Viral Pathogenesis- Test 2 Lecture 2

Courses of infection
o Acquisition
o Incubation
Time between infection and signs and symptoms
Prodrome: signs and symptoms before classic presentation of disease
Still part of the incubation period
Example: herpes simplex feel a tingling sensation before a blister shows
up
Can vary greatly (few days-2weeks or years)
Systemic/persistent usually have longer
Warts even though localized still can have a long incubation period of
50-150 days
o Primary site replication (most, not all have this)
Notable exception: West Nile virus goes straight to blood
o Spread through the body (some viruses)
Viremia: spread of virus through blood
Neuronal spread
o Replication in target tissue
How are viruses transmitted
o Respiratory route
Mucosal epithelium
Most virsues are prob. Transmitted this way
o Fomites
Survive on environmental surfaces
Nonenveloped viruses
o Enteric-route (fecal-oral)
Usually small doses of virus are ingested
o Body fluid contact/exchange
o Animal bites (arboviruses, other zoonoses)
Factors promoting transmission
o Stability of virus
Naked (protein capsid) virions are MORE stable than enveloped (lipid bilayer)
Examples of enveloped: influenza, HIV
Examples of naked: rhinovirus, enteroviruses, noroviruses
o Exception: polyoma viruses are naked but still stable. They can
cause cancer, warts, etc.
Virus shed in aerosols/secretions
Ability to spread before symptoms
Incidence of asymptomatic infections
Ineffective immune control of reinfection or recurrence

Seasonal effects
Respiratory viruses are prevalent in winter
Aerosol droplet stability (due to relative humidity, droplets are more
stable in winter)
Crowding indoors
Temperature & humidity
Others also peak in winter
Norovirus (aka winter vomiting disease
Parvo, adeno, rotavirus peak in spring
Enterovirus peaks in summer/fall
Localized infections
o This is completely separate from acute vs. chronic (those have to do with length, not
location)
o Localized infections can be cute or persistent (the same is true about systemic)
o At the site (portal of entry)
Local spread
Fluid covered mucosal surface
Aided by ciliary action
o Usually (not always) have short incubation period (days)
Exception papillomaviruses (can be months to years)
o Shedding to the exterior part of the body
o Little or no invasion of underlying tissues
o Immune response is primarily localized
o Viremia does not occur
o Failure to control may lead to disseminated disease
o Maybe associated with systemic symptoms
Example: influenza is localized to the respiratory tract but such a strong
immune response is generated that systemic system is manifested.
o Examples of localized viral infections
Oral/genital herpes simplex
Respiratory infections
Influenza
Warts
Most GI infections
Systemic infections
o Can be acute or persistent/chronic
o Charecterized by: blood-borne phase
o Incubation is usually>1 week
o longer period of shedding than localized
o symptoms usually more pronounced and systemic
o humoral antibodies (IgM, IgG, IgA) and systemic cell-mediated immune response

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disseminated throughout the body by lymphatics and the bloodstream

ultimately may cause disease at some site distant from entry (if symptomatic)
Examples of systemic viral infections
Varicella-Zoster virus (chickenpox)
Measles
Hep B and C
Fifth disease
Acute infection
Replicates via ertherprogenator cells (cells that make red blood cells)
Cytomegalovirus
HIV
How do viruses cause disease (4 ways)
o Destroy/disrupt normal tissue function
Poliovirus, rotavirus, herpes labialis (cold sore)
o Induce destructive immune responses
Hep B virus, Herpes simplex encephalitis
o Suppress immunity
HIV, Measles, influenza (measles and influenza are short term)
o Cause cancer
HPV, EBV
Cytopathogenesis
o Effects on cell are determined by tropism (of virus) and host-pathogen interactions
Example:
HSV is lytic in epithlium but usually latent in neuronal rissue
o Many potential effects
Inhibit host protein synthesis
Degrade host DNA
Membrane reorganization
Syncitia formation
This is when host cells fuse together due to the virus
Example: resipirtatory syncytial virus (RSV), Herpes simplex virus (HSV)
Cytoskeletal disruption
2 main ways a virus can cause disease
o Direct cellular damage
Example: virus lysing the cell
o Immunopathology induced by viruses
Clinical symptoms primarily result from host response to infection
indirect effect
Immunopathology
CD8+ T cell mediated
o Cytotoxic T cell destruction of cells

CD4+ T cell mediated

o Cytokine activation of PMNs and mononuclear cells
Antibody-mediated
o Immune comples reactions
o You got a lot of antibodies and can cause problems like
artheritis
o Type III allergic reaction
Autoimmune disease?
o Molecular mimicry
Immunopathogenesis (dont have to memorize)

Immunosuppression
o Clearly observed consequence of HIV infection
o Can also occur following acute infections with other viruses like measles and influenza
Great flue of 1812/Spanish flue: people died but probably due to bacterial
pneumonia that was facilitated by them being immunosuppressed by the flu
Transformation or immortalization
o Oncogenic viruses
Some DNA viruses (EBV, HBV, HOV)
Retroviruses and Hepatitis C virus (Flavivirus)
o Viral transformation usually not sufficient by itself for oncogenesis and tumor
formation
Cells more likely ot accumulate other mutations
More susceptible to cofactors and tumor promoters
o Approximately 20% of all cases of human cancer are associated w/ 5 viruses
EBV (burkits lymphoma), HBV, HCV, HTLV-I (leukemia), HPV
o Mechanisms for immortalization
Promote/provide growth stimulated genes
HTLV-I: activates growth-stimulating genes
Remove inherent braking mechanisms limiting DNA synthesis and cell growth

HPV: inactivates regulators of cell growth

Prevent apoptosis
EBV: stimulates cell growth, oncogene prevents apoptosis
Host defenses against viral infections
o Natural barriers
Skin, mucus, ciliated epithelium, gastric acid, bile
o Nonspecific immune (innate) defenses
Interferon, NK cells, fever, macrophages, complement
o Antigen-specific immune defenses
Antibody and activated T-cells (CD4, CD8)
Control of viral infections
o T cells/Cell mediated response (CMI)
Only recognize viral antigens in association with MHC antigens
Cytotoxic Tcells lyse infected cells
o Natural killer cells
Target cells with abnormal MHC expression (herpes)
Ppl who are NK cell deficient are very susceptible to herpes
o Interferon
shutdown of infected cells
Elimination of viral infections
o Antibodies
Humoral immunity
Neutralize free virus
Kill infected cells by complement-mediated cytotoxicity or anti-body dependent
cell-mediated cytotoxicity
Can prevent infection and can prevent reinfection.
T cells, NK cells and interferon work to eliminate infections
Interferons
o Produced by host cells
o Host-specific, but not virus-specific
o Hosts first active defense against viral infection
Helps shutdown protein synthesis in infected cells
Activates the innate immune response
Activates phagocytes
Stimulates NK cells
Enhances T-cell recognition of infected cells
o Types of interferons (not very important)
Type I (alpha and beta)
Produced within hours of infection
Secreted from infected cells and other innate cells
Generate anti-viral state in infected and neighboring cells

Type II (Gamma)
Produced by lymphocytes (CD4, NK, some CD8)
Activates macrophages & other phagocytic cells
o How IFN work
Release from an initially infected cell
Interferon binds to a specific cell receptor on another cell
Induces the antiviral state
Inhibition of protein synthesis
o Protein kinase R is produced
mRNA degradation
o antiviral ribonucleases are turned on
viral infection activates enzymes
o Actions of interferons
Antiviral actions (local)
Initiate antiviral state in cells
Block viral protein synthesis
Inhibit cell growth
Clinical effect of IFN
Malaise, Myalgia, Chills, fever
Immunomodulatory actions
Activate NK cells
Activate macrophages
Increase MHC expression (class I and class II)
Cellular defenses against viruses
o Natural Killer ells
Detect lack of properly expressed MHC class I to kill unusual cells
Many herpesviruses suppress MHC class I
Tumor cells may also have reduced MHC class I expression
o CD8 T cells (killer T cells)
Recognize infected cells that present specific virus antigens (1 T cell:1 antigen)
o Note: both NK and CD8 cells cause target cells to undergo apoptosis
o CD4+ T cells: coordinate adaptive and innate responses to infection
Provide help to macrophages, B cells
Secrete necessary cytokines for proper immunity
Antibodies
o Neutralize extracellular virus
o Marked infected cells for NK cell-mediated killing
o Induced by most protective vaccines
Example: flu vaccine is designed to induce antibody production against the
seasonal flu