Host directed therapy Flashcards
Nosocomial infection
Infection you acquire in hospital
Drug resistant infections
Resistance to first line antbiotics
Goal host directed therapy:
Prevent replication of pathogen > Prevent death of host
- Killing the pathogen is not always the main goal
Challenges host directed therapy
- Safety
- Efficcacy: Have to be affecting against pathogen you fight against
- Competing drugs
ED50/ TD50
Dose required to produced a (therapeutic-/toxic- effect) in 50% of the population
Therapeutic index
Toxic effect/ Efficiacy effect= How well works a drug
When host therapy used?
- Viruses and intracellular bacteria (chlamydia)
- Immune modulation to enhance or suppress response to a pathogen (inhibit cytokines)
- Multi drug resistant pathogens > (resistance not expected)
How target the pathogen in host directed therapy?
- Small molecules
- Large biologicals (Antibodies)
- Genetic engineering
Plerixafor
Against binding CXCR4
Maraviroc
Against binding CCR5
Example HIV: host therapy
limit infection and host cell death with small molecules
- Block caspase I»_space; No pyroptosis
Two types of infection virus
- Successful infection
- Abortive infection (95%): CD4 cells that aren’t infected.
Pyroptosis in HIV infection
High inflammatory programmed cell death of CD4
Example mycobacterial infection ,
host therapy
Limitation of nutrients / dissemination with small molecules.
Not target bacteria directly but via host
- Prevent outgrow of blood vessels > Prevent granuloma growth in zebrafishes
Pazipanib: Anti mycobacterial
also anti-tumor
VEGF inhibitor
VEGF = Vascular Endothelial Growth Factor
Example Toll Like Receptor, host therapy
Immune modulation to enhance or suppress response to a pathogen with small molecules
TLR: Function
Recognises pathogen associated molecular patterns
In endosome and at the surface.
Share the IRAK4 pathway
Septic shock
Due to TLR4 that recognises LPS
Oplossing:
Block dimerisation of TLR4 < Doesn’t work for long treatment
No drug yet
TLR as therapeutical target
TLR7»_space;
Imiguimod»_space; Against genital warts»_space; Boosed immune system
Example s. aureus infections, host therapy
Eradication of intracellular bacteria with large biologicals
Target small amount that are inside host cells (system effects) > Eradicate S. aureus out body with antibodies.
ADC
Antibody drug conjugates: Antibody with drug > Bind receptor > Host caspase releasse drug > Cell killed
AAC
Antibody Antibiotic conjugates: Antibody recognises pathogen.
Antibody binds bacteria > High concentration inside cell»_space; Killing bacteria in cell
- If only a antibioticum given > Works but still some bacteria survive
- AAC: No bacteria alive anymore
AAC pros
- High [antibiotic] at the infectious site
- AAC longer half life than normal antibioticum (normal antibioticum 4 hours)
- Works only on bacteria , normal antibioticum kills everything what looks like.
- Spares the commensal flora
AAC cons
- Application for a limited numer of pathogens (only intracellular) «_space;So doesn’t work against every pathogen
- Very expensive, more than normal antibiotics
- Intravenous delivery
CRISPR
Genetic code in bacteria where they place virus DNA
It’s programmable : You give a copy of DNA you want to modify and put the system into a living cell.
Bacteriophages
Place own genome into bacteria»_space; Mostly the bacteria dies»_space; Sometimes it survives and save a part of the virus DNA in their own genetic code called CRISPR»_space; In CRIPR it’s stored till needed.
- When virus attacks again > Bacterium quickly makes crRNA which bound mRNA of virus and makes it double RNA»_space; Danger signal
Protein Cas9
Scan bacterium inside for signs of the virus invader, compares every bit of DNA
When it finds virus it’s activated and cuts out the virus DNA making it useless»_space; Protecting the bacteria against the virus attack
- Cas9 is very precise
Example HIV in CRISPR
Gene editing
Curing by gene editing:
- Cut out HIV gene of patient cell and give to rat
> Inject CRISPR > Removes 50% of the virus from cells all over the body
- Crystal therapy might cure HIV and other retroviruses
- Alle viruses that hide inside the human DNA could be eradicted this way
Cons: CRISPR in HIV therapy
- Need constantly target the virus with CRISPR, because virus mutates over time and can bind again
- It’s only activated when you have HIV, so not available as vaccin,
Cas9 under death receptor - It’s very specific on bases in DNA
- Can get cancer when it binds wrong
Example Malaria in CRISPR
Prevent malaria by engineering the vector (musquitos) via large biomolecules and genetics.
- The musquitos become immune for the parasite
- Cas9 binds where normally the plasmodium binds
Normal malaria infection:
Plasmodium and malaria cycle
Plasmodium consists of single cells and veroorzaakt Malaria
Sporozoids into the skin > Hide for immune system > Become merozoids > multiple and burst into the blood stream
» Hide in membrane of infected cells , so immune system doesn’t recognize them
Transgenic anopheles stehensi
Coexpression of single chain antibodies resist plasmodium development
HIV cycle
HIV enters cell»_space; Stimulate pyroptosis»_space; Release of pro-inflammatory cytokines»_space; Inflammation»_space; Recruitment of healthy CD4 cells»_space; Infection etc..
Gene driving principle
Gene driving by gRNA and Cas9
- Guide RNA and Cas9 incorperated in DNA of plasmid were normally plasmodium binds
- Transfer ‘new’ sequence to native chormosome
- From heterogenous to homogenous
» Easy to transorm complete organisms
In malaria:
- 2 antibodies needed that recognise plasmodium
> Prevent replication and prevent spread of pathogen
