Chapter Outlines
Chapter 7 Host Resistance to Viral Infections
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7.1 Physiological Factors and Barriers Affecting Resistance
- Epidemiology triad model of disease: change in host, environment or viral pathogen produce disease.
- Host changes:
- Age
- Nutrition
- Hormones
- Fever response
- Genetic factors
- Dual infections
- Species resistance
7.2 Host Defenses Against Viral Invaders: Nonspecific Host Defenses (Innate Immunity)
The interferon (IFN) response
- IFN: the magic bullet?
- IFNs are cytokines
- 3 Types of IFNs and 13 subtypes of IFNs
- Induce an antiviral state in host cells
- PKR activated by dsRNA
- 2Ƌ'-oligo(A) synthetase
- RNase L
Type 1 IFN pathway: "Cellular Altruism"
Marketing IFN
- IFN was not the magical antiviral that researchers initially thought it could be.
- The IFN story is one of persistence
- Commercial drug "waiting for the right disease."
Apoptosis and Viral Infections: A Double-Edged Sword
- Apoptosis-programmed cell death (PCD)
- Viruses can trigger PCD, counteract PCD, or do both.
Nonspecific Defense: Phagocytosis
- Phagocytes engulf pathogens
- Macrophages
- Neutrophils
- Blood monocytes
Nonspecific Defense: Natural Killer (NK) Cells
- NK cells represent 5-15% of the total lymphocyte population
- NK cells respond within minutes to 4 hours of an infection
- NK cells are activated by IFNs and other cytokines
- NK cells release perforins, granzymes and chemokines
Complement System
- Consists of more than 30 different serum and membrane-bound glycoproteins that act in sequence
- One complement protein activates another
- Complement activation end in the formation of a membrane-attack complex (MAC)
- Hypocomplementemia-rare condition, defect in complement system
7.3 Immunity Takes Time: Specific Immune System Responses (Adapted Immunity)
- Nonspecific immunity plays a role shortly after infection and is effective against any pathogen
- Specific immunity required days to weeks before they are induced or effective in clearing viruses
- 2 arms of specific immunity: antibody (or humoral) and cell mediated responses
Key Players of the Immune System: The Lymphyocytes
- B and T lymphocytes
- Lymph supplies lymphocytes to the bloodstream
- Lymphocytes congregate in the lymph nodes and exit through the outgoing lymph vessels
- B lymphocytes are born and mature in the bone marrow
- T lymphocytes mature in the thymus gland
Antibody Production
- Memory cells express the correct antibody
- Memory B cells require periodic exposure to an antigen for their maintenance
- Antibody structure (see Figure 7-16)
- Classes of immunoglobulins
- IgM, IgG, IgA involved in combating viruses
- Viral Neutralization Assays (see Figure 7-18)
- T-Cell Mediated Immunity (see Figure 7-19)
- T cells recognize "cells" that contain foreign antigens (e.g. virally infected cells).
- At least two defined populations of T cells
- Cytotoxic T cells
- T helper cells
7.4 Antibody Production: Cell Mediated Response (B and T cells Work Together)
7.5 Some Final Comments on Cell-Mediated Immunity
- The same system that protects against pathogens is also used to clear tumor cells and other abnormal cells and antigens from the body.
7.6 Viral Evasion Strategies
- Many of the viruses that that evade the immune system establish persistent and chronic infections.
- Molecular mimicry
- Synthesis of excessive amounts of viral antigens
- Inactivation of cytokines
- Inactivate immune cells
- Block apoptosis, complement, IFN pathways
7.7 History of Immunotherapy
- Passive antibody therapy
- Experiments by Emil von Behring and Shibasabura Kitasato
- Passive immunity is still used today (e.g. treatment of Hepatitis A infections)
- Complication: serum sickness
- Redness and itching at injection site
- Skin lesions/eruptions
- Joint pain/arthritis
- Fever
- Malaise
- Swollen lymph nodes
- Flushing
- More serum sickness complications
- Difficulty breathing/wheezing
- Runny nose
- Edema
- Low blood pressure (rare)
- Muscle pain
- Diarrhea
- Nausea
- Abdominal cramping
- Renal, cardiovascular, pulmonary, neurologic manifestations
Vaccination
- People have tried to inoculate against infectious diseases for centuries.
- Active immunity elicits long-term protection
- Active immunity means the immune system is active
- T and B memory cells are formed
- Traditional vaccines:
- Killed or inactivated vaccines
- Uses avirulent mutant viruses as vaccines
- The live virus multiplies inside of the recipient host and elicits a long lasting immune response but it causes little or no disease
- Live, attenuated viruses
- Viruses may be attenuated in virulence through the repeated culturing in nonhuman cultured cells or at different temperatures
- Live attenuated vaccines produce strong cellular responses that are similar to natural infection
- Usually only 1 or 2 doses are required
Advantages and Disadvantages of Traditional Vaccines
- Not all viruses can be cultivated (therefore no vaccines can be created).
- Batches of vaccines may not be adequately inactivated or attenuated (inadvertently causing disease).
- Reversion of attenuated viruses.
- Not all viruses can be prevented by traditional vaccines (e.g. HIV, Hepatitis C virus).
Newer Generation Vaccines
- Made using recombinant DNA methods
- Usually safer (uses parts rather than whole viruses)
- Recombinant subunits
- Peptides
- Live vectors
- Reassortment viruses
- Naked DNA
- Edible plants
7.8 Immunizing the Compromised Host
- Immune compromised hosts:
- Transplant patients on immunosuppressive drugs to prevent organ rejection
- HIV-infected individuals
- Cancer patients
- Use of live vaccines in not recommended
7.9 Vaccine additives
- Aluminum hydroxide to stimulate immunity
- Sulfites, or thimerosal (mercury) as preservatives
7.10 Side effects
- localized reactions
- allergic responses
7.11 Vaccine delivery
7.12 Manufacturing and Quality Assurance of Vaccines
Economics of Vaccines
- Finite number of vaccine companies
- Majority of individuals in need of vaccines are children located in impoverished countries
- UNICEF
- Global Alliance for Vaccines and Immunization
- Vaccine Fund: Bill and Melinda Gates Foundation
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