virology lec.7 host resistance to viral infections

Disease triangle model

• addresses interactions among host, agents, and environment

• Condition of the host impacts its susceptibility to viral infection

List factors that affect resistance to viral infection

• age

• Nutrition

• Hormones

• Fever

• Genetic factors

• Dual infections

• Species resistance

Age

• newborns and the elderly most vulnerable

• Newborns: passive immunity from mothers

• Elderly: become more vulnerable as immune system declines with age

Thymus is T-site and critical for immune response

Some exceptions for age

1918 influenza A- affected 20-40 yrs old

Herpesvirus- can affect all but reactivate in elderly

Shingles- can affect all but reactivate in elderly

Nutrition

Deficiencies and malnutrition interfere with integrity of skin and mucous membranes

• interfere with innate immunity and adaptive immunity

• Ex: vitamin A deficiency (VAD) in developing countries

• Vitamins A an adjuvant (enhance the immune response stimulated by an antigen) to vaccines

Hormones

Patients undergoing certain hormone therapies at increased risk for viral infections for example organ recipients undergo chronic steroid therapy to prevent rejection of the donor organ)

• Ex: Glucocorticoids

• Body’s response to one infection may increase susceptibility to secondary infection

• Immune responses to spaceflight in astronauts

Fevers

Triggered by pyrogens (endogenous substances produced by the host or exogenous produced by the microorganisms (LPS)), either directly or indirectly

• Cryogens prevent excessive temperature elevation (cytokines)

• Balance of cryogens and pyrogens determines height and duration of the fever response to immune challenge

Genetic factors

• Viral immunity has genetic component

• 5% of population seem to be resistant to HIV-1

• Genetic polymorphisms

• Individuals with defective chemokine coreceptor CCR5-Δ32 resistant to HIV-1 compared to those with wildtype CCR5 alleles

• CCR5-Δ32 gene contains premature stop codon, preventing binding of HIV-1

• Individuals with CCR2-V64I have more favorable prognosis during antiretroviral therapy

Dual infections

• Opportunistic infections are hallmark of HIV infection

• Caused by a number of common bacteria and viruses

• Occur because of decreased immunity caused by depletion of TH lymphocytes from HIV-1

• Viral infections of respiratory tract lower body’s resistance to secondary infections

• Ex: Influenza A virus resulting in potentially fatal secondary pneumonia

Species resistance

• Causes for species resistance:

• Virus–receptor interactions; some species lack receptors for viruses to bind (CD155 receptor for poliovirus, CD4 receptor for HIV)

• Intracellular host factors involved in uncoating, nuclear import, and viral RNA transcription and translation of viral mRNA (HIV doesn’t infect rhesus macaques- presence of TRIM5a that acts as an inhibitor)

• Membrane protein named tetherin ( CD137, BST2)- becomes incorporated into enveloped virions. During the process of budding, enveloped virions internalized by the host cells and routed to the endosomes for degradation

Host range

Range of cells that can act as a host for a virus

Innate immunity

• nonspecific or innate immunity protects us against any pathogen, regardless of the species or type of microbe

• Ex. Microphages

• Immune cells and enzymes or proteins involved do not retain any “memory” from prior encounters with pathogens

Mechanical immunity

• first line of defense

• Trapping of viruses by mucus and phagocytes in mucosal tract

Phagocytosis

• phagocytes engulf and infest viruses and bacteria

• Ex. Macrophages, neutrophils, and monocytes

• Macrophages are larger than monocytes and contain more lysosomes

• innate immunity

Macrophages

Macrophages are specialized white blood cells of the innate immune system that engulf and digest cellular debris, microbes, and cancer cells through a process called phagocytosis.

Viral recognition

Body defense cells contain pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patters (PAMPs)

Viral PAMPs are absent in uninfected cells- PAMPs trigger innate immunity responses

Jules Hoffmann and Bruce Beutler’s research (both were awarded Nobel Prize in physiology, 2011)

• Discoveries concerning activations of innate immunity

• Toll receptors and toll-like receptors (TLRs) (sensors of innate immunity)

• TLR3 was the first TLR - on surface of endosomes of dendritic cells and macrophages

• Recognizes dsRNA viral PAMPS – triggering antiviral innate responses (type 1 interferon pathways and proinflammatory cytokines)

Defensins

• Small peptides 29–42 amino acids long

• Positively charged (cationic) molecules

• Hydrophilic and hydrophobic properties

Human α and β defensins

• Direct antiviral actions inhibit enveloped and naked viruses

• 6 different α defensins

• 31 different β defensins

α defensins

• part of innate immunity

work via direct interaction with viruses by blocking

infection of different naked viruses: Clumping and blocking

receptors-

• inhibition of viral uncoating (human adenoviruses)

• Blocking viral genome entry to the nucleus of its host cell (HPV)

β defensins

block enveloped viruses respiratory syncytial virus (RSV)

α and β defensins

inhibit HSV (enveloped virus)

Dendritic cells

• Present in tissues in contact with environment

• Skin (Langerhan’s cells), mucous membranes, lining of nose and lungs, and GI tract

• Internalize pathogen, digest it, and display or present foreign peptides on the surface through MHC II molecules to TH cells

• MHC class I and II molecules expressed on surfaces of dendritic cells

Natural killer (NK) cells recognize:

• Cells that undergo a declined expression of MHC molecules, or

• Cells that contain surface antigens displayed by some tumor cells, or

• Virally infected cells

Once activated, NK cells

release pore-forming proteins

called perforins, granzymes (proteases), and chemokines

• End result is death of target cell

NK cells, monocytes, macrophages, and neutrophils

• NK cells, monocytes, macrophages, and neutrophils

express receptors for the fragment crystallizable (Fc)

region of antibodies

• A kind of cytotoxicity referred to as antibody-dependent cell-mediated cytotoxicity (ADCC)

Isaacs and Lindenmann

• first described interferons

• Called the magic bullet

The interferon response

• Interferons (IFNs) are cytokines

• Three types of IFNs (I, II, and III) based on amino acid composition

• Type I: Bind to a receptor complex called human IFN-αβ receptor (IFN-αβR)

• Type II: Humans have only one, IFN-γ, which upregulates immune response

• Type III: IFN-λ possess antiviral activity

The Type I IFN Pathway

Two key actions of IFNs:

1. Directly interfere with viral replication

2. Upregulate expression of adaptive immune response genes

Don’t require specific killing

Marketing IFN

• The IFN story

• Represents complexities in development of commercial

drug therapies

• Development and randomized control studies required

commitments from drug companies, governments,

regulators, physicians, researchers, and patients and their

families

• Today, IFN used to treat diverse range of viral diseases

(hepatitis C and B infections), immune disorders,

nonmalignant tumors, and cancers

Apoptosis

• Apoptosis is programmed cell death (PCD)

• Viruses can trigger PCD, counteract PCD, or do both

• Activation of caspases (proteases)- dormant in healthy cells, converted into active enzymes in response to cell-death stimuli

Viruses that trigger apoptosis

West Nile virus (CNS), Coxsackie virus B3 (heart)

The complement system

• Consists of more than 30 different serum- and membrane- bound glycoproteins that act in sequence

• One complement protein activates another

• Complement activation ends in the formation of a

membrane attack complex (MAC)

• Hypocomplementemia: Rare condition, defect in

complement system

Distinguish how viruses are initially detected by the innate immune response

Viruses are first detected when pattern-recognition receptors (PRRs) recognize viral components called PAMPs, such as viral RNA or DNA. This triggers responses including interferon production, inflammation, and activation of natural killer (NK) cells.