Viruses

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Viruses
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What are Viruses?

• Viruses are pieces of RNA or DNA enclosed in a
  protective coat(s)
• Viruses are parasites
• Evolved to reproduce inside cells they infect
• Evolved to survive outside cells they infect
• Can do much with little and do it elegantly
• Hepatitis B is smallest known human virus
• has only four genes
• over 1 million people die each year
• Hepatitis B associated liver disease

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Structure of Viruses

• Very small
• 20-300 nanometers
• Contain either DNA or RNA (the genome)
• which codes for the few proteins necessary for
  replication
• Proteins assembled to form a tight shell capsid
• Capsid made up of protein subunits called
  capsomeres
• The of capsomeres is characteristic for a
  particular virus
• Nucleocapsid genome capsid
• Some viruses acquire an outer lipoprotein coat by
  budding through host cell membranes enveloped

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Structure of Viruses (cont.)

• All viral proteins have reactive epitopes
• Epitope aka antigenic determinant, part of
  macromolecule (protein) that is recognized by the
  immune system
• The hosts defense mechanisms
• Cellular and humoral mediated responses are
  directed against these epitopes
• Viruses gain entry into host cells by binding to
  specific receptors

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Specific receptor examples

• HIV binds to CD4 receptors
• Can infect cells with these receptors
• Monocytes, macrophages, T-helper cells
• EBV (Epstein-Barr) binds to receptor present for
  CR2
• CR2 Complement receptor type 2 found in B cells
• Influenza binds to glycophorin A
• Glycophorin A is found on many cell types
• Rhinoviruses use ICAM receptors
• Have the capacity to infect many different cells

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Replication

• Adsorption
• Uptake/Entry
• Uncoating
• Genomic activation
• Assembly
• Release
• (animation)

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3 Problems human viruses must solve

• How to reproduce
• How to spread from person to person
• How to evade host defenses
• These solutions must fit together in an overall
  plan of infection
• Wouldnt make sense for a virus that reproduces
  only in liver cells to be spread by coughing
• It wouldnt do for a virus to evolve to reproduce
  in the intestines, yet not evolve a strategy that
  protects the virus from acidic conditions present
  in the stomach

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How to reproduce

• Gain entry to cell via specific receptors
• Hijack machinery
• Turn cells into factories that make many copies
  of the virus
• Make both genome (DNA or RNA) and the proteins
• DNA viruses use bits and pieces of the cellular
  DNA replication machinery to copy their own
  genomes
• Problem in cells that are mature and not actively
  replicating their own DNA resting
• Figure out how to turn infected cell back on
  (give it a kick)
• Bring its own substitutes for parts of cellular
  copy machines not active at the time of entry

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How to reproduce (cont.)

• RNA viruses
• Bring their own copy machines
• RNA-dependent RNA polymerases
• Or have genes which encode the proteins required
  to assemble these copy machines within the
  infected cell
• By bringing their own many RNA viruses are able
  to replicate their genomes in resting cells
• animation

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How to spread

• Viruses have solved transmission problem in
  ways that take advantage of human behavior as
  varied as coughing or having sex
• Once it reaches its new host, traveling virus
  must locate cells in which it can reproduce
• Cell must have appropriate receptors
• Humans have abut 200 different types of cells a
  given virus usually will be able to infect only a
  few of these many different cell types

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Viral Pathogenesis

• Most human viruses cause some form of disease in
  their hosts
• although some pathological conditions affect only
  a small subset of infected humans, or are so mild
  that they are virtually undetectable.
• The disease that viruses cause are the
  consequences of the way each virus has chosen to
  solve the problems of reproduction, spread, and
  evasion

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Viral Pathogenesis (cont.)

• Viral pathology can result from
• Actions of the virus itself
• Killing the cell it infects
• Hosts reaction to the virus
• Host immune response
• Most of the hosts defenses against viruses are
  not finely focused resulting in collateral damage
• A hosts shotgun approach to defending against
  a viral infection is somewhat like trying to kill
  a mosquito with a machete
• You may kill that mosquito, but most of the blood
  on the floor will be yours

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Adsorption

• Viruses have reactive sites on their surface with
  interact with specific receptors on suitable host
  cells
• Usually passive (doesnt require E)
• Specificity of reaction defines and limits the
  host species as well as the type of cell that is
  infected
• Damage to binding sites (disinfectants, heat) or
  blocking (specific Ab) can render a virus non
  infectious

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Uptake/Entry

• After adsorption, uptake/entry can occur in
  different ways
• the coat of enveloped virus may fuse with host
  cell membrane release the nucleocapsid into
  host cytoplasm
• Endocytosis-invagination of the cell membrane to
  form vesicles in the cytoplasm

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Uncoating

• Release of the viral genome from its protective
  capsid
• enables the nucleic acid to be transported within
  the cell and transcribed to form new progeny

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Genomic activation

• DNA viruses (replicate Io in the nucleus)
• mRNA is transcribed from viral DNA and codes for
  viral proteins that are translated by host cells
• RNA viruses (replicate Io in the cytoplasm)
• Most carry a protein, RNA-dependent RNA
  polymerase which directs both transcription
  replication of viral RNA genome
• During this process the foreign proteins are
  recognized and incorporated into the major
  histocompatibility complex I molecule (link)
• Nucleic acid replication produces new viral
  genomes for incorporation into progeny viral
  particles

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Assembly

• Assembly of viral nucleocapsids occurs primarily
  in the
• nucleus
• For DNA viruses
• Cytoplasm
• For RNA viruses

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Release

• Final stage of replication
• Release of new infectious viral particles
  (progeny)
• May occur by budding-many enveloped viruses
• Carry with them a piece of hosts cell membrane
• Lysis (disintegration) of infected cell can also
  release new infectious viral particles

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Retrovirus

• contain viral RNA and several copies of reverse
  transcriptase
• reverse transcriptase (DNA polymerase) is used to
  make the initial copies of viral DNA from viral
  RNA.
• Once a DNA strand has been synthesized, a
  complementary viral DNA strand is made.
• These double strand copies of viral DNA are
  inserted into the host-cell chromosome
• host-cell RNA polymerase is used to make
  virus-related RNA.
• These RNA strands serve as templates for making
  copies of the viral chromosomal RNA and serve
  also as mRNA.
• mRNA is translated into viral proteins that are
  used to make the virus envelope.
• New viral particles are assembled, bud from the
  plasma membrane, and are released.
• HIV (human immunodeficiency virus) is a retrovirus

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Oncovirus

• Virus associated with cancer
• Can be a DNA virus
• Adenovirus
• Can be a RNA virus
• T-cell Leukemia
• Oncogenic mechanisms (link)
• Insert additional oncogenic genes in host DNA or
• Enhance already exsisting oncogenic genes in the
  genome
• Viral DNA incorporates a section of the host DNA
  which contains genes for growth promotion
• Proto-oncogenes

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Influenza (flu)

• Infectious disease of birds and mammals caused by
  RNA viruses of the family Orthomyxoviridae
  (influenza virus)
• Influenza from the latin influentia meaning
  influence (link)
• Two types that cause epidemic human disease
• Influenza A
• Further categorized into subtypes on the basis of
  2 surface antigens
• Hemagglutinin (H)
• Neuraminidase (N)
• Influenza B (not divided into subtypes)

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Influenza (cont.)

• New variants result from frequent antigenic
  change aka antigenic drift
• Results from point mutations that occur during
  viral replication
• Influenza A gt B (with regard to antigenic drift)
• A persons immunity to surface antigens (e.g.
  hemagglutinin) reduces
• Likelihood of infection
• Severity of disease if infection occurs
• Antibody (Ab) against one strain confers limited
  or no protection against another strain

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Epidemics of Influenza

• development of antigenic variants via antigenic
  drift is the basis for seasonal epidemics
• Epidemics typically occur during the winter
  months
• About 36,000 deaths/year in U.S. (1990-1999)
• Pandemics- dramatic ? in rates of illness/death
• Due to antigenic shift
• Morbidity highest among children
• Mortality highest among elderly (gt 65 years)
  individuals with pre-existing medical conditions

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Symptoms of Influenza

• Coryza acute rhinitis
• Fever
• Body aches
• Malaise
• Generalized muscular aches
• Loss of appetite
• A lot of different illnesses can have similar
  symptoms (including common cold)

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Complications of Influenza

• Guillain-Barre Syndrome
• Nerve damage, polio-like paralysis, coma.
  Usually follows recovery from disease or
  immunization to the disease
• Reyes Syndrome
• Fever, protracted vomiting, lethargy, sleepy,
  disorientation, incoherence. Liver brain
  damage. Elevation in blood ammonia. High
  mortality. May be associated with aspirin use
  during disease.

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Vaccine for Influenza

• Vaccine contains the inactivated virus
• Several strains of both A and B are included

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Manual treatment for influenza

• Some historical perspectives from the osteopathic
  profession.
• Letter one
• Letter two

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Rhinovirus

• Non-enveloped positive-stranded RNA virus
  belonging to the family picornavirus (pico
  small) along with enteroviruses.
• Most common viral infective agents in humans
• cause of common cold
• Icosahedral (20 faces) in structure
• Replicate in the secretory mucous membranes
• Transmission
• Person to person
• Via aerosols of respiratory droplets
• Contaminated surfaces

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Rhinovirus (cont.)

• Can lead to (sequelae) but highly unlikely.
• Secondary bacterial pneumonia
• Otitis media
• Sinusitis
• Prefer lower temperature (33 deg C.)
• Tend to stay in nose

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Coronavirus

• RNA virus belonging to family coronaviridae
• Cause respiratory infections (common)
• Enteric infections primarily in infants
  (occasionally)
• Neurological syndromes (rarely)
• Transmitted by aerosols of respiratory
  secretions, or by fecal oral route, or by
  mechanical transmission
• Usually localized to the epithelium of URT

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Coronavirus (cont.)

• Most infections cause a mild, self limited
  disease
• Classical cold
• SARS (Severe Acute Respiratory Syndrome)
• Viral pneumonia associated with the LRT
• Very common worldwide
• Incidence is seasonal, highest in winter in
  children
• of serotypes extent of antigenic variation ??

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Adenovirus

• DNA virus belonging to family of adenoviruses
• A few types serve as animal models for cancer
  induction (some are oncogenic)
• 42 known human serotypes
• Cause URT or LRT infection
• Bronchitis (Types 1,2,3,5)
• Resembles whooping cough-pertussis syndrome
• Signs
• Fever, HA, myalgia, pharyngitis, hoarseness,
  conjunctivitis

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Adenovirus (cont.)

• Clinical presentation varies based on serotype
• Bronchitis (1,2,3,5)
• Sore throat
• Tonsillitis
• Conjunctivitis
• Pneumonia
• Hepatic disorders (3,7)
• Gastroenteritis (9,12,13,18,25-28, 40-42)
• Musculoskeletal disorders (7)
• Genital infections (19)
• Skin infections (32, 34-35)

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Respiratory Syncytial Virus (RSV)

• negative-sense, single-stranded RNA virus
• Paramyxovirus Family
• Family contains viruses that cause mumps
  measles
• RSV most common cause of bronchiolitis
  pneumonia among infants (lt 1 yr.)
• Onset fever, runny nose, cough (wheezing)
• During 1st RSV 25-40 of children have S/S of
  bronchiolitis or pneumonia
• .5-2 require hospitalization (most lt 6 months)
• Most recover in 1-2 weeks

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RSV (cont.)

• Repeat infections common throughout life
• Moderate-severe cold symptoms
• Severe LRT infection may occur
• esp. in compromised individuals
• Compromised cardiac, pulmonary or immune systems
• Spread from respiratory secretions
• Close contact with infected individuals or
  contaminated surfaces/objects
• Sneeze/cough (aerosol particles)
• Route of entry
• Mucous membranes (eyes, mouth, nose)

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Metapneumovirus

• Negative sense RNA virus (paramyxovirus fam.)
• Discovered in the Netherlands in 2001
• Very common cause of colds in adults
• more severe symptoms in children (severe cough
  wheezing)
• 12 of severe illness
• 15 of common colds
• 33 of colds complicated by middle-ear infections
• Diminished severity in repeat infections
• Second to RSV as a cause of severe LRTI (2/3)

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Fifth Disease/Erythema Infectiosum

• DNA virus-Human Parvovirus B19 (link)
• Not the same as animal parvovirus (no
  interspecies transfer)
• Affects primarily children
• Grows in stem cells, lyses cell to spread
• Rash produces a slapped cheek appearance
• Proceeds from face to trunk limbs (like
  measles)
• Mild systemic respiratory illness
• Aplastic crisis in individuals with chronic
  anemia
• Virus infects erythroid precursor cells (reduced
  Hgb)
• Hydrops fetalis spontaneous abortion as fetus
  infected

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Varicella (chickenpox)

• Double stranded DNA virus (Herpesviridae fam.)
• Prior to mandated vaccine
• 3.2-4.0 million cases/yr. ? 9000 hospitalizations
  ? 90 deaths (mortality rate 2.25 X 10-5)
• Among the most communicable of all diseases
• Transported by respiratory droplets skin
  contact
• Incubation period 14-21 days
• Begins in the respiratory tract, symptoms of
  fever, HA, malaise, passes via the blood
  localizing in peripheral nerves skin (fluid
  filled vesicles)

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Varicella (cont.)

• Varicella (latin for little vessel)
• Vesicles form crusts eventually falling off with
  or without a scar
• Reyes syndrome may occur during recovery (linked
  to aspirin use during illness)
• Complications (increase with age)
• Pneumonia, encephalitis, secondary bacterial
  infection of the skin, fetal damage in pregnancy
• (link)

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Herpes Zoster/Shingles

• Caused by the varicella virus that remains in the
  nerve roots after chicken pox
• Contagious to people who have not had chickenpox,
  however you cannot catch shingles from someone
  else.
• Common after age 50, risk ?with?age
• Numbness, itching, severe pain followed by
  clusters of blister-like lesions in strip like
  pattern
• Pain can persist for weeks, months, or years
  after rash heals ? post-herpetic neuralgia

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Herpes Zoster/Shingles (cont.)

• May experience headaches, facial paralysis,
• One of the more devastating conditions that is
  likely to recur due to
• physical/emotional stress
• Suppressed immune system
• 10-20 of adults will experience at least one
  attack during lifetime

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Poliomyelitis/Polio

• RNA-picornaviridae (Greek- gray matter)
• Three antigenic types
• Type I/Brunhilde strain
• Causes a major of epidemics
• Type II/Lansing strain
• Occurs sporadically, but invariably paralytic
• Type III/Leon strain
• Usually remains in intestines, but can cause
  paralysis
• Enters body via mouth, multiplies in tonsils,
  then lymphoid tissue of GI tract causing nausea,
  vomiting, cramps

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Poliomyelitis/Polio (cont.)

• Virus may pass via blood into the NS, localizing
  in
• Meninges, causing meningitis
• Anterior horn, causing muscle weakness, paralysis
• Brain stem (bulbar), affecting the medulla
  (worst)
• Difficulty swallowing, paralysis of diaphragm,
  affects breathing (iron lung), paralysis of
  tongue, facial neck ms.
• Vaccine
• Salk-killed virus (some viruses could still be
  fxn)
• Sabin-attenuated (grown in monkey kidney)
• Sequelae
• Post polio syndrome (20-30 yrs.) after initial
  infection
• Muscle weakness

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Viral Gastroenteritis

• General name for a common illness occuring in
  both epidemic endemic forms
• 2nd in freq to common cold in U.S.
• Usually explosive onset with varying
• Diarrhea, nausea, vomiting, low grade fever,
  cramps, headache, malaise
• Can be severe in infants, the elderly, persons
  compromised by other illnesses
• Associated with
• Reoviruses, rotoviruses, enteroviruses

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Reoviruses

• Double stranded DNA (link)
• Antigenically 3 human types- orthoreovirus
• REO respiratory enteric orphan
• Enters oropharnx replicates in respiratory
  tract intestines
• Ab against it present in 10 days
• By age 16
• 50-80 of population have Ab to all 3 types
• an orphan is a virus without a famous disease

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Rotaviruses

• Most common cause of severe diarrhea among
  children
• In U.S 55,000 hospitalizations/yr
• Worldwide 600,000 deaths/yr
• Incubation period 2 days
• Vomiting and watery diarrhea for 3-8 days
• Fever abdominal pain occur frequently
• Immunity after infection is incomplete, but
  repeat attacks are less severe

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Rotovirus (cont.)

• Primary mode of transmission
• Fecal-oral
• Virus is stable in environment
• Transmission via ingestion of contaminated
  food/water, or contact with contaminated surfaces
• Highest incidence in infants/young children
• Most children in U.S. infected by 2 yrs.
• Disease in adults tend to be mild

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Enteroviruses

• RNA viruses (picornaviridae)
• Noroviruses- named after Norwalk virus
• Four groups divided into at least 20 genetic
  clusters
• Fecal-oral
• Highly contagious
• Incubation 24- 48 hours
• Acute onset
• Vomiting, watery diarrhea, abdominal cramps,
  nausea, with occasional low grade fever
• Dehydration is most common complication
• Symptoms last 24-60 hours
• Recovery usually complete with no sequelae

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Enteroviruses (cont.)

• Coxsackie virus
• Two groups
• A (link)- Associated with diseases with vesicular
  lesions
• B (body) (link)- Most frequently associated with
  myocarditis and pleurodynia
• 29 different variants causing a variety of divers
  distinct disease entities
• Conditions
• Herpangina- Sores inside the mouth, sore throat
  fever
• Pleurodynia- Severe pleuritic pain, fever,
  headache
• Aseptic Meningitis associated with mild paresis
  (transient)
• Myocardiopathy arrhythmias, tachycardia, can
  cause permanent heart damage
• Common cold
• Diabetes Mellitus
• Hand, Foot, Mouth Disease- rash (vesicles to
  ulcers)

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Enteroviruses (cont.)

• Echovirus (link)
• Enteric Cytopathogenic Human Orphan
• Occur in many strains
• Symptoms
• Gastroenteritis
• Aseptic meningitis (not associated with bacterial
  infection)
• Rash
• Common cold
• Fairly viable in sewage/water
• 31 different virus in this group
• Upper respiratory tract is portal of entry

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Host Defenses

• To protect against viral attacks, humans have
  evolved potent defenses
• Each new host defense has been countered by new
  viral evasion strategies
• On going struggle between host defenses viral
  counter-defenses even to this day
• Humans have three types of layered defenses
• Physical barriers
• Innate immune system
• Adaptive immune system

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Physical Barriers

• Skin-most difficult barrier for virus to
  penetrate because viruses only infect living
  cells skin has multiple layers of dead cells
• Respiratory tract- muscosal surface
• mucociliary elevator preventing viruses from
  getting a grip
• Macrophages on the loose-phagocytosis

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Physical Barriers (cont.)

• Digestive tract
• Saliva contains compounds active against viruses
• E.g. secretory leukocyte protease inhibitor
• Acid conditions of the stomach-pH as low as 2.5
• Pepsin can break down viral proteins
• Digestive enzymes in sm. intestine from pancreas
• Break down CHO, fats, proteins
• Bile salts from liver (detergents) help break up
  dietary fats viral envelopes

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Physical Barriers (cont.)

• Reproductive tract
• Vagina protected by stratified epithelium
  (multiple layers) of squamous (non-proliferating)
  cells
• viruses may gain entry via small tears in vagina
• Mucous that lines the reproductive tract provides
  some protection
• Normal bacterial flora produce lactic acid
  keeping pH at about 5.0 providing further
  protection against viruses which many are
  sensitive to acidic conditions

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Innate Defense System

• Professional Phagocytes
• Macrophages
• Phage is Greek to eat therefore big eaters
• Patrol tissue and collect garbage including
  debris from dead or dying cells
• Can eat viruses but occasionally can become
  infected by an ingested virus
• Phagocytes circulating in the blood that can exit
  bloodstream (diapedesis-cross endothelium)
• Young Macrophages (monocytes)
• Neutrophils
• 70 of circulating WBC
• Provide backup to sentinel macrophages

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Innate defense system (cont.)

• Complement System (very old-sea urchins)
• About 20 different proteins that work together
  to
• Help destroy invaders signal immune system
• Proteins produced mainly by the liver
• Most abundant compliment protein is C3 which is
  continuous broken into two smaller proteins
• C3a-recruits more macrophages neutrophils
• C3b-can bind to chemical groups on surface of
  viruses
• Opsonization-preferred targets for phagocyte
  ingestion-? appetite
• Binds to enveloped viruses ?membrane attack
  complexes
• Create holes in protective coat of invading virus
  
• One major flaw-only get at viruses outside of
  cells

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Innate Immune System (cont.)

• Interferon Warning System
• Human cells under viral attack produce interferon
  alpha beta (type I interferons)
• Interferon can be made exported by most cells
  in the body which then bind to receptors on
  surfaces of nearby uninfected cells (warns them)
• alerts them that they be soon under attack, if
  they are they must commit suicide (apoptosis)
  which limits the spread of the virus
• Shutdown protein synthesis destruction of RNA
• The large amount of viral double stranded RNA is
  the trigger for interferon production

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Innate Defense System (cont.)

• Natural Killer Cell
• Specilize in killing virus infected cell that
  dont make class I MHC molecules
• Kill signal by infected cell
• Infected cell that does not make class I MHC
  molecules
• These MHC proteins are used by virus infected
  cells to present viral proteins-alerting killer T
  cells (adaptive) but without class I MHC
  molecules killer T cells are blind to the fact
  the cell is infected, so NK cells pick up the
  slack
• Cooperation among innate defenses
• Cytokines (interferon) amp up macrophages
• TNF (from macrophages) further activate NK cells

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Adaptive Immune System

• B cells Antibodies
• IgM
• IgG
• IgA
• Killer T cells
• Activation
• Selection of Weapons
• Weaknesses-
• slow to react,
• must be custom made