Host defense in Viral Infections Flashcards
Innate Immune System
immediate response; relatively non-specific, physical and molecular mechanism; not influenced by prior exposure, short-lived (days) and resets,
Adaptive Immune System
response to antigenic exposure; highly specific; lag- takes time to develop (days-weeks); long-term immunologic memory
Sensing and responding to viruses
1) virus detection of things specific to viruses 2) signaling to nucleus (through kinases etc.) 3) production and amplification of alarm signals (IFN alpha/beta) 4) production of antiviral effector proteins (IFN stimulated proteins)
PAMPS
- general indicators of viruses (double stranded RNA, cytoplasmic DNA, naked nuclear DNA, capsid proteins, viral genome replication intermediates)
- detected by PRRs (pattern recognition receptors)
PRRs
- TLR- toll-like receptors- endosomes and plasma membrane
- RLRs- RIg-1-receptors- cytoplasm (mitochondria anchored)
- NLRs- NOD-like receptors- cytoplasm
- CDRs- cytoplasmic DNA receptors
- C-type lectin receptors- plasma membrane
TLRs
- examples: TLR 3 for dsRNA, TLR7/8 for ssRNA
- recognize disassembled virions (uncoating and entry are simultaneous)
- signaling pathway: nucleus -> transcription of genes ( cytokines -> synthesized -> secreted -> detected by neighbors or self -> alarms signals -> primes neighbors so they have proteins ready to be prepared for infection)
Virus detection via sensing cytoplasmic nucleic acids
- signals relayed via 2nd messengers
1) OAS (oligoadenylate synthase) is activated by viral dsRNA- initiates a conformational switch and acts as a mesenger to activate RNase L; this forms a crossed dimar and degrades mRNA of host and virus
2) cGAS (cyclic GMP-AMP synthase) is activated by cytoplasmic dsDNA; produces cGAMP enzyme; binds and activates STING (stimulator of interferon genes) receptor resulting in cytokine gene expression; can work in self or travel to neighboring cells
Interferon Types
1: IFN alpha and beta; front line of disease, from cells coming into contact with lots of pathogens (fibroblasts, epithelial cells, macrophages, monocytes, dendritic cells) stimulated by viruses
2: IFN gamma; come from T and NK cells, stimulated immune cells themselves;
3: IFn- delta; from dendritic and epithelial cells; stimulated by viruses/microbial products; similar to type 2
IFN signaling
1) Recognize by receptors on neighboring cells
2) Receptors activate kinases, then phosphorylates signaling molecules/ transcription factors ( on STATs)
3) Phosphorylated STATs go into nuclei -> join to make promoter complexes -> activate transcription of genes
4) These are ISGs, the specific gene turned on depends on the specific IFNs
- Depending on the cell type and IFN levels, a stimulated cell may express 200-500 different ISGs
Diverse action of ISGs
- each type of virus is controlled by a unique combo of many ISGs
- Many ISGs show specificity in antiviral action
- can action: + standed RNa viruses, - stranded RNA viruses, DNA viruses
Pros and Cons of IFNs as therapy
Good:
- Sometimes its paired wth drugs more targeted to replication for that viral type
- Can effect viral or non viral diseases
- IFNs can help non viral genes by activated those ISGs
Bad:
- symptoms (flu-like symptoms and even more severe) are from the IFN ISGs not the virus itself
- can lead to hepatoxicity, immunosuppression through decreased neutrophil levels
Viruses evading IFNs
- most viruses target the pathways at multiple levels, forcus body to keep tweaking its pathways
- poliovirus prevents degradation
- Influenza NS1 targets RIG-1
- PAramycovirus V targets MDA 5
Viruses blocking ISG function
Normally: IFN signaling ->OAS ->active RNase L -> mRNA degration OR Ifn signaling -> PRK -> activate PRK -> phosphorylate eIF-2alpa -> inhibit protein synthesis
- HSV 1 blocks the RNase L
- HSV 4,5 will dephosphorylate eIF-2 alpha so it can keep working
AGS ( problem with innate immunity –> autommunity)
aicardi- goutieres syndrome:
- clinical features (incl. neurological damage) mimic in utero acquired infections and/or systemic lupus erythematosus
- Inherited mutations lead to inappropriate accumulation of self-derived nucleic acids that induce sustained type I interferon signaling
- ex. MDA5- detects RNA accumulating in ways it shouldn’t , leads to sustained expression and signaling when they should be turn off
Lupus and sustained IFN alpha signaling
- pDCs (plasamcytoid dendritic cells) produce IFN-alpha in a sustained fashion, making RNA and proteins more often than they should
- Over stimulation of these different things that should normally not be there just further stimulates dendritic cells to make IFN-alpha
