Intrinsic and Innate Immune Response Flashcards
1
Q
What must viruses do during an infection?
A
Must enter the susceptible and permissive host cell and invade the host tissue, then get out successfully
2
Q
What must the host do during an infection?
A
Create barriers and generate a robust immune response- innate and adaptive, when viruses overcome existing barriers.
3
Q
Possible outcomes of viral infection (4)
A
- No consequences
- Asymptomatic
- Symptomatic- when viruses spread in the tissues
- Manifestation of disease
4
Q
Signs of infection
A
Visible or apparent results of an infection, like a rash. Signs and symptoms may overlap
5
Q
Symptoms of infection
A
May be apparent only to the patient, like pain.
6
Q
Incubation period
A
The initial period of infection before symptoms are obvious. Transmission may or may not occur during this time
7
Q
Incidence of infection
A
The number of people infected divided by the population
8
Q
Morbidity rate
A
The number of individuals who became ill divided by the number of individuals at risk
9
Q
Mortality rate
A
The number of deaths divided by the number of individuals who are at risk
10
Q
Case fatality ratio
A
The number of deaths divided by the number of individuals with illness
11
Q
R naught (R0)
A
The number of secondary infections that can arise in a large population of susceptible hosts from a single infected individual during its life span. Each virus has a characteristic R0
12
Q
Latent period
A
The period between clinical signs of disease and a person producing an infectious virus particle
13
Q
If R0 is <1
A
It is impossible to sustain an epidemic; in fact, it may
be possible to eradicate the pathogen. This R0 indicates that an infected person may not be able to transmit the virus
14
Q
Infectious period
A
The time between when the latent period ends, throughout the time a person exhibits clinical signs of illness
15
Q
If R0 is >1
A
An epidemic is possible, but random fluctuations in the
number of transmissions in the early stages of infection in a
susceptible population can lead to either extinction or explosion of the infection
16
Q
If R0 is much greater than 1
A
An epidemic (or perhaps a pandemic) is almost certain
17
Q
Which viruses have the longest incubation period?
A
Viruses that cause chronic disease, like HIV
18
Q
Requirements for successful infection (3)
A
- Enough virus- consider PFU
- Cell accessibility (that are susceptible and permissive)
- Overcoming the local antiviral defense
19
Q
Which host responses occur at which time during infection? (4)
A
- Continuous- physical barriers
- Immediate- intrinsic
- Minutes/hours- innate
- Hours/days- adaptive
20
Q
Physical barriers (7)
A
- Mucus
- Saliva
- Stomach acid
- Tears- lysozymes
- Skin- dead cells on the surface
- Scabs
- Defensins- found on the skin
21
Q
Components of the intrinsic immune system (5)
A
- Interferons
- Autophagy
- Apoptosis
- MicroRNAs
- CRISPRs
22
Q
Components of the innate immune system (4)
A
- NK cells
- Complement
- Antigen presenting cells
- Neutrophils
23
Q
Adaptive immune system
A
B cells and T cells
24
Q
Layers of the skin
A
- Epidermis
- Dermis
- Subcutaneous fat
25
Epidermis
The top epidermal layer, called the stratum corneum, is composed of dead (keratinized) cells. Below this is the live epidermal layer
26
Dermis
Contains blood vessels, lymphatic vessels, fibroblasts, nerve endings, and macrophages. Mosquito proboscis penetrates through
dermis while taking a meal
27
Components of the epidermis
1. Stratum corneum- dead cells
2. Stratum Malpighi- living cells. A virus would at least need access to these cells
28
Respiratory tract infections
Creates a barrier to infection with respiratory viruses. Either the upper or lower respiratory tract can be impacted. Upper respiratory tract infections, like colds and covid, then to be less severe. Lower respiratory tract infections, like bronchitis, are more severe. Viruses infecting the alveoli will kill these cells, impacting gas exchange
29
Ciliated cells
In the respiratory tract- continuously beat to promote upward movement of the mucus, bringing the pathogens with the mucus to expel them
30
Influenza virus release
These viruses are released in the apical site of the airways, and excreted as aerosols through coughing or sneezing
31
Measles virus release
After causing viremia, it is released in the apical site of the airway. Shed in aerosols during sneezing or coughing
32
Vascular stomatitis virus release
Released at the basolateral site into lymphatic vessels, then blood vessels to cause systemic infection
33
Hematogenous infection
When the virus makes its way from the basement membrane into the lymph nodes and circulation
34
How viruses travel from blood to tissues (3 methods)
1. By infecting endothelial cells, which will shed toward the tissue site
2. By transcytosis (endocytosis)- taken up by endothelial cells, and the virus is released on the other side of the tissue
3. Trojan horse
35
Capillary barriers
A pericyte (glial cell in the CNS) is one example. Specialized endothelial cells form a continuous structure with the help of tight junction proteins. Around them, they have the basement membrane and adjacent cells. Includes the CNS, skeletal muscle, lungs. It is the tightest barrier in the human body.
36
Venule barriers
The blood vessel is continuously covered by the endothelial cells, with pores and the basement membrane. Not as selective as capillary barriers. Includes the intestine, pancreas, endocrine glands
37
Trojan horse method of infection
Infected cells adhere to the endothelium using specific molecules like selectins. They are then able to migrate through the barrier into the tissue. One example is HIV
38
Intrinsic immunity
The main goal is to eliminate a foreign invader with minimal damage to host cells and tissues
39
APOBEC3
An intrinsic host restriction factor which has anti-HIV properties. It is one of the most ubiquitous host restriction factors. Deaminase function- it removes the amino group to convert cytosine (C) to uracil (U) on negative strand DNA. APOBEC3 induces hypermutation by converting C into U, as it messes up the entire viral genetic sequence. It is packaged into the virus particle while budding.
40
HIV-Vif
An accessory protein produced by HIV, it is not required for structure formation. Vif allows for immune evasion. It binds to APOBEC3 and recruits proteasomal degradation machinery to degrade APOBEC3, so it won't be packaged in the virus particle
41
Intrinsic host restriction factors (5)
1. APOBEC3
2. Epigenetic silencing
3. Apoptosis
4. CRISPR
5. Tetherin
42
Epigenetic silencing
The cell regularly chromatinizes any DNA that comes into the nucleus, compacting it. This means that host transcription machinery can't access the viral genome
43
Which factors are involved in epigenetic silencing?
Histones and histone modifying enzymes that repress DNA. These enzymes include HDACs, HATs, HMTs, and DNMTs
44
Histone deacetylases (HDACs)
Remove an acetyl group- acetylated histones allow for an open chromatin structure. Removal of the acetyl group allows for condensed chromatin
45
Histone methyl transferases (HMTs)
Add methyl groups to histone tails. This renders compaction of chromatin.
46
DNA methyl transferases (DNMTs)
Methylate specific cytosines present in CPG islands (DNA regions that are rich in CpG dinucleotide repeats, and are typically found near promoters).
47
Histone acetyl transferases (HATs)
Add acetyl groups, which open up the chromatin and allow transcription
48
PML bodies
Complexes of multiple host proteins that are all involved in maintaining the integrity of the chromatin. If a viral DNA is present in the PML bodies, it is transcriptionally inactive. HCMV 1E1, EBV Ebna5 nuclear antigen and Adv E4 orf3 protein affect
the PML protein localization or synthesis
49
HCMV countermeasures against epigenetic silencing
Viral protein pp71 binds to- and degrades cellular Daxx that is
required for DNMTs to repress transcription
50
Herpesvirus countermeasure against epigenetic silencing
Viral ICPo accumulates in PML bodies and degrades
protein components of the PML bodies so viral DNA can't be repressed (promyelocytic leukemia nuclear bodies )
51
Apoptosis
Viruses encode machinery to modulate host cell death as per
their requirements. The cells experience nuclear shrinkage, blebbing of the plasma membrane, and form apoptotic bodies. Macrophages can take up apoptotic bodies and present the antigens to naive CD4 T cells to induce an adaptive immune response
52
Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR)
An ancient defense system that was identified in Archaea and Bacteria to defend against the pathogens that infect these organisms, like bacteriophages. Allows for adaptive immunity
53
How does CRISPR work?
Bacteria take a sample of bacteriophage DNA and integrate into specific loci on the bacterial cell genome. The host DNA then has specific fragments of DNA from past phage infection, allowing for adaptive immunity. The genomic regions are continually transcribed, producing crRNA. In the future, if a bacteriophage releases its DNA into the cytoplasm, the crRNA undergoes complementary base pairing to the DNA. The hybridization alerts host nucleases, which will cleave phage DNA
54
Tetherin
Also known as Bst-2 and CD137. It is a dimer found in the plasma membrane and tethers budding virus particles at the cell surface. Tetherin has a two transmembrane domain, with the C terminal having a GPI anchor. HIV-1 Vpu can antagonize Tetherin by targeting it from degradation. Tetherin links intrinsic, innate, and adaptive immunity. May have an anti-inflammatory function by sequestering microparticle release.
55
Innate immune response
The response induced within minutes to hours following the infection. Components include cytokines, sentinel cells (DC, NKs, macrophages), and the complement system. The innate immune system will relay the information to the adaptive response if the infection is overwhelming
56
Discovery of the Toll signaling pathway
Discovered in 1980- Eric Wieschaus and Christiane Nüsslein-Volhard identified
Toll signaling pathway, essential for establishment of dorsal-
ventral axis in Drosophila embryo. (Nobel, 1995). Toll’ a German slang term comparable to Cool! or Awesome!. 1996: Eventually this pathways was identified to initiate immune
response to microbial infection in Drosophila larvae and adults. 1997: Toll like receptors were identified in mammals
57
PAMPS
Pathogen associated molecular patterns, which are recognized by pathogen recognition receptors (PRRs).
58
Pathogen recognition receptors
Recognize PAMPs. The receptors are encoded by toll genes. TLRs recognize specific antigens from specific pathogens, and they may be present either on the plasma membrane surface or the endosome. For example, RIG-1 and MDA-5 are cytosolic TLRs
59
How can PRRs recognize DNA as foreign?
Host DNA is methylated, while pathogen DNA is not
60
What happens when PRRs recognize PAMPs?
PRRs initiate downstream signaling from adaptor proteins, like MyD88. Engagement of PRRs on the innate immune cells activate microbicidal and pro-inflammatory responses required to eliminate (or at least to contain) infectious agents. One major result is the secretion of small biologically active proteins (cytokines) that induce inflammation in order to recruit other immune cells to the infected tissue
61
Major families of pattern recognition receptors (PRRs)
1. Toll-like receptors (TLRs)
2. C-type lectin receptors (CLRs)
3. Nucleotide-binding oligomerization
domain (NOD)- Leucin Rich Repeats (LRR)-containing receptors (NLR)
4. Retinoic acid-inducible gene 1
(RIG-1)-like receptors (RLR; aka
RIG-1-like helicases—RLH)
62
Toll-like receptors
One type of transmembrane PRR located on the cell membrane or within endosomes. They are a family of 10 genes which encode TLRI-10. They have an extracellular domain for recognizing pathogens and a cytoplasmic domain that signals this information to the inside of the cell. TLRs are important in innate cell activation. When pathogens are degraded by macrophages, their nucleic acids are delivered to endosomes for recognition by TLRs
63
Extracellular vs intracellular TLRs
Extracellular TLRs recognize extracellular microbial ligands, while intracellular TLRs recognize intracellular microbial ligands (RNA and DNA)
64
Synthesis of pro-inflammatory cytokines by TLRs (8 steps)
1. On recognizing LPS, TLR4 activates the transcription factor NFκB, which instructs the macrophage to produce inflammatory cytokines. These cytokines induce a state of inflammation in the infected tissue.
2. The cytoplasmic tail of activated TLR4 binds the adaptor protein MyD88
3. MYD88 binds the protein kinase IRAK4, which self-phosphorylates.
4. IRAK4 now binds and phosphorylates TRAF6, which initiates a kinase cascade that activates the kinase IKK.
5. In the absence of a signal, NFκB is bound by the IκB inhibitor, which prevents NFκB from entering the nucleus.
6. In the presence of a signal, activated IKK phosphorylates IκB, causing NFκB to be released from the complex; IκB is degraded.
7. NFκB enters the nucleus to activate the genes encoding inflammatory cytokines or interferons.
8. Messenger RNA directs the synthesis of the cytokines in the cytoplasm, and the cytokines are secreted via the endoplasmic reticulum (ER)
65
Stimulator of interferon genes (STING) pathway (4)
1. Cyclic GAMP Synthase (cGAS) detects vDNA, or microbial DNA as well as mitochondrial DNA
2. cGAMP stimulates STING (ER resident protein)
3. STING translocate to Golgi and binds TANK-binding kinase (TBK)
4. IRF3/NF-kB activation transcription of IFNs
66
TANK
TRAF associated NF-kB activator
67
Viral antagonists
Allow viruses to inhibit components of the innate pathway. Viral proteins can target the host immune response by modulating sensing of PAMPs, gene expression, intercellular signaling
68
Which adaptor proteins do viral antagonists target?
STING, MAVS, TRIF/MYD88, Inflammasome
69
Which transcription factors do viral antagonists target?
Interferon regulatory factors (IRFs), NF-kB
70
Interferons
Discovered in 1957, when cytokines produced by flu- infected chicken cells "interfered" with infection of other cells, causing antiviral activity. Both infected and non-infected cells can produce interferons when they sense viral products. They are produced within the first few hours post-infection
71
Types of interferons (3)
1. Type 1- IFN-alpha (13 subtypes) and IFN-beta (1 subtype)
2. Type 2- IFN-gamma
3. Type 3- IFN-lambda
72
Type 1 interferons
A collective name for interferons alpha and beta. They are cytokines produced by virus-infected cells that interfere with viral replication by the infected cell. They also signal to neighboring infected cells to prepare to resist infection. Type 1 interferons have functions similar to those of cytokines. Found in macrophages and dendritic cells
73
Interferon receptors
They are constitutively expressed on human cell surfaces, ready to bind interferon in response to infection. Interferons can act as ligands to receptors on the same cell they were secreted by, or different cells
74
How do interferons interfere with infection?
IFNs induce interferon stimulated genes that have anti-viral functions, and more than 1000 ISGs have been identified. Interferons act as signals, while ISGs are what allow for actual anti-viral activity. Interferons signal to neighboring cells to prepare to resist infection. Also, they alert the immune system that infection is present and cause virus-infected cells to become more vulnerable to attack by NK cells. All nucleated human cells can be infected by viruses, and they all make interferon. Interferons are barely detectable in the blood of healthy people but will increase when infection is present
75
Type 1 interferon signaling
After binding to interferon receptors as heterodimers, the interferon transduces its signal downstream, to JAK1 or tyrosine kinase 2 proteins. This induces the JAK/STAT signaling pathway, and STAT translocates into the nucleus
76
Type 2 interferon signaling
Found in T cells and NK cells. The type 2 interferon is recognized by its receptor as a dimer and transduces its signal to a downstream signaling pathway- JAK2 and JAK1 proteins
77
Type 3 interferon signaling
Found in the endothelium and epithelium. Induces downstream signaling, TYK2 and JAK1 are involved
78
Interferon signaling genes (ISGs)
Interferons signal for the expression of ISGs, which carry out actual anti-viral activities. Tetherin and PKR are examples, as well as IFIT1 and IFITM3
79
Cholesterol hydroxylase (CH25H)
An ISG that blocks fusion of the viral membrane and viral protein maturation
80
MX1
An ISG that inhibits endocytosis and viral transcription
81
IFIT1
An ISG that binds to the 2'-O position on viral mRNA. Cellular mRNAs have their first 2 nucleotides methylated at the 2'-0 position. If viral mRNA doesn't have 2'-0 methylation, IFIT1 can bind to it, blocking translation by preventing the translation machinery from binding
82
Viral countermeasures against IFIT1
1. Viral N-7 and 2'-0 methyl transferases
2. Host-N-7 and 2'-0 methyl transferases
3. Cap-snatching mechanism
4. Cap-independent translation
83
Viral N-7 and 2'-0 methyl transferases
Viruses can encode their own methyltransferases, and they must encode their own methyltransferases if they are replicating in the cytoplasm
84
Host-N-7 and 2'-0 methyl transferases
Generally occurs in DNA viruses- they replicate inside the nucleus so they will have access to host machinery and be able to methylate at the 2'-0 position
85
Cap-snatching mechanism
These viruses don't have to bring any genes for methyl transferase activity. They bind to cellular mRNA and clip it downstream from the cap. The 5' end of cellular mRNA is used for the virus to synthesize its own mRNA to be translated
86
IFITM3
Found in influenza A virus and Zika virus. A protein that inhibits fusion of membranes during viral entry. IFITM3 is present in all membrane structures- its N terminal alpha helix fits in between the phospholipid heads and causes a bend in the membrane. This compromises the fluidity of the membrane and prevents fusion
