Lecture 15: immune Response to Viruses and Parasites Flashcards
what is the primary mechanism in the defense against viruses
the killing of virus infected cells by cytotoxic T cells
explain virus pathogenesis
virus binds receptor
- enters cell via endocytosis or fusion
- nucleic acid released from capsid
- replication occurs (host machinery hijacked, only viral components produced)
- new nucleic acids are packaged into new capsids
- new virions exit cell or cell disintegrates, releasing virions
What TLRs detect foreign nucleic acids
TLR 3, 7, 8, 9
what are intracellular nucelic acid sensors, present in all nucleated cells
RIG 1, MDA5
innate response to viruses includes…
- interferons
- lysozyme
- bile / intestinal enzymes
- conglutinin
- mannose binding lectin
- surfactant proteins A + D
- defensins
- apoptosis of host cells to prevent viral replication
immunity response to parasites is characterized by what?
Th2 response and IgE production
how do obligate intracellular pathogens work
they use cellular machinery of the host
limits the # of identifiable pathogen-specific antigens
what is the result of the downregulating of MHC-1 expression
reduced effectiveness of NK cells and cytotoxic T cells
what type of parasites are helminths (worms)
obligate parasites, host-adaptation is important
what are the 5 ways parasites are able to evade the immune system
- immunosuppressants
- prostaglandins
- antioxidants
- protease inhibitors
- immunoglobulin splitting proteases
What are the ‘additional’ mechanisms by which parasites are able to evade the immune system
- shedding of glycocalyx upon antibody exposure
- absorption of host antigens onto worm
- interference w/ antigen presentation
- antigenic variation
what is Taeniastatin, what are its functions
a protease inhibitor produced by taenia taeniaformis
1. inhibits neutrophil chemotaxis
2. inhibits complement activation
3. inhibits Tcell proliferation
4. inhibits IL-2 production
what is the the IgE mediated self-cure reaction to helminths
- worm secretes antigens in saliva
- triggers mast cell degranulation
- vasoactive, other molecules released
- stimulates smooth muscle contractions, vascular permeability (dislodges and flushes worm)
- IL-13 stimulates epithelial proliferation, sloughs worm
*results in detachment of worms, expulsion in feces
what type of reaction is the IgE mediated ‘self cure’ reaction
Allergic (type I, immediate hypersensitivity)
what does it mean that viruses are obligate intracellular pathogens
they require the use of the cell’s own machinery to replicate
what does it mean for viruses to be host-adapted
they have evolved mechanisms to evade the host’s immune system
how do DNA viruses (like canine parvovirus) replicate inside a cell
undergo replication of the viral DNA, followed by transcription to viral RNA and then translation into viral proteins.
How do RNA viruses (such as influenza) replicate inside a cell
they undergo replication and translation
How do “lentiviruses” or “retroviruses” replicate inside a cell
ex: equine infectious anemia virus, feline immunodeficiency virus, and human immunodeficiency virus
RNA is reverse transcribed into DNA, then transcribed into RNA and then protein
recognition of viruses occurs via….
TLRs 3, 7, 8, 9
intracellular nucleic acid receptors RIG-1 and MDA5 NOD-like receptors.
what is a major effector mechanism of the innate immune system to viruses
The production of interferons
what are interferons
glycoproteins secreted by virus infected cells
Interferon- _____ is secreted by plasmacytic dendritic cells (via TLR7/9), lymphocytes, monocytes, macrophages
Interferon-α
what interferon is secreted by virus-infected fibroblasts
Interferon-β
what interferon is produced by lymphocytes, monocytes, and trophoblast of many species.
Interferon-ω/αII
what interferon is produced by ruminant trophoblast and is involved in maternal recognition of pregnancy
Interferon-τ
what interferon is produced by pig trophoblast
Interferon-δ
what interferon is produced by keratinocytes
Interferon-κ
what is the one type II interferon?
interferon-γ (produced by antigen-stimulated T-cells and pig trophoblast)
what interferons are produced very rapidly by virus-infected cells
Interferons α, β
what is the importance of Natural killer cells in viral infections?
- they have a more rapid response than cytotoxic T cells
- they kill virus-infected cells
- they are stimulated by interferon
- produce interferon-γ
do neutrophils produce interferons?
no
what are the 6 important viral defense pathways
1) 2’5’ OAS: degrades viral RNA
2) protein kinase R: prevents viral translation
3) Mx GTPase: blocks the assembly of viral components
4) ISG15: destroys viral proteins
5) viperin: inhibits lipid rafts formation
6) tetherin prevents the release of virions
antibody-mediated mechanisms response to viruses
- respond to capsid and envelope proteins as antigenic targets
- can target viral antigens produced by infected cells
- can block adsorption of virus into cells
- can stimulate phagocytosis
- can initiate complement-mediated lysis of virus.
Antibody-mediated destruction of host cells is important in what cases of disease
- Newcastle disease
- rabies
- BVD (bovine virus diarrhea virus)
- FLV (feline leukemia virus)
- avian infectious bronchitis
Cell-mediated mechanisms in response to viruses
Viral antigens may be expressed on infected cells before new virus is reassembled, resulting in the destruction of the cell
- antigens are presented on the cell surface by
MHC-I - Cytotoxic T-cells recognize the viral peptide as foreign and kill the infected cells, thus preventing the
release of more virus
How does antigenic variation allow viruses to evade the host’s immune defense
Antigenic drift- creates influenza viruses with slightly modified antigens
antigenic shift - generates viruses with entirely new antigens
**These mechanisms result in the reduced effectiveness of antibodies.
What are other ways besides antigenic variation that viruses can evade the immune system
- blocking of interferon
- downregulate expression of MHC-I, which reduces the effectiveness of NK-cells and cytotoxic T-cells
How does Equine herpesvirus type 1 (EHV-1) evade the host’s defense
downregulation MHC-I
- reduces the effectiveness of antigen presentation and limits the ability of additional virus to enter the cell.
What makes EHV-1 a notable virus
- it can enter cells of many species and can enter multiple cell types in the horse (epithelial cells, endothelial cells, and mononuclear cells)
- It uses MHC-I as an entry molecule
- Cell associated viremia allows rapid spread throughout the body, resulting in neurologic disease and abortion.
- It has several strategies for immune evasion including hiding envelope proteins, downregulating MHC-I and inhibiting cytokines via its gG protein
what allows helminth parasites present their own unique challenges to the immune system
- they have many life stages and each stage can have different antigens
- they are obligate parasites so host-adaptation is key = many mechanisms to evade immune system
- they have a thick cuticle that protects them from damage (can’t be destroyed easily by complement/MAC or cytotoxic T cells)
- Eosinophils are important effectors in the destruction of parasites.
What cell type is an important effector in the destruction of parasites?
eosinophils
factors of host that play a role in immunity to helminths
-** genetics:** some MHC-1 haplotypes are more resistant to infections
- age and gender
- Chitinases (substances that act upon chitin in helminth cuticle) produced by mast cells, macrophages and neutrophils
**- L-arginases: drive granuloma formation, reduce local availability of arginine and have an anti-inflammatory effect via reduced T cell function
- population dynamics of parasite: if high burden exists, it may prevent additional infection**
aquired immunity to helminths
A Th2 response is the primary response,
involving interleukin 4 (also 10, 13), IgE, mast cells and eosinophils
the role of eosinophils in parasite immunity
- degranulating mast cells produce substances chemotactic for eosinophils
- Th2 cells produce IL5, mobilizing eosinophils from bone marrow
- macrophages produce molecules that influence eosinophils
- Fc receptors on eosinophils bind antibody covered parasites and degranulate, applying granule contents directly to the cuticle.
what are the granule contents of eosinophils
- Major basic protein
- eosinophil cationic protein
- eosinophil neurotoxin
- eosinophil peroxidase
ways that eosinophils can degranulate
-
classic degranulation : the
granule membrane fuses with the cell membrane to release contents - piecemeal degranulation :certain substances are released via a vesicle transport system. Intact granules may also be released
immune and homeostatic functions of eosinophils
- T-cell activation
- dendritic cell, and T-cell recruitment
- maintenance of plasma cells
- tissue repair and regeneration
- angiogenesis
- fibrosis
- metabolic homeostasis and adipose cell function
- mammary gland and intestinal development.
when might T-cells attack worms
-
- if worms are deeply embedded such as during migration
- if parasite is dying and can’t moodulate an immune respnse, so Th1 response occurs
what 2 mechanisms are used by T-cells to attack worms
- delayed type hypersensitivity (Type IV) involving T-cells and NK cells
- or a direct attack.
explain how defense against parasites can depend on life stage
**Larvae **- can be walled off, immobilized or destroyed. Their development can also be delayed
Adults - can be subjected to cuticular destruction, other morphologic changes, reduced fertility and granulomatous reactions
**Eggs ** - can be subject to granulomatous reactions and decreased fertility
