane antigen
* Humans natural host
* Infects mainly lymphoid cells primarily B lymphocytes
* In latently infected cells EBV DNA is in the nucleus & is not integrated into cellular DNA
* Some (not all) genes are transcribed & only subset of these are translated to protein

84

Replicative cycle for Epstein-Barr virus

Similar to that of HSV. EBV enters B lymphocytes at the site of the receptor for the C3 component of compliment

85

How is Epstein-Barr transmitted?

1) Primarily by exchange of saliva (kissing)
- Saliva of people w/a reactivation of a latent infection as well as w/an active infection can serve as source
2) Blood transmission rare
3) One of most common infections worldwide
- More than 90% adults in US have antibody
4) Infection in first few years of life usually asymptomatic
- Early infection tends to occur in individuals in lower socioeconomic groups
5) Frequency of clinically apparent infectious mononucleosis is highest in those who are exposed to virus later in life (college)

86

The infection of Epstein-Barr first occurs in the?

Oropharynx & then spread to the blood, where it infects B lymphocytes. Cytotoxic T lymphocytes react against the infected B cells. The T cells are the atypical lymphs seen in the blood smear. EBV remains latent w/in B lymphocytes

87

Describe the immune response to the Epstein-Barr virus

1) Consists 1st of IgM antibody to the VCA
2) IgG antibody to the VCA follows & persists for life
3) IgM response is therefore useful for diagnosing acute infection, IgG response best for revealing prior infection
4) Lifetime immunity against second episodes of infectious mononucleosis is based on antibody to the viral membrane antigen

88

In addition to the Epstein-Barr virus specific antibodies, nonspecific heterophil antibodies are found. The term "heterophil" refers to?

* Antibodies that are detected by tests using antigens different from the antigens that induced them.
* The heterophil antibodies formed in infectious mononucleosis agglutinate sheep or horse red blood cells in the lab

89

Infectious mononucleosis caused by Epstein-Barr virus is characterized primarily by?

* Fever, sore throat, lymphadenopathy, & splenomegaly. Anorexia & lethargy are prominent
* Hepatitis is frequent; encephalitis occurs in some patients
* Spontaneous recovery usually occurs in 2 to 3 weeks
* Splenic rupture, associated w/contact sports such as football, is a feared but rare complication of the splenomegaly

90

Epstein-Barr virus also causes a severe, often fatal what?

Progressive form of infectious mononucleosis that occurs in children with an inherited immunodeficiency called X-linked lymphoproliferative syndrome. The mutated gene encodes a signal transduction protein required for both T-cell & NK cell function.
* Mortality rate 75% by 10yrs
* Bone marrow or cord blood transplants may cure the underlying immunodeficiency

91

Epstein-Barr virus also causes hairy leukoplakia, which is?

* A whitish, non-malignant lesion w/an irregular "hairy" surface on the lateral side of the tongue
* Occurs in immunocompromised (AIDS)

92

Epstein-Barr virus is associated with several cancers

1) Burkitt's lymphoma
2) Some form of Hodgkins lymphoma
3) Nasopharyngeal carcinoma
* The word associated refers to the observation that EBV infections is the initiating event that causes the cells to divide but that event itself doesn't cause a malignancy. It requires additional steps for malignant transformation to occur
* Reduced cell mediated immunity predisposes to the uncontrolled growth of the EBV infected cells

93

Posttransplant lymphoproliferative disorder (PTLD) is another Epstein-Barr associated disease. What is it?

* Most common form of PTLD is a B-cell lymphoma
* Occurs following both bone marrow transplants & solid organ transplants
* Main predisposing factor is immunosupression required to prevent rejection of the graft
* Lymphoma will regress if the degree of immunosupression is reduced

94

The diagnosis of infectious mononucleosis in the clinical laboratory is based on two approaches

1) Hematologic approach: Absolute lymphocytosis, 30% abnormal lymphocytes (atypical, large)
2) Immunologic approach: 2 serologic tests; heterophil antibody test (early diagnosis) & the EBV specific antibody test (difficult cases)

95

Treatment for Epstein-Barr virus

* No antiviral therapy necessary for uncomplicated infectious mononucleosis
* Acyclovir has little activity agains EBV, administration of high doses may be useful in life threatening EBV infections

96

Prevention for Epstein-Barr virus

There is no vaccine

97

Epstein-Barr virus infection is associated with cancers of lymphoid origin they include

1) Burkitt's lymphoma in African children
2) other B-cell lymphomas
3) nasopharyngeal carcinoma in the Chinese population
4) thymic carcinoma in the US.

98

What are the DNA enveloped viruses

1) Herpes simplex virus 1 (HSV-1)
2) Herpes simplex virus 2 (HSV-2)
3) Varicella-zoster virus (VZV)
4) Epstein-Barr virus (EBV)
5) Cytomegalovirus (CMV)
6) Herpes virus 8 (Kaposi's sarcoma associated herpes virus)

99

What does Herpes virus 8 cause?

* May be the cause of Kaposi's sarcoma (KS) the most common cancer in patients with AIDS
* Most KS cells taken from AIDS patients contain the DNA of this virus
* DNA of this virus also found in KS cells arose in non-HIV infected patients
* Most HIV infected patients w/KS had antibodies to HHV-8
* Current estimate of HHV-8 infection in general pop. ranges from 3% in US & England to about 50% in East Africa

100

Herpes virus 8 (HHV-8) causes malignant transformation by a mechanism similar to that of other DNA viruses (human papilloma), namely?

Inactivation of a tumor suppressor gene

101

A protein encoded by Herpes virus 8 (HHV-8) called nuclear antigen inactivates the?

Retinoblastoma (RB) tumor supressor protein, which causes the cells to grow in an uncontrolled manner

102

Transmission of Herpes virus 8 (HHV-8)

* Primarily sexually
* Also transmitted in transplanted organs, such as kidneys, and appears to be cause of transplantation associated KS
* DNA of HHV-8 found in cells of transplantation associated cancers

103

Kaposi's sarcoma (KS) in AIDS patients is a malignancy of vascular endothelial cells that contains many spindle-shaped cells & erythrocytes. Lesions dark purple, flat to nodular, & often appear at multiple sites such as the?

* Skin oral cavity & soles (not palms)
* Internally they appear in GI tract & lungs
* HHV-8 also infects B-cells inducing them to proliferate & produce type of lymphoma called primary effusion lymphoma

104

Type of treatment for Kaposi's sarcoma (KS)

Depends on the site & number of lesions. Surgical excision, radiation, & systemic drugs, such as alpha interferon or vinblastin, can be used.

105

Treatment for Herpes virus 8 (HHV-8)

No antiviral therapy and no vaccine

106

Clinical findings for Herpes virus 8 (HHV-8)

* In upper respiratory tract, adenoviruses cause such infections as pharyngitis, pharyngoconjunctival fever & acute respiratory disease characterized by sore throat, coryza (runny nose), and conjunctivitis
* In lower respiratory tract cause bronchitis & atypical pneumonia
* Hematuria & dysuria prominent in hemorrhagic cystitis
* Gastroenteritis w/non-bloody diarrhea occurs in children younger than 2
* Most adenovirus infections resolve spontaneously (half of all infections asymptomatic)

107

Laboratory diagnosis of Herpes virus 8

Most frequent methods are isolation of virus in cell culture & detection of fourfold or greater rise in antibody titer

108

Prevention for Herpes virus 8

* 3 live, non-attenuated vaccines against serotypes 4,7, & 21 available (not used by military)
* Each one is monovalent (each contains only one serotype)
* Viruses administered separately because they interfere w/each other
* Vaccines delivered in an enteric-coated capsule, which protects the live virus from inactivation by stomach acid
* Virus infects GI tract where it causes an asymptomatic infection & induces immunity to respiratory disease (not available for civilian use)
* Epidemic Keratoconjunctivitis is an iatrogenic disease, preventable by strict asepsis & hand washing by health care personnel who examine eyes

109

What diseases is cause by the human papilloma virus?

* Causes papillomas which are benign tumors of squamous cells (warts on the skin)
* Some HPV types, especially types 16 & 18, cause carcinoma of the cervix & penis

110

Important properties of the human papilloma virus

* Non enveloped w/double stranded circular DNA & an icosahedral nucleocapsid
* 2 early genes (E6 & E7) are implicated in carcinogenesis. They encode proteins that inactivate proteins encoded by tumor suppressor genes in human cells (e.g the p53 gene & retinoblastoma (RB) gene)
* Inactivation of p53 & RB proteins is an important step in the process by which a normal cell becomes a cancer cell
* at least 100 types classified on basis of DNA restriction fragment analysis
* Pronounced predilection of certain types to infect certain tissue (skin warts are caused by HPV-1 through HPC-4, genital warts are caused by HPV-6 & HPV-11)
* Approximately 30 types of HPV infect the genital tract

111

Replicative cycle for human papilloma virus

* Grows poorly, if at all, in cell culture
* Infectious virus particles are found in differentiated squamous tissue rather than basal cells
* Initially infects cells of basal layer but no virus is produced by those cells
* Infectious visions are produced by squamous cells on surface which enhances transmission
* In malignant cells viral DNA is integrated into host DNA in vicinity of cellular proto-oncogenes, & E7 & E6 are over expressed
* In latently infected nonmalignant cells, viral DNA is episomal & E6 & 7 are not over expressed
* There is a difference because an early gene E2 controls E6 & E7 expression, this gene is functional when the viral DNA is episomal & inactivated when its integrated

112

Transmission of human papilloma virus

* By skin to skin & genital contact
* Genital warts most common sexually transmitted diseases
* Skin warts more common in kids & young adults & regress with age
* HPV transmitted from an infected mother to neonate during childbirth causes warts in mouth & respiratory tract
* Many animal species infected with own types of this virus but not source of human infection

113

Papilloma virus infect squamous epithelial cells & induce w/in those cells a characteristic cytoplasmic vacuole. These vacuolated cells (koilocytes), which are the hallmark of infection by these viruses. Most warts are benign and do not progress to malignancy. However HPV infection is associated with?

Carcinoma of the uterine cervix and penis. The proteins encoded by viral genes E6 & E7 interfere w/the growth inhibitory activity of the proteins encoded by the p53 & RB tumor suppressor genes & thereby contribute to oncogenesis by these viruses

114

For the human papilloma virus both cell-mediated immunity & antibody are induced by

Viral infection & are involved in the spontaneous regression of warts. Immunosuppressed patients (AIDS) have more extensive warts, & women infected w/HIV have a very high rate of carcinoma of the cervix

115

Papillomas of various organs are the predominant finding. These papillomas are caused by specific HPV types. For example skin & plantar warts are caused primarily by? Where as genital warts are caused primarily by? HPV-6 & HPV-11 also cause?

Skin & plantar: HPV-1 through HPV-4
Genital warts: HPV-6 and HPV-11 which also cause respiratory tract papillomas, especially pharyngeal papillomas in young children.

116

Carcinoma of the uterine cervix, the penis, and the anus, as well as premalignant lesions called intraepithelial neoplasia are associated with which type of HPV?

HPV 16 & HPV-18 infection

117

Laboratory diagnosis of human papilloma virus

* Infections usually diagnosed clinically
* Presence of koilocytes in the lesions indicates HPV infection

118

Treatment & preventions for human papilloma virus

* Genital warts treatment is podophyllin; alpha interferon is effective & better at preventing recurrences than are non antiviral treatments
* Liquid nitrogen used for skin warts
* Plantar warts removed surgically or treated w/salicyclic acid topically
* Severe HPV infections use cidofovir
* Recombinant vaccine against 4 types of HPV (Gardasil)
* C-section in preventing transmission from mother to baby

119

What does rotavirus cause?

Most common cause of viral gastroenteritis in young children

120

Important properties of rotavirus

* Segmented double stranded RNA genome surrounded by double layered icosahedral capsid w/no envelope
* 11 segments
* Virion contains an RNA-dependent RNA polymerase (required because human cells do not have RNA polymerase that can synthesis mRNA from a double stranded RNA template)
* Many domestic animals are infested w/their own strains of rotavirus (not source of human disease)
* 6 serotypes of human rotavirus
* Outer surface protein is type specific antigen & elicits protective antibody

121

Replicative cycle for rotavirus

* Attaches to cell surface at site of B-adrenergic receptor
* After entry RNA dependent RNA polymerase synthesizes mRNA from each 11 segments w/in cytoplasm
* 11 mRNAs translated to corresponding number of structural & nonstructural proteins
* One of these, an RNA polymerase, synthesizes minus strands that will become part of the genome of its progeny virus
* Capsid proteins form incomplete capsid around minus strand, then plus strands of progeny genome segments are synthesized
*Virus released from cytoplasm by lysis of cell (not budding)

122

Transmission of rotavirus

* Transmitted by fecal-oral route
* Infection occurs worldwide
* By age 6 most children have antibodies to at least one serotype

123

Rotavirus replicates in the?

Mucosal cells in the small intestine, resulting in the excess secretion of fluid & electrolytes into the bowel lumen. The consequent loss of salt, glucose, & water leads to non-bloody diarrhea. No inflammation.

124

The virulence of certain reoviruses (rotavirus) in mice has been localized to the proteins encoded by?

Several specific genome segments. For example one gene governs tissue tropism, whereas another controls the inhibition of cell RNA & protein synthesis

125

Immunity of rotavirus infection is unclear. It is likely that the intestinal IgA directed against specific serotypes protects against?

Reinfection and that colostrum IgA protects newborns up to the age of 6 months

126

Clinical findings for rotavirus

* Rotavirus infection is characterized by nausea, vomiting, and watery non-bloody diarrhea
* Gastroenteritis is most serious in young children in whom dehydration and electrolyte imbalance are a major concern
* Adults usually have minor symptoms

127

Laboratory diagnosis for rotavirus

* Diagnosis can be made by the detection of rotavirus in the stool by using radioimmunoassay or ELISA
* Diagnosis can also be made by observation of a fourfold or greater rise in antibody titer

128

Treatment and prevention for rotavirus

* 2 vaccines available, both contain live virus and given orally.
- one is a live attenuated vaccine (Rotarix), contains the most common rotavirus serotype (G1) causing disease in US
- other live reassortant vaccine (Rotateq), contains 5 Rotavirus strains
* Hygienic measures such as proper sewage disposal & hand washing are helpful
* No anti-viral therapy

129

Describe the Rotateq vaccine for Rotavirus

* The 5 rotaviruses in this vaccine reassortants in which the gene for the outer human surface protein is inserted into a bovine strain of rotavirus (rotavirus has a segmented genome). The bovine strain is non-pathogenic for humans but the human outer surface protein in the vaccine virus elicits protective IgA immunity in the GI tract

130

What disease does norovirus (norwalk) cause?

* Common cause of viral gastroenteritis in adults both in the US and worldwide
* Named for an outbreak gastroenteritis in school in Norwalk OH in 1969

131

Transmission for norovirus

* Fecal-oral route, often involving the ingestion of contaminated seafood or water
* Outbreaks typically occur in group settings (cruise ships, hospitals, schools, camps, and nursing homes)
* Person-person transmission also occurs
* animal caliciviruses, no evidence that they cause human infection
* Infection enhanced by several features of the virus: low infectious dose, excretion of virus in the stool for several weeks after recovery, & resistance to inactivation by chlorination and to drying in the environment
* Thought to remain infectious for several days on environmental surfaces (i.e. door handles)

132

Pathogenesis and immunity for norovirus

* Infection limited to mucosal cells of the intestinal tract
* Watery diarrhea w/out red cells or white cells occurs
* Many asymptomatic infection occurs, as determined by detection of antibodies
* Immunity following infection appears to be brief & reinfection can occur

133

Clinical findings for norovirus

* Characterized by sudden onset of vomiting and diarrhea accompanied by low-grade fever & abdominal cramping
* Neither emesis nor stool contain blood
* Ilness typically lasts several days and no long term sequelae, except in certain immunocompromised patients in whom a prolonged infection can occur
* Some outbreaks certain patients manifests signs of central nervous system involvement such as headache, meningismus, photophobia, & obtundation

134

Laboratory diagnosis for norovirus

* Diagnosis primarily a clinical one
* Polymerase chain reaction (PCR)-based test on the stool is performed when there are public health implications

135

Prevention & treatment for norovirus

* No antiviral therapy or vaccine available
* Dehydration & electrolyte imbalance caused by vomiting and diarrhea may require intravenous fluids
* Personal hygiene, such as handwashing, and public health measures, such as proper sewage disposal are helpful

136

What disease does Rhinovirus cause?

These viruses are the main cause of the common cold

137

Important properties of Rhinovirus

* More than 100 serological types
* Replicate better at 33 degrees C than at 37 degrees C, which explains why they affect the nose & conjunctiva rather than the lower respiratory tract
* Acid-labile so they are killed by gastric acid when swallowed
* Host range limited to humans and chimpanzee

138

Transmission for rhinovirus

There are two modes of transmission for these viruses
1) Transmitted directly from person to person via aerosols of respiratory droplets
2) Indirect mode where respiratory droplets are deposited on the hands or on a surface such as a table then transported by fingers to nose or eyes

139

Epidemiology for rhinovirus

* Common cold most common human infection
* Occurs worldwide, causing disease mostly in fall & winter reason for this is unclear
* Low temps. per se do not predispose to cold, but crowding that occurs at schools for example may enhance transmission during fall & winter
* Frequency high in childhood & tapers off during adulthood
* Few serotypes are prevalent during one season, only to be replaced by other serotypes during following season
* Population builds up immunity to prevalent serotypes but remains susceptible to the others

140

Pathogenesis and immunity for rhinovirus

* Portal of entry upper respiratory tract, infection limited to that region
* Rarely cause lower respiratory tract disease, probably because they grow poorly at 37 degrees C
* Immunity is serotype specific & a function of nasal secretory IgA rather than humoral antibody

141

Clinical findings for rhinovirus

* After incubation period of 2-4 days, sneezing, nasal discharge, sore throat, cough, and headache are common
* Chilly sensation may occur, but few other systemic symptoms
* Lasts about 1 week
* Other viruses cause the common cold symptoms

142

Laboratory diagnosis for rhinovirus

* Diagnosis can be made by isolation of the virus from nasal secretions in cell culture, but rarely attempted
* Serological tests not done

143

Treatment and prevention for rhinovirus

* No specific antiviral therapy available
* Vaccines impractical because of large number of serotypes
* Paper tissues impregnated with a combination of citric acid (which inactivates rhinoviruses) and sodium lauryl sulfate (a detergent that inactivates enveloped viruses such as influenza virus and respiratory syncytial virus) limit transmission when used to remove viruses from fingers contaminated with respiratory secretions.
* High doses of vitamin C have little ability to prevent
rhinovirus-induced colds
* zinc gluconate are available for the treatment of the common cold, but their efficacy remains unproved

144

Influenza pathogens are important human pathogens because?

They cause both outbreaks of influenza that sicken & kill thousands of people each year as well as infrequent but devastating worldwide epidemics (pandemics)

145

Influenza viruses are the only members of the orthomyxovirus family. This family differs from the paramyxovirus family primarily in that?

The former have a segmented RNA genome (usually 8 pieces), whereas the RNA genome of the latter consists of a single piece.
- the orthomyxovirus are smaller than parmyxoviruses

146

What diseases does influenza A, B, and C cause?

Influenza A- Worldwide epidemics (pandemics) of influenza
Influenza B- Major outbreaks of influenza
Influenza C- Mild respiratory tract infections but does not cause outbreaks of influenza

147

When do influenza pandemics occur?

When a variant of influenza A virus, which contains a new hemagglutinin against which people do not have preexisting antibodies, is introduced into the human population

148

How often do influenza pandemics occur?

Pandemics caused by influenza A virus occur infrequently, but major outbreaks caused by this virus occur virtually every year in many countries.

149

Each year influenza is the most common cause of?

Respiratory tract infections that result in physician visits & hospitalization in the US

150

Influenza B virus does not cause pandemics, and the major outbreaks caused by this virus do not?

Occur as often as those caused by influenza A virus. It is estimated that approximately 36,000 die from influenza each year in the US

151

Influenza virus is composed of?

* Segmented single-stranded RNA genome
* Helical nucleocapsid & outer lipoprotein envelope
* Virion contains RNA dependent RNA polymerase which transcribes the negative-polarity genome into mRNA

152

Describe the envelope of influenza

* Covered w/two different types of spikes, a hemagglutinin & a neuraminidase
* Influenza A has 16 antigenically distinct of hemagglutinin (HA) and 9 antigenically distinct types of neuraminidase (NA)

153

What is the function of hemagglutinin in influenza?

To bind to the cell surface receptor to initiate infection of the cell.
-Also the target of neutralizing antibody

154

HSV-1
1) Primary infection
2) Usual site of latency
3) Recurrent infection
4) Route of transmission

1) Primary infection: Gingivostomatitis
2) Usual site of latency: Cranial sensory ganglia
3) Recurrent infection: Herpes labialis (cold sore), keratitis, encephalitis
4) Route of transmission: Via respiratory secretions and saliva

155

HSV-2
1) Primary infection
2) Usual site of latency
3) Recurrent infection
4) Route of transmission

1) Primary infection: Herpes genitalis, perinatal disseminated disease
2) Usual site of latency: Lumbar or sacral sensory ganglia
3) Recurrent infection: Herpes genitalis
4) Route of transmission: Sexual contact, perinatal infection

156

Varicella-zoster virus
1) Primary infection
2) Usual site of latency
3) Recurrent infection
4) Route of transmission

1) Primary infection: Varicella
2) Usual site of latency: Cranial or thoracic sensory ganglia
3) Recurrent infection: Zoster
4) Route of transmission: Via respiratory secretions

157

Epstein-Barr virus
1) Primary infection
2) Usual site of latency
3) Recurrent infection
4) Route of transmission

1) Primary infection: Infectious mononucleosis
2) Usual site of latency: B-lymphocytes
3) Recurrent infection: None
4) Route of transmission: Via respiratory secretions and saliva

158

Cytomegalovirus
1) Primary infection
2) Usual site of latency
3) Recurrent infection
4) Route of transmission

1) Primary infection: Congenital infection (in utero), mononucleosis
2) Usual site of latency: Uncertain
3) Recurrent infection: Asymptomatic shedding
4) Route of transmission: Intrauterine infection, transfusions, sexual contact, via secretions (saliva, urine)

159

HHV-8
1) Primary infection
2) Usual site of latency
3) Recurrent infection
4) Route of transmission

1) Primary infection: Uncertain
2) Usual site of latency: Uncertain
3) Recurrent infection: Kaposi's sarcoma
4) Route of transmission: Sexual or organ transplantation

160

The neuraminidase of influenza cleaves neuromic acid to release progeny virus from infected cell. The hemagglutinin functions at the beginning of infection, whereas the neuraminidase functions at the end. Neuraminidase also degrades?

The protective layer of mucus in the respiratory tract. This enhances the ability of the virus to gain access to the respiratory epithelial cells.

161

Influenza viruses, especially influenza A, show changes in the antigenicity (capacity to induce an immune response) of their hemagglutinin & neuraminidase proteins, this property contributes to their capacity to?
What are the changes?

Cause worldwide epidemics (pandemics).
There are two types of antigenic changes:
1) Antigenic shift: Major change based on the ressortment of segments of the genome RNA
2) Antigenic drift: Minor change based on mutations in genome RNA

162

Influenza A virus has two matrix proteins, explain

1) The M1 matrix protein is located between the internal nucleoprotein and the envelope and provides structural integrity
2) M2 matrix protein which forms an ion channel between the interior of the virus & the external milieu. This ion channel plays an essential role in the uncoating of the virion after it enters the cell. It transports protons into the virion causing the disruption of the envelope which frees the neucleocapsid containing the genome RNA, allowing it to migrate to the nucleus

163

Influenza viruses have both type-specific and group specific antigens

Group specific antigen:
1) The internal ribonucleoprotein which distinguishes influenza A, B, and C virus
Type-specific antigen:
2) Hemagglutinin and the neuraminidase are located on the surface. Antibody against the hemagglutinin neutralizes the infectativity of the virus (and prevents disease), whereas antibody against the group-specific antigen (located internally) does not. Antibody against the neuraminidase does not neutralize infectivitiy but does reduce disease by decreasing the amount of the virus released from infected cell and thus reducing the spread of the virus to adjacent cells

164

An important determinant of the virulence of the influenza virus is a nonstructural protein called NS 1 encoded by the genome RNA of influenza virus. NS 1 has several functions, but the one pertinent to virulence is?

Its ability to inhibit the production of interferon mRNA and as a result innate defenses are reduced and viral virulences is enhanced

165

Many species of animals have their own influenza A viruses. These animal viruses are the source of the?

RNA segments that encode the antigenic shift variants that cause epidemics among humans.
There is evidence that aquatic birds (waterfowl) are a com- mon source of these new genes and that the reassortment event leading to new human strains occurs in pigs. In other words, pigs may serve as the "mixing bowl" within which the human, avian, and swine viruses reassort.

166

There are 16 types of HA (HI to H16) and 9 types of NA (Nl to N9) found in waterfowl. In humans there are?

Three types of HA (HI, H2, and H3) and two types of NA (Nl and N2) predominate.

167

Because influenza B virus is only a human virus, there is no animal source of new RNA segments. Influenza B virus therefore does not undergo antigenic shifts. It does, however, undergo what?

Enough antigenic drift that the current strain must be included in the new version of the influenza vaccine produced each year. Influenza B virus has no antigens in common with influenza A virus.

168

Describe the replicative cycle of the influenza virus

1) The virus adsorbs to the cell when the viral hemagglutinin interacts with sialic acid receptors on the cell surface.
2) The virus then enters the cell in vesicles and uncoats within an endosome. Uncoating is facilitated by the low pH within the endosome.
3) Protons pass through the ion channel formed by the M2 protein into the interior of the virion. This disrupts the virion envelope and frees the nucleocapsid to enter the cytoplasm and then migrate to the nucleus where the genome RNA is transcribed.
4) The virion RNA polymerase transcribes the eight genome segments into eight mRNAs in the nucleus. (happens there because a methylated guanosine "cap" is required)
5) Most of the mRNAs move to the cytoplasm, where they are translated into viral proteins.
6) Some of the viral mRNAs remain in the nucleus, where they serve as the template for the synthesis of the negative-strand RNA genomes for the progeny virions.
7) Replication of the progeny genomes is performed by a different subunit of the viral RNA polymerase (acting as a replicase) from the subunit that functioned earlier as a transcriptase that synthesized the mRNAs.
8) Two newly synthesized proteins, P protein and matrix protein, bind to the progeny RNA genome in the nucleus and that complex is transported to the cytoplasm.

169

Describe the end of the replicative cycle for influenza

The helical ribonucleoprotein assembles in the cytoplasm, matrix protein mediates the interaction of the nucleocapsid with the envelope, and the virion is released from the cell by budding from the outer cell membrane at the site where the hemagglutinin and neuraminidase are located. The neu- raminidase releases the virus by cleaving neuraminic acid on the cell surface at the site of the budding progeny virions. Influenza virus, hepatitis delta virus, and retroviruses are the only RNA viruses that have an important stage of their repli- cation take place in the nucleus.

170

Transmission of influenza virus

The virus is transmitted by airborne respiratory droplets. The ability of influenza A virus to cause epidemics is dependent on antigenic changes in the hemagglutinin and neuraminidase.

171

Pathogenesis of influenza:
After the virus has been inhaled, the neuraminidase degrades the protective mucus layer, allowing the virus to gain access to the cells of the upper and lower respiratory tract. The infection is limited primarily to?

This area because the proteases that cleave the hemagglutinin are located in the respiratory tract.

172

Immunity of influenza depends mainly upon?

Secretory IgA in the res- piratory tract. IgG is also produced but is less protective. Cytotoxic T cells also playa protective role.

173

Clinical findings of influenza virus

* After incubation period of 24-48 hours fever, myalgia, headache, sore throat, & cough develop suddenly
* symptoms usually resolve spontaneously in 4-7 days
* Reye's syndrome life threatening complication in children following some viral infections

174

Clinical findings of influenza virus

* After incubation period of 24-48 hours fever, myalgia, headache, sore throat, & cough develop suddenly
* symptoms usually resolve spontaneously in 4-7 days
* Reye's syndrome life threatening complication in children following some viral infections

175

Influenza treatment

* Oseltamivir & zanamivir (neuraminidase inhibiters) used for treatment and prevention against influenza A and B
* Some resistant strains are known
* Vaccine available

176

Prevention for influenza

* Vaccine which consists of influenza A and B viruses, 2 A strains and one B strain
* A strains H1N1 H3N2
* Vaccine reformulated each year to contain current antigenic strains

177

Prevention for influenza

* Vaccine which consists of influenza A and B viruses, 2 A strains and one B strain
* A strains H1N1 H3N2
* Vaccine reformulated each year to contain current antigenic strains
* 2 types of vaccines available

178

In 1997 the H5N1 strain of influenza A viruses that causes avian influenza caused an?

Aggressive form of human influenza with high mortality in Hong Kong

179

Swine influenza

* Primarily effects young people
* Symptoms are in general mild w/few fatalities occurring in medically compromised patients

180

The measles virus causes what?

Measles, a disease characterized by maculopapular rash. occurs primarily in childhood

181

Important properties of the measles virus

* Virion has 2 types of envelope spikes, one with hemagglutinating activity & the other with cell fusing and hemolytic activities
* Humans natural host

182

Replicative cycle for the measles

1)

183

Replicative cycle for the measles

1) After absorption to the cell surface via its hemagglutinin, the virus penetrates and uncoats and the virion RNA polymerase transcribes the negative-strand genome into mRNA
2) Multiple mRNAs are synthesized, each of which is translated into the specific viral proteins
3) The helical nucleocapsid is assembled, the matrix protein mediates the interaction with the envelope, and the virus is released by budding from the cell membrane

184

How are measles transmitted?

* Measles virus is transmitted via respiratory droplets pro- duced by coughing and sneezing both during the prodromal period and for a few days after the rash appears
* Measles occurs worldwide, usually in outbreaks every 2 to 3 years, when the number of susceptible children reaches a high level
*

185

How are measles transmitted?

* Measles virus is transmitted via respiratory droplets pro- duced by coughing and sneezing both during the prodromal period and for a few days after the rash appears
* Measles occurs worldwide, usually in outbreaks every 2 to 3 years, when the number of susceptible children reaches a high level

186

Epidemiology of the measles

* attack rate is one of the highest of viral diseases
* When this virus is introduced into a population that has not experienced measles, devastating epidemics occur
* In malnourished chil- dren, especially those in developing countries, measles is a much more serious disease than in well-nourished children
* Vitamin A deficiency is especially important in this regard, and supplementation of this vitamin greatly reduces the sever- ity of measles
* Patients with deficient cell-mediated immunity, e.g., AIDS patients, have a severe, life-threatening disease when they contract measles

187

Pathogenesis for the measles

Infects the cells lining the upper respiratory tract, the virus enters the blood and infects reticuloendothelial cells, where it replicates again. It then spreads via the blood to the skin. The rash is caused primarily by cytotoxic T cells attacking the measles virus-infected vascular endothelial cells in the skin. Antibody-mediated vasculitis may also play a role. Shortly after the rash appears, the virus can no longer be recovered and the patient can no longer spread the virus to others. Multinucleated giant cells, which form as a result of the fusion protein in the spikes, are characteristic of the lesions.

188

Life long Immunity for the measles virus

* occurs in individuals who have had the disease. Although IgG antibody may play a role in neutralizing the virus during the viremic stage, cell-mediated immunity is more important. The importance of cell-mediated immunity is illustrated by the fact that agammaglobulinemic children have a normal course of disease, are subsequently immune, and are protected by immunization. Maternal antibody passes the placenta, and infants are protected during the first 6 months of life.

189

Infection with measles virus can transiently depress cell- mediated immunity against other intracellular microorgan- isms, such as Mycobacterium tuberculosis, leading to a loss of PPD skin test reactivity, reactivation of dormant organisms, and clinical disease. The proposed mechanism for this unusual finding is that?

When measles virus binds to its recep- tor (called CD46) on the surface of human macrophages, the production of IL-12, which is necessary for cell-mediated immunity to occur, is suppressed.

190

Infection with measles virus can transiently depress cell- mediated immunity against other intracellular microorgan- isms, such as Mycobacterium tuberculosis, leading to a loss of PPD skin test reactivity, reactivation of dormant organisms, and clinical disease. The proposed mechanism for this unusual finding is that?

When measles virus binds to its recep- tor (called CD46) on the surface of human macrophages, the production of IL-12, which is necessary for cell-mediated immunity to occur, is suppressed.

191

Clinical findings for the measles

* incubation period (10-14 days), then prodromal phase (fever, conjunctivitis (causing photophobia), running nose, & coughing) occurs
* Koplik's spots

192

What are Koplik's spots for the measles virus?

bright red lesions with a white, central dot that are located on the buccal mucosa and are virtually diagnostic.

193

Clinical findings for the measles

* incubation period (10-14 days), then prodromal phase (fever, conjunctivitis (causing photophobia), running nose, & coughing) occurs
* Koplik's spots then turns to maculopapular rash on face and gradually down body to lower extremities (palms and soles) rash develops brownish hue days later

194

Complications of measles

* can be severe
* Encephalitis occurs at a rate of 1 per 1000 cases of measles
* mortality rate of encephalitis is 10%, and there are permanent sequelae (deafness and mental retardation in 40% of cases)
* both primary measles (giant cell) pneumonia and secondary bacterial pneumonia occur
* Bacterial otitis media is quite common. Subacute sclerosing panencephalitis (SSPE) is a rare, fatal disease of the central nervous system that occurs several years after measles

195

Complications of measles

* can be severe
* Encephalitis occurs at a rate of 1 per 1000 cases of measles
* mortality rate of encephalitis is 10%, and there are permanent sequelae (deafness and mental retardation in 40% of cases)
* both primary measles (giant cell) pneumonia and secondary bacterial pneumonia occur
* Bacterial otitis media is quite common. Subacute sclerosing panencephalitis (SSPE) is a rare, fatal disease of the central nervous system that occurs several years after measles

196

Measles in a pregnant woman leads to an?

increased risk of stillbirth rather than congenital abnormalities. Measles virus infection of the fetus is more severe than rubella virus infection, so the former typically causes fetal death, whereas the latter causes congenital abnormalities.

197

Atypical measles occurs in some people who were given the killed vaccine and were subsequently infected with measles virus. It is characterized by an?

Aatypical rash without Koplik's spots. Because the killed vaccine has not been used for many years, atypical measles occurs only in adults and is infrequent.

198

Treatment for measles

There is no antiviral therapy available.

199

Prevention for measles

* Immunization with the live, attenuated vaccine. The vaccine is effective and causes few side effects
* given subcutaneously to children at 15 months in combination with rubella and mumps. vaccine should not be given to children prior to 15 months because maternal antibody in the child can neutralize the virus and reduce the immune response. Because immunity can wane, a booster dose is recommended.
* The vaccine contains live virus, so don't give to immunocompromised persons/pregnant women.
* The vaccine has decreased the number of cases of measles in US
* outbreaks still occur among unimmunized individuals, e.g., children in inner cities and in developing countries.
* killed vaccine should not be used.
* Immune globulin can be used to modify the disease if given to unimmunized individuals early in the incubation period, especially if unimmunized individuals are immunocompromised

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What disease does the mumps virus cause?

This virus causes mumps, characterized by parotid gland swelling. Occurs primarily in childhood

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Important properties of the mumps

* genome RNA and nucleocapsid are those of a typical paramyxovirus.
* virion has two types of envelope spikes: one with both hemagglutinin and neuraminidase activities and the other with cell-fusing and hemolytic activities
* single serotype
* Neutralizing antibody is directed against the hemagglutinin
* The internal nucleocapsid protein is the S (soluble) antigen detected in the complement fixation test used for diagnosis
* Humans are host

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Replication cycle for the mumps

Same as the measles virus

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Transmission & Epidemiology for the mumps virus

* transmitted via respiratory droplets
* occurs worldwide, with peak incidence in winter
* About 30% of children have a subclinical (inapparent) infection, which confers immunity.
* There were only 683 reported cases of mumps in the United States in 1997- a finding attributed to the widespread use of the vaccine. However, in 2006, a resurgence of mumps occurred with 6584 cases being recorded despite a high (87%) coverage rate for the vaccine.

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Pathogenesis for the mumps

1) infects the upper respiratory tract and then spreads through the blood to infect the parotid glands, testes, ovaries, pancreas, and, in some cases, meninges.
2) Alternatively, the virus may ascend from the buccal mucosa up Stensen's duct to the parotid gland

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Immunity for the mumps

* Lifelong immunity occurs in persons who have had the disease
* misconception that unilateral mumps can be followed by mumps on the other side. Mumps occurs only once; subsequent cases of parotitis can be caused by other viruses such as parainfluenza viruses, by bacteria, and by duct stones.
* Maternal antibody passes the placenta and provides protection during the first 6 months of life

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Clinical findings for mumps

* incubation period (18-21 days), a prodromal stage of fever, malaise, and anorexia followed by tender swelling of the parotid glands, either unilateral or bilateral.
* characteristic increase in parotid pain when drinking citrus juices.
* disease typically benign and resolves spontaneously within 1 week.

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Complications of the mumps

Two complications are of significance:
1) orchitis in post pubertal males: if bilateral, can result in sterility. Postpubertal males have a fibrous tunica albuginea, which resists expansion, thereby causing pressure necrosis of spermatocytes. Unilateral orchitis does not lead to sterility
2) meningitis: usually benign, self-limited, and without sequelae. Mumps virus, Coxsackie virus, and echovirus are the three most frequent causes of viral (aseptic) meningitis. --The widespread use of the vaccine in the United States has led to a marked decrease in the incidence of mumps meningitis.

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Complications of the mumps

Two complications are of significance:
1) orchitis in post pubertal males: if bilateral, can result in sterility. Postpubertal males have a fibrous tunica albuginea, which resists expansion, thereby causing pressure necrosis of spermatocytes. Unilateral orchitis does not lead to sterility
2) meningitis: usually benign, self-limited, and without sequelae. Mumps virus, Coxsackie virus, and echovirus are the three most frequent causes of viral (aseptic) meningitis. --The widespread use of the vaccine in the United States has led to a marked decrease in the incidence of mumps meningitis.

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Treatment for mumps

There is no antiviral therapy for mumps.

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Prevention for mumps

* immunization with the live, attenuated vaccine
* vaccine effective and long-lasting (at least 10 years) causes few side effects
* Two immunizations recommended: one at 15 months and booster dose @ 4 to 6 yrs in combination with measles and rubella vaccines.
* Because live vaccine don't give to immunocompromised persons/pregnant women.
* Immune globulin is not useful for preventing or mitigating mumps orchitis

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In the late 1980s, outbreaks of mumps occurred in both immunized and unimmunized people. This led to the recommendation in 1989 that?

a second course of MMR (measles, mumps, rubella) vaccine be administered. The incidence of mumps fell and outbreaks did not occur until 2006 when 6584 cases occurred, primarily in college-age individuals who had received two doses of the vaccine. Waning immunity after the second dose and immunization with a different genotype from the genotype that caused the outbreak are explanations.

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The paramyxovirus family contains four important human pathogens: measles virus, mumps virus, respiratory syncytial virus (RSV), and parainfluenza viruses

* composed of one piece of single- stranded RNA
*helical nucleocapsid, and an outer lipoprotein envelope
* virion contains RNA-dependent RNA polymerase, which transcribes the negative-polarity genome into mRNA. The genome therefore not infectious
* The envelope is covered with spikes, which contain hemagglutinin, neuraminidase, or a fusion protein that causes cell fusion and, in some cases, hemolysis

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What disease does rubella cause?

causes Rubella (German measles) and congenital rubella syndrome. Congenital rubella syndrome is characterized by congenital malformations.

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Important properties of rubella virus

* member of toga virus family
* composed of one piece single-stranded RNA, an icosahedral nucleocapsid, and a lipoprotein envelope. * unlike paramyxoviruses (measles & mumps) it has a positive-strand RNA therefore has no virion polymerase.
* surface spikes contain hemagglutinin
* single antigenic type. Antibody against hemagglutinin neutralizes infectivity
* Humans are the natural host

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Replicative cycle of rubella

1)

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Replicative cycle of rubella

replication is incomplete, the following cycle is based on the replication of other toga viruses
1) After penetration of the cell and uncoating, the plus-strand RNA genome is translated into several nonstructural and structural proteins. One of the nonstructural proteins is an RNA-dependent RNA polymerase, which replicates the genome first by making a minus-strand template and then, from that, plus-strand progeny.
2) Both replication and assembly occur in the cytoplasm, and the envelope is acquired from the outer membrane as the virion exits the cell.

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Transmission & Epidemiology for rubella virus

* transmitted via respiratory droplets and from mother to fetus transplacentally
* disease occurs worldwide. In areas where the vaccine is not used, epidemics occur every 6 to 9 years.

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Epidemiology for rubella virus

* In 2005, the Centers for Disease Control and Prevention (CDC) declared rubella eliminated from the United States.
* The few cases that occurred in the United States were acquired outside and imported into this country. Elimination was made possible by the widespread use of the vaccine. As a result, cytomegalovirus is a much more common cause of congenital malformations in the United States than is rubella virus.

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Pathogenesis for rubella

Initial replication of the virus occurs in the nasopharynx and local lymph nodes. From there it spreads via the blood to the internal organs and skin. The origin of the rash is unclear; it may be due to antigen/antibody-mediated vasculitis.

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Immunity for rubella

Natural infection leads to lifelong immunity. Second cases of rubella do not occur; similar rashes are caused by other viruses, such as Coxsackie viruses and echoviruses. Antibody crosses the placenta and protects the newborn.

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Clinical findings for rubella

1) milder, shorter disease than measles
2) After 14-21 day incubation period a brief prodromal period with fever and malaise is followed by a maculopapular rash, which starts on the face and progresses downward to involve the extremities.
3) Posterior auricular lymphadenopathy is characteristic
4) rash typically lasts 3 days
5) When rubella occurs in adults, especially women, polyarthritis caused by immune complexes often occurs.

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What is congenital rubella syndrome?

significance of rubella virus is not as a cause of mild childhood disease but as a teratogen. When a nonimmune pregnant woman is infected during the first trimester, significant congenital malformations can occur as a result of maternal viremia and fetal infection. The increased rate of abnormalities during the early weeks of pregnancy is attributed to the very sensitive organ development that occurs at that time. The malformations are widespread and involve primarily the heart (e.g., patent ductus arteriosus), the eyes (e.g., cataracts), and the brain (e.g., deafness and mental retardation)

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What is congenital rubella syndrome?

1) significance of rubella virus is not as a cause of mild childhood disease but as a teratogen. When a nonimmune pregnant woman is infected during the first trimester, significant congenital malformations can occur as a result of maternal viremia and fetal infection. The increased rate of abnormalities during the early weeks of pregnancy is attributed to the very sensitive organ development that occurs at that time. The malformations are widespread and involve primarily the heart (e.g., patent ductus arteriosus), the eyes (e.g., cataracts), and the brain (e.g., deafness and mental retardation)
2) some children infected in utero can continue to excrete rubella virus for months following birth, which is a significant public health hazard because the virus can be transmitted to pregnant women. Some congenital shedders are asymptomatic and without malformations and hence can be diagnosed only if virus is isolated. Congenitally infected infants also have significant IgM titers and persistent IgG titers long after maternal antibody has disappeared

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Treatment for rubella

No antiviral therapy

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Prevention for rubella

* immunization with live, attenuated vaccine. effective and long-lasting (at least 10 years) and few side effects, except for transient arthralgias in some women. given subcutaneously to children at 15 months (usually in combination with measles and mumps vaccine) and to unimmunized young adult women if not pregnant and will use contraception for the next 3 months. There is no evidence that the vaccine virus causes malformations.
* Because it is a live vaccine, it should not be given to immunocompromised patients/pregnant women
* vaccine has caused significant reduction in incidence of rubella and congenital rubella syndrome. induces some respiratory IgA interrupting spread of virulent virus by nasal carriage.
*Immune serum globulins (IG) given to pregnant women first trimester, who have been exposed to case of rubella and for whom termination of the pregnancy is not an option.

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Prevention for rubella

* live, attenuated vaccine. effective long-lasting (at least 10 years) few side effects, except for transient arthralgias in some women. given subcutaneously to children at 15 months (usually in combination with measles and mumps vaccine) and to unimmunized young adult women if not pregnant and will use contraception for the next 3 months. There is no evidence that the vaccine virus causes malformations.
* Because it is a live vaccine, it should not be given to immunocompromised patients/pregnant women
* vaccine has caused significant reduction in incidence of rubella and congenital rubella syndrome. induces some respiratory IgA interrupting spread of virulent virus by nasal carriage.
*Immune serum globulins (IG) given to pregnant women first trimester, who have been exposed to case of rubella and for whom termination of the pregnancy is not an option.
*To protect pregnant women from exposure to rubella virus, many hospitals require their personnel to demonstrate immunity