Viruses
Viruses
• Cause many infections of humans, animals,
plants, and bacteria
• Cannot carry out any metabolic pathway
• Neither grow nor respond to the environment
• Cannot reproduce independently
• Obligate intracellular parasites
Characteristics of Viruses
• Cause most diseases that plague industrialized
world
• Virus – miniscule, acellular, infectious agent
having one or several pieces of either DNA or
RNA
• No cytoplasmic membrane, cytosol, or
organelles
• Have extracellular and intracellular state
Characteristics of Viruses
• Extracellular state
–
–
–
–
–
Called virion
Protein coat (capsid) surrounding nucleic acid
Nucleic acid and capsid also called nucleocapsid
Some have phospholipid envelope
Outermost layer provides protection and recognition sites for
host cells
Characteristics of Viruses
• Intracellular state
– Capsid removed
– Virus exists as nucleic acid
•
•
•
•
•
•
How Viruses Are Distinguished
Type of genetic material they contain
Kinds of cells they attack
Size of virus
Nature of capsid coat
Shape of virus
Presence or absence of envelope
Sizes of Viruses
Figure 13.4
Genetic Material of Viruses
• Show more variety in nature of their genomes
than do cells
• May be DNA or RNA; never both
• Primary way scientists categorize and classify
viruses
• Can be dsDNA, ssDNA, dsRNA, ssRNA
• May be linear and composed of several
segments or single and circular
• Much smaller than genomes of cells
Hosts of Viruses
• Most only infect particular kinds of host’s cells
– Due to affinity of viral surface proteins or
glycoproteins for complementary proteins or
glycoproteins on host cell surface
• May only infect particular kind of cell in host
• Generalists – infect many kinds of cells in many
different hosts
Capsid Morphology
• Capsids – protein coats that provide protection for viral
nucleic acid and means of attachment to host’s cells
• Capsid composed of proteinaceous subunits called
capsomeres
• Come capsids composed of single type of capsomere;
other composed of multiple types
The Viral Envelope
• Acquired from host cell during viral replication
or release; envelope is portion of membrane
system of host
• Composed of phospholipid bilayer and proteins;
some proteins are virally-coded glycoproteins
(spikes)
• Envelope’s proteins and glycoproteins often play
role in host recognition
Viral Replication
• Dependent on host’s organelles and enzymes to
produce new virions
• Replication cycle may or may not result in death
of host cell
• Stages of lytic replication cycle
– Attachment
– Entry
– Synthesis
– Assembly
– Release
Attachment of Animal Viruses
• Chemical attraction
• Animal viruses do not have tails or tail fibers
• Have glycoprotein spikes or other attachment
molecules that mediate attachment
Attachment
14
Entry/Penetration
15
Entry/Penetration
Synthesis of Animal Viruses
• Each type of animal virus requires different
strategy depending on its nucleic acid
• Must consider
– How mRNA is synthesized?
– What serves as template for nucleic acid
replication?
Genome Replication and Protein
Synthesis
Figure 13.13
Assembly and Release of Animal
Viruses
• Most DNA viruses assemble in and are released from
nucleus into cytosol
• Most RNA viruses develop solely in cytoplasm
• Number of viruses produced and released depends on
type of virus and size and initial health of host cell
• Enveloped viruses cause persistent infections
• Naked viruses released by exocytosis or may cause lysis
and death of host cell
Release
Enveloped and Naked
• Lysis
• Exocytosis
20
Release
–Enveloped
• Budding
Latency of Animal Viruses
• When animal viruses remain dormant in host
cells
• May be prolonged for years with no viral activity,
signs, or symptoms
• Some latent viruses do not become
incorporated into host chromosome
• When provirus is incorporated into host DNA,
condition is permanent; becomes permanent
physical part of host’s chromosome
The Role of Viruses in Cancer
• Normally, animal’s genes dictate that some cells
can no longer divide and those that can divide
are prevented from unlimited division
• Genes for cell division “turned off” or genes that
inhibit division “turned on”
• Neoplasia – uncontrolled cell division in
multicellular animal; mass of neoplastic cells is
tumor
• Benign vs. malignant tumors
– Metastasis
– Cancers
How Viruses Cause Cancer
• Some carry copies of oncogenes as part of their
genomes
• Some stimulate oncogenes already present in host
• Some interfere with tumor repression when they insert
into host’s repressor gene
• Several DNA and RNA viruses are known to cause ~15%
of human cancers
–
–
–
–
Burkitt’s lymphoma
Hodgkin’s disease
Kaposi’s sarcoma
Cervical cancer
Oncogene Theory
Figure 13.15
Culturing Viruses in the Laboratory
• In Whole Organisms
– Bacteria
– Plants and Animals
• Embryonated Chicken Eggs
• In Cell (Tissue Culture)
Culturing Viruses in Embryonated Chicken Eggs
Figure 13.17
Culturing Viruses in Cell (Tissue)
Culture
Figure 13.18
Characteristics of Prions
• Proteinaceous infectious agents
• Composed of single protein PrP
• All mammals contain gene that codes for primary
sequence of amino acids in PrP
• Two stable tertiary structures of PrP
– Normal functional structure with α-helices called cellular PrP
– Disease-causing form with β-sheets called prion PrP
• Prion PrP converts cellular protein into prion PrP by
inducing conformational change
Tertiary Structures of PrP
Figure 13.21
Prion Diseases
• All involve fatal neurological degeneration,
deposition of fibrils in brain, and loss of brain
matter
• Large vacuoles form in brain; characteristic
spongy appearance
• Spongiform encephalopathies – BSE, CJD, kuru
• Only destroyed by incineration; not cooking or
sterilization
DNA Viruses
– Classified based on the type of DNA they contain,
the presence or absence of an envelope, size, and
the host cells they attack
• Contain either double-stranded DNA (dsDNA) or
single-stranded DNA (ssDNA) for their genome
•
Double-stranded DNA viruses
– Poxviridae, Herpesviridae, Papillomaviridae,
Polyomaviridae, and Adenoviridae
Poxviridae
•
•
•
•
•
Double-stranded DNA viruses
Have complex capsids and envelopes
Largest viruses
Infect many mammals
Most animal poxviruses are species specific
– Unable to infect humans because they cannot attach
to human cells
• Infection occurs primarily through the inhalation
of viruses
• Close contact is necessary for infection by
poxviruses
Poxviridae
• Smallpox and molluscum contagiosum are the
two main poxvirus diseases of humans
• Some diseases of animals can be transmitted to
humans
• All poxviruses produce lesions that progress
through a series of stages
Figure 24.2
Smallpox
• In the genus Orthopoxvirus
• Commonly known as variola
• Exists in two forms
– Variola major causes sever disease that can result in
death
– Variola minor causes a less severe disease with a
much lower mortality rate
• Both forms infect internal organs and then move
to the skin where they produce pox
• Scars result on the skin, especially on the face
Smallpox
• There are a number of factors that allowed
eradication of smallpox
– Inexpensive, stable, and effective vaccine
– No animal reservoirs
– Obvious symptoms allow for quick diagnosis and
quarantine
– Lack of asymptomatic cases
– Virus is only spread via close contact
Smallpox as a Bioweapon
•
•
•
•
•
•
can be produced in large quantities
stable for storage and transport
stable in aerosolized form (up to 2 days)
high mortality
highly infectious (person-to-person spread)
most of the world has little to no immunity
Therapy/Prevention of Smallpox
• Vaccination
– vaccination stopped in 1979 (1972 in U.S.)
• last case in U.S. 1949
• 2 million deaths Worldwide in 1967
– Vaccinia virus
• leaves scar
• Supportive therapy – no effective antiviral
once infected
Molluscum Contagiosum
• Caused by Molluscipoxvirus
• Spread by contact among infected children
• Sexually active adults can sometimes contract a genital
form of the disease
• Skin disease characterized by smooth, waxy, tumorlike
nodules on the face, trunk, and limbs
• Virus produces a weak immune response
• Causes neighboring cells to divide rapidly thus acting
like a tumor-causing virus
Other Poxvirus Infections
• Poxvirus infections also occur in animals
• Transmission of these poxviruses to humans
require close contact with infected animals
• Infections of humans are usually mild
• Can result in pox and scars but little other
damage
• Cowpox was used by Edward Jenner to
immunize individuals against smallpox
Papillomavirus Infections
• Causes papillomas, commonly known as warts
– Benign growths of the epithelium of the skin or
mucous membranes
• Papillomas form on many body surfaces
• Often painful and unsightly
• Genital warts are associated with an increased
risk of cancer
Epidemiology and Pathogenesis of
Papillomavirus Infections
• Transmitted via direct contact and via fomites
• autoinoculation
• Viruses that cause genital warts invade the skin
and mucous membranes during sexual
intercourse
• Genital warts are a common sexually
transmitted disease
Diagnosis, Treatment, and Prevention
• Diagnosis
– Usually based on observation of the papillomas
– Diagnosis of cancers results from inspection of the
genitalia and by a PAP smear in women
• Treatment
– Some warts can be removed through various
methods
– Treatment of cancers involves radiation and chemical
therapy
Diagnosis, Treatment, and Prevention
• Prevention
– Prevention of most types of warts is difficult
– Genital warts can be prevented by abstinence and
perhaps safe sex
HPV vaccine
• 2006 - Advisory committee on immunization
practices (ACIP) recommended the HPV vaccine
– recommended for girls/women 9-26 yrs old
• before sexual contact
• recommended at 11-12 years of age
– vaccine (Gardasil) protects against 4 HPV strains (HPV
6, 11, 16, and 18)
Adenoviridae
• One of the causative agents of the common cold
• Spread via respiratory droplets
• Respiratory infections
– Viruses are taken into cells lining the respiratory
tract via endocytosis
– Symptoms include sneezing, sore throat, cough,
headache, and malaise
Adenoviridae
• Infection of the intestinal tract can produce
mild diarrhea
• Infection of the conjunctiva can result in
pinkeye
Adenovirus pathology
• diarrhea in children
• respiratory infection in children and adults
– military recruits
•
•
•
•
close contact
physical activities (deep inhalation of virus into lungs)
stress
after infection, see immunity
Herpesviridae
• Viruses attach to a host cell’s receptor and enter
the cell through the fusion of its envelope with
the cell membrane
• Herpesviruses can have latency
– They may remain inactive inside infected cells
– Viruses may reactivate causing a recurrence of
manifestations of the disease
Herpesviridae
• Herpesviruses include various genera
– Simplexvirus, Varicellovirus, Lymphocryptovirus,
Cytomegalovirus, Roseolovirus
• Herpesviruses are also designated by “HHV” (for
“human herpesvirus”) and a number indicating
the order in which they were discovered
“Newer” nomenclature of the
Herpesviridae
•
•
•
•
•
•
•
•
HHV1 = HSV1
HHV2 = HSV2
HHV3 = VZV
HHV4 = EBV
HHV5 = CMV
HHV6 = roseola infantum (major cause)
HHV7 = roseola infantum (minor cause)
HHV8 = KS
52
Herpes Simplex Infections
• Often result in slowly spreading skin lesions
• Viruses of this genus are commonly known as
herpes simplex virus or HSV
• 2 species of herpes simplex
– Herpes simplex virus type 1 (HSV-1)
– Herpes simplex virus type 2 (HSV-2)
Epidemiology and Pathogenesis of HSV
Infections
• Active lesions are the usual source of infection
• Aysmptomatic carriers can shed HSV-2 genitally
• Transmission of the viruses occurs through close bodily
contact
• Viruses enter the body through cracks or cuts in
mucous membranes
• Skin lesions result from inflammation and cell death at
the site of infection
• Herpes virions can spread from cell to cell through the
formation of syncytia
Epidemiology and Pathogenesis of
HSV Infections
• HSV-1 infections typically occur via casual
contact in children
• HSV-2 infections are acquired between the ages
of 15 and 29 from sexual activity
• Herpes infections often result in the recurrence
of lesions
• Up to two-thirds of patients experience
recurrences due to activation of the latent virus
Figure 24.5
Diagnosis, Treatment, and Prevention
• Diagnosis
– Characteristic lesions, especially in the genital region
and on the lips, is often diagnostic
Diagnosis, Treatment, and Prevention
– HSV infections are among the few viral diseases that
can be controlled with chemotherapeutic agents
– Topical applications of the drugs limit the duration of
the lesions and reduce viral shedding
– The drugs don’t cure the diseases or free nerve cells
of latent viral infections
Varicella-Zoster Virus Infections
• Commonly referred to as VZV
• Causes two diseases
– Varicella
• Often called chicken pox
• Typically occurs in children
– Herpes zoster
• Also called shingles
• Usually occurs in adults
Epidemiology and Pathogenesis of VZV
Infections
• Chickenpox is a highly infectious disease
seen most often in children
• Viruses enter the skin through the
respiratory tract and the eyes
• Virus replicate at the site of infection then
travel via the blood throughout the body
• Chickenpox in adults is typically more
severe than the childhood illness
Epidemiology and Pathogenesis of
VZV Infections
• Latent virus can reactivate producing a rash
known as shingles
• The rash is characteristic for its localization
along a dermatome - dorsal roots from the
spine
Figure 24.10
Epstein-Barr Virus Infections
• Also referred to as EBV or HHV-4
• Can cause a number of different diseases
Epidemiology and Pathogenesis of EBV
Infections
• Transmission of EBV usually occurs via saliva
• Virions initially infect the epithelial cells of the
pharynx and parotid salivary glands
• The virus then enters the bloodstream where it
invades the B lymphocytes
Epidemiology and Pathogenesis of EBV
Infections
• The viruses become latent in B cells and
immortalize them by suppressing apoptosis
• Symptoms of infectious mononucleosis arise
from the immune response
– Cytotoxic T cells kill virus infected B
lymphocytes
Epidemiology and Pathogenesis of EBV
Infections
• Cancer development appears to depend in part
on various cofactors
• Extreme diseases arise in individuals with T cell
deficiency
– Such individuals are susceptible because infected
cells are not removed by cytotoxic T cells allowing
the virus to proliferate
Cytomegalovirus
• Also referred to as CMV
• Cells infected with this virus become enlarged
• CMV infections is one of the more common
infections of humans
Cytomegalovirus
• Transmission occurs through bodily secretions
– Requires close contact and a large exchange of
secretion
– Usually occurs via sexual intercourse
– Also transmitted by in utero exposure, vaginal birth,
blood transfusions, and organ transplants
• Most CMV infections are asymptomatic
Cytomegalovirus
• Fetuses, newborns, and immunodeficient
patients can develop complications
– CMV can cause birth defects and may result in death
– AIDS patients or other immunocompromised adults
may develop pneumonia, blindness, or
cytomegalovirus mononucleosis, which is similar to
infectious mononucleosis
• CMV causes infectious mononucleosis (second
to EBV)
Other Herpesvirus Infections
• Human herpesvirus 6 (HHV-6)
– In the genus Roseolovirus
– Causes roseola which is characterized by a pink rash
on the face, neck, trunk, and thighs
– Linked to multiple sclerosis by some researchers
– Can cause mononucleosis-like symptoms
– Infection with HHV-6 may make individuals more
susceptible to AIDS
Other Herpesvirus Infections
• Human herpesvirus 8 (HHV-8)
– Associated with Kaposi’s sarcoma, a cancer seen in
AIDS patients
– The virus is not found in cancer-free patients or in
normal tissues of victims
RNA Viruses
• Positive RNA acts like mRNA and can be used by
a ribosome to translate protein
• Negative RNA must first be transcribed as mRNA
to be processed by a ribosome
• RNA viruses are categorized by their genomic
structure, the presence of an envelope, and the
size and shape of their capsid
Picornaviridae
• Enteroviruses
– Polio
– Hepatitis A
• Rhinovirus
73
Enteroviruses
• Found
– in respiratory secretions
– stool of an infected person
– Parents, teachers, and child care center workers
may also become infected by contamination of
the hands with stool from an infected infant or
toddler during diaper changes.
Poliomyelitis
• First described by Michael Underwood in
1789
• First outbreak described in U.S.
in 1843
• 21,000 paralytic cases reported in the U. S.
in 1952
• Global eradication in near future
Poliovirus
•
•
•
•
Enterovirus (RNA)
Three serotypes: 1, 2, 3
Minimal immunity between serotypes
Rapidly inactivated by heat, formaldehyde,
chlorine, ultraviolet light
• Most poliovirus infections are asymptomatic
Poliomyelitis Pathogenesis
• Fecal oral entry
• Replication in pharynx, GI tract,
local lymphatics
• Hematologic spread to lymphatics and central
nervous system
• Viral spread along nerve fibers
• Destruction of motor neurons
Poliomyelitis—United States, 1950-2007
25000
Inactivated vaccine
Cases
20000
15000
10000
Live oral vaccine
Last indigenous case
5000
0
1950
1960
1970
1980
1990
2000
Comparison of Polio Vaccines
Table 25.2
Polio Vaccination Recommendations
• Exclusive use of IPV recommended in 2000
• OPV no longer routinely available in the
United States
Schedules that Include
Both IPV and OPV
• Only IPV is available in the
United States
• Schedule begun with OPV should be
completed with IPV
• Any combination of 4 doses of IPV and OPV
by 5 years constitutes a complete series
Polio Vaccine Adverse Reactions
• Rare local reactions (IPV)
• No serious reactions to IPV have been
documented
• Paralytic poliomyelitis (OPV)
Hepatitis A
•
•
•
•
Epidemic jaundice described by Hippocrates
Differentiated from hepatitis B in 1940s
Serologic tests developed in 1970s
Vaccines licensed in 1995 and 1996
Hepatitis A Virus
•
•
•
•
Picornavirus (RNA)
Humans are only natural host
Stable at low pH
Inactivated by high temperature (185°F or
higher), formalin, chlorine
Hepatitis A Pathogenesis
• Fecal oral entry
• Viral replication in the liver
• Virus present in blood and feces 10-12 days
after infection
• Virus excretion may continue for up to 3
weeks after onset of symptoms
Hepatitis A - United States, 1966-2007
70000
Vaccine
Licensed
60000
Cases
50000
40000
30000
20000
10000
0
1966
1970
1975
1980
1985
Year
1990
1995
2000
2005
Hepatitis A Vaccines
• Inactivated whole virus vaccines
• Pediatric and adult formulations
– Pediatric formulations vaccines approved for
persons 12 months through 18 years
– Adult formulations approved for persons 19 years
and older
Hepatitis A Postexposure Prophylaxis
• For healthy persons 12 months through 40
years of age:
– single-antigen hepatitis A vaccine should be
administered as soon as possible after exposure
• For persons older than 40 years:
– immune globulin is preferred
– vaccine can be used if IG cannot be obtained
MMWR 2007;56(No.41):1080-4
Rhinovirus
• Cause most cases of the common cold
• Infections are limited to the upper respiratory
tract
• A single virus is often sufficient to cause a cold
• The virus can be spread through aerosols, via
fomites, or via hand-to-hand contact
Rhinovirus
• Direct person-to-person contact is the most
common means of transmission
• Individuals can acquire some immunity against
serotypes that have infected them in the past
– As a result, the number of infections tends to
decrease with age
Diseases of Coronaviruses
• Named due to the corona-like halo formed by
their envelopes
• Transmitted via large droplets from the upper
respiratory tract
• Second most common cause of colds
• Can cause gastroenteritis in children
• Diseases are mild
• No treatment or vaccine is available
0
Diarrhea
Nausea &
Vomiting
Running
nose
Sore throat
Sputum
Dizziness
Headache
Cough
Myalgia
Chills & Rigor
Fever
% of patients
Common Symptoms
100
90
80
70
60
50
40
30
20
10
Introduction to
the Norwalk Virus
 Norwalk – genus name for original
Norwalk virus and other Norwalk-like
viruses. Family Calicivirus.
 Calicivirae found worldwide, infecting
humans, primates, and cattle, among
others.
 Increasingly being recognized as leading
cause of food borne illness.
History
Virus first identified in Norwalk, Ohio, 1973.
 Noted to commonly be a problem on cruise
ships.
Associated with contaminated food or water
supplies.
Infection
Noroviruses found in stool and vomit of
infected.
Very contagious – infection via eating
contaminated food, contact with sick
individual or contaminated surfaces.
Symptoms
Acute gastroenteritis.
Illness begins suddenly, from 12-48 hours after
ingestion. Brief illness period.
Very young, elderly, and those with weakened
immune systems may experience more severe
symptoms.
Infectiousness may last up to 2 weeks, no
evidence of long-term carriers.
Measles
• One of five classical childhood diseases
• Spread in the air via respiratory droplets
• Viral spread requires large, dense populations of
people
• Viruses infect the respiratory tract and then
spread throughout the body
Measles
• Characteristic lesions called Koplik’s spots
appear on the mucous membrane of the mouth
• Lesions then appear on the head and spread
over the body
Measles
• Highly contagious viral illness
• First described in 7th century
• Near universal infection of childhood in
prevaccination era
• Common and often fatal in developing areas
Measles Virus
•
•
•
•
Paramyxovirus (RNA)
Hemagglutinin important surface antigen
One antigenic type
Rapidly inactivated by heat and light
Measles Pathogenesis
• Respiratory transmission of virus
• Replication in nasopharynx and regional
lymph nodes
• Primary viremia 2-3 days after exposure
• Secondary viremia 5-7 days after exposure
with spread to tissues
Measles Clinical Features
• Incubation period 10-12 days
• Prodrome
– Stepwise increase in fever to
103°F or higher
– Cough, coryza, conjunctivitis
– Koplik spots (rash on mucous membranes)
Coryza = Head cold
Measles Clinical Features
• Rash
– 2-4 days after prodrome, 14 days after exposure
– Maculopapular, becomes confluent
– Begins on face and head
– Persists 5-6 days
– Fades in order of appearance
Measles Complications
Condition
Diarrhea
Otitis media
Pneumonia
Encephalitis
Hospitalization
Percent reported
8
7
6
0.1
18
0.2
Death
Based on 1985-1992 surveillance data
Measles Laboratory Diagnosis
• Isolation of measles virus from a clinical
specimen (e.g., nasopharynx, urine)
• Significant rise in measles IgG by any standard
serologic assay (e.g., EIA, HA)
• Positive serologic test for measles IgM
antibody
Measles - United States, 1950-2007
Cases (thousands)
900
800
700
Vaccine Licensed
600
500
400
300
200
100
0
1950
1960
1970
1980
1990
2000
Measles Mumps Rubella Vaccine
• 12 months is the recommended and
minimum age
• MMR given before 12 months should not be
counted as a valid dose
• Revaccinate at 12 months of age or older
Adults at Increased Risk of Measles
• College students
• International travelers
• Healthcare personnel
– All persons who work in medical facilities
should be immune to measles
Mumps
• Acute viral illness
• Parotitis and orchitis described by Hippocrates
in 5th century BCE
• Viral etiology described by Johnson and
Goodpasture in 1934
• Frequent cause of outbreaks among military
personnel in prevaccine era
Mumps Virus
•
•
•
•
Paramyxovirus
RNA virus
One antigenic type
Rapidly inactivated by chemical agents, heat,
and ultraviolet light
Mumps Pathogenesis
• Respiratory transmission of virus
• Replication in nasopharynx and regional
lymph nodes
• Viremia 12-25 days after exposure with spread
to tissues
• Multiple tissues infected during viremia
Mumps Complications
CNS involvement
15% of clinical cases
Orchitis
20%-50% in post- pubertal
males
Pancreatitis
2%-5%
Deafness
1/20,000
Death
Average 1 per year
(1980 – 1999)
Mumps—United States, 1980-2007
14000
12000
Cases
10000
8000
6000
4000
2000
0
1980
1985
1990
Year
1995
2000
2005
Mumps Clinical Case Definition
• Acute onset of unilateral or bilateral tender,
self-limited swelling of the parotid or other
salivary gland lasting more than 2 days
without other apparent cause
What Is Bronchiolitis?
• Bronchiolitis is acute inflammation of the
airways, characterised by wheeze
• Bronchiolitis can result from a viral
infection
• Respiratory Syncytial Virus (RSV) may be
responsible for up to 90% of bronchiolitis
cases in young children
Hall CB, McCarthy CA. In: Principles and Practice of Infectious Diseases 2000:1782-1801;
Panitch HB et al. Clin Chest Med 1993;14:715-731
115
Diagnosis, Treatment, and Prevention
• Diagnosis is based on the signs of respiratory
distress verified by immunoassay
• Treatment is supportive
• Ribavirin is used to treat extreme cases
Influenza
• Caused by two species of orthomyxovirus,
designated types A and B
• Infection occurs primarily through
inhalation of airborne viruses
• Rarely attack cells outside the lungs
118
Influenza
• Death of the epithelial cells infected with
influenza viruses eliminate the lungs first
line of defense against infections, the
epithelial lining
• Flu patients become more susceptible to
secondary bacterial infections
TRANSMISSION
• AEROSOL
– 100,000 TO 1,000,000
VIRIONS PER DROPLET
• 18-72 HR INCUBATION
• SHEDDING
120
SYMPTOMS
•
•
•
•
•
•
FEVER
HEADACHE
MYALGIA
COUGH
RHINITIS
OCULAR SYMPTOMS
121
CLINICAL FINDINGS
• SEVERITY
– VERY YOUNG
– ELDERLY
– IMMUNOCOMPROMISED
– HEART OR LUNG
DISEASE
122
PULMONARY COMPLICATIONS
• CROUP (YOUNG CHILDREN)
• PRIMARY INFLUENZA VIRUS PNEUMONIA
• SECONDARY BACTERIAL INFECTION
– Streptococcus pneumoniae
– Staphlyococcus aureus
– Hemophilus influenzae
123
Reye’s syndrome
•
•
•
•
liver - fatty deposits
brain - edema
vomiting, lethargy, coma
risk factors
– youth
– certain viral infections (influenza, chicken pox)
– aspirin
124
NON-PULMONARY
COMPLICATIONS
• cardiac complications
• encephalopathy
• liver and CNS
– Reye’s syndrome
• peripheral nervous system
– Guillian-Barré syndrome
125
Guillian-Barré syndrome
• 1976/77 swine flu vaccine
– 35,000,000 doses
• 354 cases of GBS
• 28 GBS-associated deaths
• recent vaccines much lower risk
126
MORTALITY
• MAJOR CAUSES OF INFLUENZA VIRUSASSOCIATED DEATH
– BACTERIAL PNEUMONIA
– CARDIAC FAILURE
• 90% OF DEATHS IN THOSE OVER 65 YEARS OF
AGE
127
ANTIGENIC DRIFT
• HA and NA accumulate mutations
– RNA virus
• immune response no longer protects fully
• sporadic outbreaks, limited epidemics
128
Figure 25.39
ANTIGENIC SHIFT
• “new” HA or NA proteins
• pre-existing antibodies do not protect
• may get pandemics
130
Figure 25.39
Influenza epidemiology
• Influenza A has wide host range
– Birds (natural), sea mammals, horses, pigs, humans
• Strains are described by antigenicity of HA and NA, which are
designated by numbers
• Currently 15 HA (1-15) and 9 NA (1-9) described
–
–
–
–
–
1918 “Spanish flu” pandemic – H1N1
1957 “Asian flu” epidemic – H2N2
1968 “Hong Kong flu” pandemic – H1N2
1977 “swine flu” epidemic – H1N1
1999 – current threat is H5N1, similar to 1918 strain
• Epidemiology involves close contact of humans, farm animals,
and birds – this especially in Asia
• Kills >20,000 per year in the US normally
VACCINE
• ‘BEST GUESS’ OF MAIN ANTIGENIC TYPES
– CURRENTLY
•
•
•
•
type A - H1N1
type A - H3N2
type B
each year choose which variant of each subtype is the
best to use for optimal protection
133
VACCINE
• inactivated
• egg grown
• sub-unit vaccine for children
• reassortant live vaccine approved 2003
– for healthy persons (those not at risk for
complications from influenza infection) ages 5-49
years
134
SUPPORTIVE TREATMENT
• REST, LIQUIDS, ANTI-FEBRILE AGENTS (NO
ASPIRIN FOR AGES 6MTHS-18YRS)
• BE AWARE OF COMPLICATIONS AND TREAT
APPROPRIATELY
135
Enveloped, Unsegmented Negative ssRNA
Viruses
• Includes the Paramyxoviridae, Rhabdoviridae,
and Filoviridae families
Enveloped, Unsegmented Negative
ssRNA Viruses
• Rhabdoviridae
– Include a variety of plant and animal pathogens
– Rabies is the most significant pathogen
• Filoviridae
– Cause a number of emerging diseases
– Include Ebola and Marburg hemorrhagic fevers
Rabies
• Rabies virus is the causative agent
• Classical zoonotic disease of mammals
• Primary reservoir of rabies in urban areas is the
dog
• Bats are the source of most cases of rabies in
humans
Rabies
• Rabies virus is the causative agent
• Classical zoonotic disease of mammals
• Primary reservoir of rabies in urban areas is the
dog
Rabies
• When the virus infects the central nervous
system neurological manifestations specific to
rabies develop (such as hydrophobia)
• Death results from respiratory paralysis and
other neurological complications
Diagnosis, Treatment, and Prevention
• Diagnosis
– Neurological symptoms of rabies are unique and
usually sufficient
– By the time symptoms and antibodies occur it is too
late to intervene
• Treatment
– Treatment of the site of infection
– Injection of human rabies immune globulin
– Vaccination with human diploid cell vaccine (HDCV)
• Viral replication and movement to the brain is slow
enough to allow effective immunity to develop before
disease develops
Diagnosis, Treatment, and Prevention
• Prevention
– Vaccination of domestic dogs and cats can help
control rabies
– Little can be done to eliminate rabies in wild animals
Source: Centers for Disease Control and Prevention, November 2010
Hemorrhagic Fevers
• Marburg virus and Ebola virus are the causative
agents
• The natural reservoir and mode of transmission
to humans are unknown
• Spread from person to person via contaminated
bodily fluids, primarily blood, and contaminated
syringes
• The virions attack many cells of the body,
especially macrophages and liver cells
• Infections results in uncontrolled bleeding under
the skin and from every body opening
Hemorrhagic Fevers
• The only treatment involves fluid replacement
• Up to 90% of human victims die
Viral Structure of Ebola
• It is a member of the Filoviridae family (the only other
member is Marburgvirus).
• ss, negative sense RNA
• Has a distinct characteristic “6” shape.
History
• First found in a province in Sudan and its neighboring
country, Zaire (1976). The Zaire outbreak 280/318
cases resulted in death. The Sudan strain caused
death in 397/602 cases.
• 1989: Ebola made its way to the United States. A lab
worker was infected by the monkeys he was working
with (Maccaca fascicularis). Workers developed
antibodies to Ebola, but did not get sick.
• 1994: Cote d’ Ivory- only one case here: a scientist
conducted an autopsy on a wild chimpanzee. He fell
ill, but did not die.
Strains Summary
In total, there are 4 known, documented strains of
Ebola:
–
–
–
–
Ebola Zaire (EBO-Z): a 90% death rate
Ebola Sudan (EBO-Z): lower death rate
Ebola Reston
Ebola Cote d’ Ivory
All strains of Ebola are classified as Biosafety Level 4,
meaning Hazmat suits, multiple airlocks,
ultraviolet light rooms. Workers must be cleared
to handle BSL4.
Transmission
• One of the easiest methods of transmission
in Ebola is through bodily fluids (blood,
secretions).
• Handling infected animals can also lead to
infection with Ebola.
• While monkeys were able to transfer Ebola
between themselves via airborne particles,
this type of aerosol transfer has not been
demonstrated setting in a laboratory setting.
Symptomology
• Incubation periods can be anywhere from 2-21 days.
• Common symptoms include: sudden onset of fever,
headaches, sore throat, muscle pains, and intense
weakness.
• More intense symptoms include: maculopapular
rash, kidney/liver disfunction.
• Possible internal/external bleeding.
Coagulpathy
• Internal bleeding is caused by Ebola’s coagulpathy
ability. This describes a dysfunction in the host blood
clotting system.
• When infected, host macrophages begin to express
Tissue Factor (TF). TF attracts clotting molecules from
the blood, leaving the rest of the body susceptible.
• Small holes in the capillaries are then cut by Ebola.
Without clotting factors, the host bleeds
continuously, dying of what some have called “a
million cuts.”
Reservoirs
• Unfortunately, no
reservoirs have
been identified for
Ebola. Several
times, scientists
have brought in
rodents, bats,
primates, plants,
and arthropods to
test for Ebola.
• Ebola could not be
detected or
isolated from any
of these reservoirs.
Treatment
• As there is no known cure for Ebola,
treatment options are very limited for
patients.
• Typically, supportive therapy is used
(balancing patient’s fluids, electrolytes,
maintaining oxygen status and blood
pressure).
• While there are no cures yet, that does not
mean several groups are not working to create
one.
Barrier Nursing Techniques
•
•
•
•
Barrier Nursing Techniques are employed to prevent further infection. Screens
are placed around the patient’s bed.
Anyone treating the patient must wear gowns, masks, and gloves.
Any items used to treat the patient are immediately put into a sterilizing
solution afterwards.
Changing sheets must also be done with care, to minimize the possibility of
launching airborne particles or droplets of contagious material.
Cures/Vaccines
• 1999: BBC researchers, led by Dr. Maurice Iwu,
investigated the garcin kola plant, typically eaten in
Western Africa. Medicine men in those areas had long
been using it and introduced it to the researchers. In a
lab setting, the plant has been shown to inhibit Ebola
multiplication.
• 2001: Mice injected subcutaneously with Ebola did not
become sick, but mounted an immune response.
Serum from these mice were used to treat new mice
before or after Ebola injection. All of the mice treated
with serum survived.
Reoviruses
• Cause infantile gastroenteritis
• Account for approximately 50% of all cases of
diarrhea in children requiring hospitalization
• Transmitted via the fecal-oral route
• usually self-limited
• replacement of water and electrolytes
• A vaccine is available that provides some
protection but has been linked to a rare bowel
blockage condition in some children
Rotavirus
• First identified as cause of diarrhea in
1973
• Most common cause of severe diarrhea in
infants and children
• Nearly universal infection by 5 years of
age
• Responsible for up to 500,000 diarrheal
deaths each year worldwide
Rotavirus Pathogenesis
• Entry through mouth
• Replication in epithelium of small intestine
• Replication outside intestine and viremia
uncommon
• Infection leads to isotonic diarrhea
Rotavirus Immunity
• Antibody against VP7 and VP4 probably
important for protection
• First infection usually does not lead to
permanent immunity
• Reinfection can occur at any age
• Subsequent infections generally less severe
Rotavirus Clinical Features
• Short incubation period (usually less than 48
hours)
• First infection after age 3 months generally
most severe
• May be asymptomatic or result in severe
dehydrating diarrhea with fever and
vomiting
• Gastrointestinal symptoms generally resolve
in 3 to 7 days
Rotavirus Complications
•
•
•
•
•
Severe diarrhea
Dehydration
Electrolyte imbalance
Metabolic acidosis
Immunodeficient children may have
more severe or persistent disease
Risk Groups for Rotavirus Diarrhea
• Groups with increased exposure to virus
– Children in child care centers
– Children in hospital wards (nosocomial
rotavirus)
– Caretakers, parents of these children
– Children, adults with immuno- deficiency
related diseases (e.g. SCID, HIV, bone
marrow transplant)
Enveloped, Positive ssRNA Viruses
• Includes the Togaviridae, Flaviviridae, and
Coronaviridae families
• Togaviridae and Flaviviridae
– Enveloped, icosahedral, +ssRNA viruses
– Designated arboviruses because they are often
transmitted by arthropods
• Coronaviridae
– Enveloped, helical, +ssRNA viruses
Rubella
•
•
•
•
•
•
•
•
Togaviridae
“German measles’
Rubella virus is the causative agent
One of the five childhood diseases that
produces skin lesions
Infection begins in the respiratory system but
spreads throughout the body
Characterized by a rash of flat, pink to red spots
Infections in children are usually not serious
Adults can develop arthritis or encephalitis
Rubella
• Rubella infections of pregnant women can result
in congenital defects or death of the child
• Vaccination has been effective at reducing the
incidence of rubella
Rubella
• From Latin meaning "little red"
• Discovered in 18th century - thought to be
variant of measles
• Congenital rubella syndrome (CRS) described
by Gregg in 1941
Rubella Pathogenesis
• Respiratory transmission of virus
• Replication in nasopharynx and regional
lymph nodes
• Viremia 5-7 days after exposure with spread
to tissues
• Placenta and fetus infected during viremia
Rubella Clinical Features
• Incubation period 14 days
(range 12-23 days)
• Prodrome of low-grade fever
• Maculopapular rash 14-17 days after
exposure
• Lymphadenopathy in second week
Epidemic Rubella – United States,
1964-1965
•
•
•
•
•
12.5 million rubella cases
2,000 encephalitis cases
11,250 abortions (surgical/spontaneous)
2,100 neonatal deaths
20,000 CRS cases
– deaf - 11,600
– blind - 3,580
– mentally retarded - 1,800
Congenital Rubella Syndrome
• Infection may affect all organs
• May lead to fetal death or premature delivery
• Severity of damage to fetus depends on
gestational age
• Up to 85% of infants affected if infected during
first trimester
Congenital Rubella Syndrome
•
•
•
•
•
•
•
Deafness
Cataracts
Heart defects
Microcephaly
Mental retardation
Bone alterations
Liver and spleen damage
Rubella Laboratory Diagnosis
• Isolation of rubella virus from clinical
specimen (e.g., nasopharynx, urine)
• Positive serologic test for rubella IgM antibody
• Significant rise in rubella IgG by any standard
serologic assay (e.g., enzyme immunoassay)
Rubella and CRS in the United States
• Most reported rubella in the U.S. since the
mid-1990s has occurred among foreign-born
Hispanic adult
• Majority of CRS since 1997 occurred in
children of unvaccinated women born to
Hispanic women, most born in Latin America
Rubella - United States, 1980-2007
4500
4000
3500
3000
2500
2000
1500
1000
500
0
1980
CRS
40
35
30
25
20
15
10
5
0
1985
1990
1995
Year
2000
2005
CRS Cases
Rubella Cases
Rubella
Rubella Case Definition
• Acute onset of generalized maculopapular rash,
and
• Temperature of >99°F (37.2 °C), if measured,
and
• Arthralgia or arthritis, lymphadenopathy, or
conjunctivitis
Enveloped, Segmented Negative
ssRNA Viruses
• Includes the Orthomyxoviridae, Bunyaviridae,
and Arenaviridae families
• Orthomyxoviridae
– Flu viruses
• Bunyaviridae, and Arenaviridae
– Include hundreds of viruses that normally infect
animals but can be transmitted to humans
Family Bunyaviridae
5 genera, 250 species
Genus
Human disease
Bunyavirus
LaCrosse encephalitis, others
Phlebovirus
Rift Valley fever, sandfly fever
Nairovirus
Crimean-Congo hemorrhagic fever
Tospovirus
Plant virus, no known human disease
Hantavirus
Hemorrhagic fever with renal syndrome
Hantavirus pulmonary syndrome
Diseases of Bunyaviruses
• Most bunyaviruses are zoonotic pathogens
• Usually transmitted to humans by biting
arthropods
• Infections result with an initial viremia spreading
the virus to target organs
Diseases of Bunyaviruses
• Symptoms are usually mild
• Hantviruses are the exception
– Transmitted to humans via inhalation of virions in
dried deer-mouse urine or feces
– American strains can cause a rapid, severe, and
often fatal pneumonia called hantavirus pulmonary
syndrome
Hantavirus Outbreak in the US
• HPS was first described in the United States in May 1993
during the investigation of a cluster of cases of acute adult
respiratory distress in the Four Corners region.
• HPS was found to be caused by a previously unknown
hantavirus, Sin Nombre, detected in deer mice.
• Sin Nombre caused approximately 200 confirmed cases of
HPS during the outbreak, that led to a 50% mortality rate.
Hantavirus Genus
• Hantavirus Similarities
– RNA viruses
– Lipid membrane
– Tri-segmented genome
• Hantavirus Differences
– Hantavirus transmitted through aerosolized
rodent urine, feces and saliva.
– Others genera transmitted through arthropod
vectors.
Epidemiology and Rodent Hosts
• Each strain of hantavirus has a specific rodent
host
• Hantavirus species appear to have co-evolved
with host rodent species
• Rodents carrying hantavirus are asymptomatic
Transmission of Hantaviruses
Chronically infected
rodent
Horizontal transmission of infection by
intraspecific aggressive behavior
Virus is present in
aerosolized excreta,
particularly urine
Virus also present in
throat swab and feces
Secondary aerosols, mucous
membrane contact, and skin breaches
are also sources of infection
Courtesy of CDC
Hantavirus Pulmonary Syndrome
Countries with
reported cases
of HPS
(no of cases)
Canada (36)
Countries with
no reported
cases of HPS
United States
(335)
Panama (31)
Bolivia (20)
Chile (273)
Brazil
(168)
Paraguay (74)
Uruguay (23)
Argentina (404)
Hantavirus and Host Cells
• Virus replication typically halts host
macromolecule synthesis
• Hantavirus replication does not affect host
cell’s natural functions
• Hantavirus release does not require host cell
lysis
• Hantavirus is able to establish a persistent
infection in rodent host cells
Hantavirus Infection Pathogenesis
• Binding of Hantavirus glycoproteins integrin
causes disruption of vascular integrity
• Capillaries become more permeable
• Arteriole vasoconstriction and vasodilation are
disrupted
• Binding to platelet receptors affects clotting
and platelet function
Immune Reaction
• Immune system activated against Hantavirus
epitopes
• Virus epitopes expressed on surface of host
cells triggers cytotoxic T-cell attack on host
tissues
• Symptoms are consistent with inflammatory
response
Laboratory Diagnosis of Hantavirus
• Hantavirus is difficult to culture, so
morphological identification is difficult
• RT-PCR using primers for conserved genome
regions allows confirmation of infection
• PCR product can be sequenced and compared
to known viral sequence database for species
identification
Clinical Presentation of Hantavirus
Infection
Three different clinical manifestations of
hantavirus infection caused by different viral
strains
Hemorrhagic fever with renal syndrome (HFRS)
• Found in Europe and Asia
Nephropathia Epidemica (NE)
• Found in Europe
Hantavirus pulmonary syndrome (HPS)
• Found in north and south America
HPS
• 1993 four corners outbreak
• Cases found in almost all of the Americas
• ~50% fatality
Stages of Hantavirus Pulmonary Syndrome
(HPS)
1)
2)
3)
4)
5)
Incubation (4-30 days)
Febrile phase
Cardiopulmonary phase
Diuretic phase
Convalescent phase
Febrile Phase
• 3-5 days
• Fever, myalgia, malaise
• Other symptoms: headache, dizziness,
anorexia, nausea, vomiting, and diarrhea.
Cardiopulmonary Phase
• 4-24 hours
• Presentation and rapid progression of shock and pulmonary
edema (4-24h non-productive cough and tachypnea
(shortness of breath)
• Decreased blood volume fromleakage of high protein fluid
from blood to lung
• Death within 24-48 hours due to hypoxia (lack of oxygen)
and/or myocardial failure
Diuretic Phase
•
•
•
•
•
Several days to several weeks
Beginning of recovery
Rapid clearance of pulmonary edema
Resolution of fever and shock
Anorexia, fatigue due to dehydration
Convalescent Phase
• Up to 2 months
• Results in chronic decreased small-airway
volume and diminished alveolar diffusing
capacity
Clinical Testing for HPS
• Many lab tests and radiographs appear normal
• Serological tests more effective
• ELISA IgM capture assay, using either SNV, Laguna Negra, or
Andes antigens are used in all countries that have
previously detected cases
• Immunofluorescent test for the presence of antibodies
• Blood analysis also may find thrombocytopenia with
platelet count less than 150,000 mm in 98% of cases
Problems Diagnosing HPS
• Symptoms often confused with influenza
• Common signs of upper respiratory disease
such as sore throat, sinusitis, and ear pain not
usually present
• Abdominal pain often misinterpreted as
appendicitis
• Many doctors outside endemic regions fail to
recognize or have sufficient testing