L23 - Killing Pathogens 2: Intracellular Microbes Flashcards
(25 cards)
What advantages do pathogens gain by living inside host cells?
• Hidden from immune effector mechanisms:
• Avoid antibodies, complement, and immune cells like neutrophils.
• Immune system is trained not to attack self, so intracellular pathogens can hide safely inside host cells.
• Access to nutrients and host cellular machinery (e.g., viruses hijack replication machinery).
• Mobility: Can spread within the host more easily.
• Innate immunity often cannot control intracellular pathogens alone — adaptive immunity (especially T cells) is crucial.
What are the main categories of intracellular microbes and their cellular targets?
Phagocytosed microbes that:
• Survive inside phagolysosomes or
• Escape into cytoplasm
Microbes infecting non-phagocytic cells (e.g., epithelial cells):
Some pathogens infect a wide range of cells, including immune and non-immune cells (e.g., HIV targets Th cells, macrophages, DCs; Ebola and Measles infect multiple immune and structural cells).
Why infect immune cells?
Micro are trying to rapidly eat you anyway, so if you can evade their killing mechanisms, then they make infection easier
Perfect transporters - immune cells migrate readily around host
Immune evasion - manipulate immune pathways of host if you are inside the cell
Diff types of intracellular microbes require diff effector mechanisms. What is used to fight bacteria vs viruses
- bacteria → Cd4 Cd8 NK cells Th cells B cells
- virus → Thcells, NK, Type 1 interferons (macrophage protection against virus)
Which receptors detect intracellular pathogens, and where are they found?
Intracellular Pattern Recognition Receptors (PRRs) detect microbes inside host cells.
Endosomal PRRs (in phagosomes):
• Toll-like Receptors (TLRs) detect viral components like RNA and CpG DNA.
Cytosolic PRRs:
• NOD-like receptors (NOD1, NOD2) detect bacterial peptidoglycan.
• RIG-I-like receptors (e.g. RIG-I) detect viral RNA.
• These PRRs are intracellular because pathogens must be detected once they enter host cells.
What are some ways microbes use to evade phagocytosis?
- Avoid killing mechanism by preventing lysosome fusion with phagosome
- Inactivate chemicals used in phagolysosome
- Escape the phagosome before it fuses (replicates in ytosol by disrupting phagosome membrane and uses host actin to move betweeen cells)
What kind of help does macrophages need for intracellular microbes
• They need to be fully activated by IFN-γ (interferon gamma).
• Produced by NK cells and Th1 or CD8+ T cells.
• IL-12 from macrophages stimulates NK cells and Th1 to secrete IFN-γ.
• IFN-γ enhances phagolysosomal killing and improves microbial degradation.
• During primary infection, this help is delayed—adaptive response takes time.
How does Mycobacterium tuberculosis evade clearance and what pathological features result?
• M. tuberculosis resists phagolysosomal killing, leading to persistent infection.
• Chronic Th1 response produces high levels of IFN‑γ, continuously activating macrophages.
• Activated macrophages release toxic mediators (e.g., nitric oxide), which damage lung tissue.
• Granulomas form: aggregates of activated macrophages (and often multinucleated giant cells) wall off infected cells.
• Ongoing inflammation and mediator release cause fibrosis, scarring, and loss of lung function.
• T‑cell help is essential: animals lacking functional T cells are highly susceptible to TB.
What is the antiviral state and what drives it?
Viral infection stimulate production of type 1 interferon IFNa and IFNb which induce an ‘anti viral’ state in cells that protects them from being infected
What are type 1 IFN functions
Inhibit viral gene expression (antiviral state):
• Block viral transcription and translation
• Promote viral RNA degradation
• Induce autophagy to degrade viral components
Induce apoptosis (antiviral state):
• Unfolded protein response from misfolded viral proteins triggers cell death
• Shift TNF-α signaling from pro‑inflammatory to apoptotic
Promote T cell and NK cell activation:
• Sequester lymphocytes in lymph nodes for efficient priming
• Enhance cytotoxicity of CD8⁺ T cells and NK cells
• Support T helper cell differentiation
• Upregulate MHC class I:
• Increases presentation of viral peptides to CD8⁺ T cells
What is the function of natural killer cells and how do they do this? What activates it to its full potential?
- NK cells target cells infected with bacteria viruses and Protozoa
- it is kind of like the innate counterparts of CTL but less precise
- important backup mechanism to deal with intracelllar pathogens that evade CTL by inhibiting MHC class 1
- IFN-y from Th1 cells and CTL is important for their full activation
What is the 2 main ways of dying and describe both ways.
Necrosis
- uncontrolled cell death
- cell ruptures releasing contents
- highly inflammatory
Apoptosis
- programmed cell death
- fragmentation of DNA, membrane blebbing
- Cell remains cleared by phagocytosis
- non inflammatory
Describe the NK cell activation and inhibition overview
NK cells have activating and inhibitory receptors
- inhibitory recognise ligands on healthy cells (MHC class 1)
- activating recognise ligands on infected cells (markers of stress)
NK activation depends on balance of activating and inhibitory signals received
In what situations wold NK cells decide to kill and not kill
Don’t kill = inhibitory signals outweigh activation
Kill = activation signals outweigh inhibitory signals
How do Ab enhance NK cell killing
Via ADCC (antibody dependent cellular cytotoxicity)
- if pathogen Ag is left on cell Ab binds NK cells and triggers killing (not presented Ag by MHC class 1 and 2)
Which adaptive immune responses are directly and indirectly enhancing innate immunity
Indirecfrlyt: cytokines, ADCC
Directly: cytotoxic T lymphocytes (CTL), neutralising Ab
How do Th1 (CD4) and CTL (CD8) cooperate to kill pathogens?
Th1 cells produce IFN y to activate macrophages, NK cells and CTL which work together to kill phagocytosed bacterium in vesicles and infected cells in cytoplasm
How does Th1 cells enhance CD8 activation
Th1 cells (CD4) release IFNy which differentiates CD8 CTLs
How does CTL recognise infected cells
They recognise intracellular Ag presented by MHC class 1. CH8 recognises the antigen and forms a handshake so cell dies
CTL kill with high level of ___
Precision
What are the 2 killing mechanisms of CTL and NK
- Performing granzyme - perforin makes pore in infected cells membrane. Granzyme enters and induces apoptosis
- Fas/FasL - target cells express Fas. CTL/NK expresses FAS ligands (FASL) activating FAs and Fas activation signals apoptosis
How do you activate Naive CD8 CTL if dendritic cell is not infected
Cross -presentation - allows DC to take up extracellular antigens and present them on MHC class 1 instead of class 2 (bc MHC 1 only activated if its dendritic cell bc only intracellular)
How do viruses evade cytotoxic T lymphocytes (CTLs) and how do NK cells respond?
Viruses evade CTLs by disrupting MHC class I antigen presentation. They may inhibit proteasomal activity (e.g., EBV, human CMV) to block peptide generation or interfere with MHC synthesis/retention in the ER (e.g., adenovirus, CMV), preventing antigen display on the cell surface. This makes infected cells invisible to CTLs. However, NK cells can detect and kill cells with reduced or absent MHC I expression, serving as a backup defense.
How do antibodies neutralize intracellular pathogens?
Antibodies can neutralize intracellular pathogens during their extracellular stages—such as when they move between cells—by binding to key surface proteins. This prevents the pathogen from infecting new cells. For example, SARS-CoV-2 vaccines induce antibodies that target the spike protein, blocking its interaction with host cell receptors and stopping viral entry.
