Immune response to intracellular pathogens

Question 1

characteristics of intracellualr pathogen

Answer 1

• Take advantage of the environment inside cells than extracellular pathogens
  
  • typically equipped to gain access to human tissues without the need for a scratch or abrasion, and have specific mechanisms to enter cells.
  • developed strategies to colonise macrophages that would normally eat and destroy them, and can instead proliferate inside them.

Question 2

what are the two types of intracellular microbes

Answer 2

1. Obligate intracellular pathogens
   • cannot reproduce outside the host cell
   • require the cells’ metabolic energy and biosynthetic processes for their proliferation.
   • Since they still need to leave the cell to spread, they typically have a distinct extracellular form to survive in the outside environment too
   • often inactive, such as virus particles, bacterial spores, or encapsulated cells with a very low level of metabolic activity.
   2. Facultative intracellular pathogens
      • can survive and proliferate in the extracellular environment
      • but they can also invade host cells

Question 3

How do the body deals with intracellular pathogens

Answer 3

1. Starts by detecting PAMPs (DAMPs) in cell resulting in cell signalling that tells the immune system which weapons to arm,
   
   2. which can tell the cellular innate immune system (NK cells and phagocytes) to destroy and remove the infected cell(s).
   3. pathogen’s proteins/peptides can be presented to theadaptive immune system, thereby facilitating the destruction of the pathogen’s cells by cytotoxic T (TC) cells

Question 4

Three main characteristics that define what immune responses will be effective

Answer 4

1. What nucleic acid their genome is made of (DNA or RNA; single or double stranded)
   
   2. Whether or not they have a lipid envelope
   3. Whether they replicate their genome in the cytoplasm or the nucleus

Question 5

Describe the entry of virus into the cell

Answer 5

virus must first attach itself to a cell surface using a glycoprotein on the virus binding to receptor on cell

For unenveloped virus, virus binding will lead to endocytosis

For enveloped virus, the glycoprotein on the virus cause fusion of viral membrane with cell membrane and allows virus to enter the cytosol without the capsid

After entering the cytosol, virus with RNA will head to cytoplasm while retrovirus and DNa virus will head to nucleus

Question 6

Action of antibody on virus

Answer 6

antibodies neutralise virus by sticking to glycoprotein on virus, blocking them from binding to virus receptor
enveloped virus avoid detection because the envelope proteins to which antibodies bind are left on the surface of cell when virus envelope fuses with cell membrane

Question 7

Describe the pathway that senses the cytoplasmic DNA

Answer 7

1. When cGAS binds to DNA, it combines ATP with GTP to make a cyclic GMP/AMP molecule,cGAMP
2. cGAMP acts as a ’second messenger’ molecule in the cell. cGAMP binds to the proteinSTING, which is located on the membrane of the endoplasmic reticulum (ER)
3. STING in turn activates a kinase called TBK1
4. that activates interferon response factor 3 (or IRF3)
5. which then enters the nucleus and
6. activates transcription of type Iinterferons,such asIFN-α subtypes and/or IFN-β.

Question 8

What problems do sensing viral RNA has and how to solve

Answer 8

very common to find RNA in cytoplasm, and cannot rely on RNA location. Need to recognise features of viral RNA that are not shared by cellular RNAs so use RNA -sensing protein (RIG-l-like receptor) RLR family, when bind to RNA, activates a signalling cascade by driving the multimerisation of mitochondrial protein MAVS

Question 9

function of RIG-1

Answer 9

can sense short viral RNA in both nucleus and cytoplasm

Question 10

function of MDAS

Answer 10

sense long double stranded RNA,

Question 11

describe the sensing RNA pathway

Answer 11

When activated by binding RNA ,both RIG-I and MDA5 assocaite with mitochondrial antiviral signalling protein (MAVS). When multiple MAVS protein are clumped together on mitochondrial membrane by interaction with RIG-I or MDA5, they signal through kinase/phosphorylation cascade to activate IRF3, which is able to enter nucleus and trigger expression of IFNa or IFNb

Question 12

What are the three types of interferon

Answer 12

1. Type I IFNs (including all twelve α-subtypes and IFN-β)
   • produced in response to pathogen-induced signals in the infected cells;
   
   2. Type II IFN (which includes just IFN-γ)
      • produced by activated immune cells, and generally signals to modulate the responses of other immune cells;
   3. Type III IFNs (three IFN-λ subtypes)
      • structurally related to IL-10 but like type I and II IFNs lead to an antiviral state in cells infected with a virus.

Question 13

Role of interferon in response to intracellular infection signal

Answer 13

1. Signalling in response to the interferon can activate and attract cells of immune system
   
   2. Non-immune cells can also respond
      • IRF7 is activated which turns on whole suite of IFN-stimulated genes (ISGs)
      • places the cell in a state of alert: an antiviral state has been established in order to control viral replication upon and infection.
   3. ISGs include antiviral PRRs and restriction factors.
      • Restriction factors are cellular gene products which prevent specific pathogen functions
      The upregulation of ISgs places cell in an antiviral state

Question 14

What is the antiviral state

Answer 14

• Binding of interferon to cell leads to signalling cascade that triggers transcription of genes coding for protein that help fight virus
  
  • As a result of IFN signalling theseISGsare transcriptionally upregulated
  • ISGs include antiviral PRRs, components of the immunoproteasome,activatory recptors andrestriction factors.

Question 15

How do NK cells activate

Answer 15

• NK activation depends on the balance between inhibitory receptors and activating receptors.
  
  • Healthy cells are tolerated as more inhibitory receptors are ligated to the MHC I than activating receptors.
  • Missing MHC I (as in tumour cells) promotes killing of the target by NK cells as inhibitory receptors are not bound.
  • Upregulation of activating receptors to overwhelm inhibitory receptors, in response to intracellular stress signals, also leads to destruction of the cell.
  • However, activating ligands are still not identified.

Question 16

action of NK cells

Answer 16

1. NK cells produce IFN-y which activates macrophages and promotes phagocytosis.
   
   2. NK cells also produce cytotoxic granules, perforin and granzymes which lyse infected host cells.

Question 17

what are the glycoproteins on flu virus

Answer 17

haemagglutinin and neuraminidase

Question 18

How does influenza evades innate immunity

Answer 18

• Influenza encodes protein - NS1 (nonstructural protein 1 )
• Disrupts RNA sensing at several levels
1. Can bind to RIG-I/RNA complex and inhibit signalling of RIG-I to MAVS and block this RNA sensing process by the cell
2. Interfere with phosphorylation of IRF3 and processing of interferon RNA
3. Inhibit another dsRNA sensor -PKR (protein kinase RNA -activated )
• Interferon-stimulated gene so more significant in cells that have already been alerted to enter an antiviral state by IFN-b

Question 19

how does HSV stays in latent period

Answer 19

• Viruses in the latent cycle only transcribe latency-associated RNA transcript (LAT) that does not get translated into protein.
  
  • This means there is no protein to be presented on MHC I, allowing the virus to evade immune detection.
  • By hiding in the neurons, HSV is far away from the HSV undergoing the lytic cycle in the epithelial cells, away from IFN signalling

Question 20

Action of HSV

Answer 20

• HSV encodes proteins reported to target TLR signalling, acting independently against TLR3, TRAF6, and MyD88, and also RLR signalling with proteins that interfere with RIG-I, MDA5 and TBK1, and the DNA sensor IFI16.
  
  • HSV also has mechanisms to evade extracellular immune molecules: its viral glycoprotein gC can bind to C3b, and prevent it from binding other complement proteins

Question 21

Action of lysteria monocytogenes

Answer 21

• it secretes LLO and phospholipases to degrade the internalisation vacuole.
  
  • It then modifies its surface and produces virulence factors that compromise distinct cellular functions.
  • One such factor is LNTA which binds to BAHD-1 to repress its function and cause the expression of ISGs.
  • covers one of its poles with ActA which recruits small actin filaments which rapidly grow to form comet tails to facilitate bacterial movement.
    
    • This allows it to push the cell membrane into a neighbouring cell, and colonise it as well.