Immunology

Learning Objectives

• Explain common features for success by pathogenic microbes.
• Describe strategies employed by pathogens for host cell invasion.
• Highlight the cellular components of the immune system.
• Differentiate cells involved in innate and adaptive immunity.
• Understand how pathogens activate innate immune cells.
• Explain how adaptive immune cells are activated.

What are Microbes?

• Microbes (microorganisms) are living organisms of microscopic size, including:
  • Bacteria
  • Viruses
  • Protozoa
  • Fungi
• There are also non-pathogenic microbes.
  • Normal flora in the human body (microbiome) such as Lactobacillus acidophilus and Staphylococcus epidermidis.
  • Microbes involved in making yogurt: Streptococcus thermophilus and Lactobacillus bulgaricus.

Key Features of Bacterial Invasion

• Bacteria produce virulent factors (toxins) and release them into host cells.
• Some bacterial toxins are composed of two protein components: A and B subunits.
• Apart from toxins, bacteria also produce adhesins, capsules, form biofilms, and some have secretory systems to inject effector proteins into host cells.
  • A subunit: (Toxic subunit)
  • B subunit: (Receptor-binding subunit)

CT AB-subunit: Vibrio cholerae toxin mechanism

B subunit binds to Ganglioside receptor

• The A Subunit interacts with a G-protein,
• This activates adenylate cyclase
• This converts ATP into cAMP
• cAMP activates protein kinase
• This in turn phosphorylates CFTR (Cystic Fibrosis Transmembrane Conductance Regulator)
• There is an increase in the export of $Na^+, K^+, Cl^-, and HCO_3$
• This leads to an increase in $H_2O$ export, which leads to diahrrea

Mechanism of Typical Viral Host Entry

1. Binding to cell surface receptors.
2. Entry.
3. Uncoating.
4. Replication:
   • RNA viruses replicate viral RNA.
   • DNA viruses replicate viral DNA.
5. Transcription (mRNA).
6. Translation.
7. Virion assembly.
8. Release.

Key Features of Viral Invasion

• Host cell manipulation
• Drug resistance
• Host specificity
• Examples:
  • HIV-gp120
  • CCR5
  • CXCR4
  • CD4

Protozoa

• Protozoans are a diverse group of unicellular eukaryotes.
• Some require more than one host to carry out their life cycle.
• Examples of parasitic protozoans:
  • RBCs infected with Plasmodium
  • Trypanosoma brucei
  • Entamoeba histolytica

Protozoan Invasion of Host Cell (Trypanosoma cruzi)

1. Attachment to host cell-surface receptors.
2. $Ca^{2+}$ signal.
3. Fusion of lysosomes recruits lysosomes with the plasma membrane.
   • Lysosome-independent pathway
   • Lysosome-dependent pathway
4. Invasion
5. Secretion of pore-forming protein.
6. Lysis of surrounding membrane, release of the pathogen into the cytosol.

Common Features Promoting Successful Host Invasion

• Ability to enter the host and locate a suitable niche.
• Evade host immune responses (innate and adaptive).
• Replicate within the host.
• Be transmitted from an infected to an uninfected host.

Hematopoiesis

• Hematopoiesis is the process by which hematopoietic stem cells (HSCs) differentiate into mature blood cell types.
• Mature blood cell types: Red blood cells (RBCs), granulocytes, macrophages, dendritic cells, lymphocytes arise from the HSCs
• Examples:
  • Natural killer cell (NK cell)
  • Eosinophils
  • Basophils
  • Neutrophils
  • Dendritic cells (DCs)
  • Macrophage
  • Mast cell
  • B cell
  • T cell
  • Platelets
  • RBCs

Where Immune Cells Develop

• Thymus: T cells
• Bone marrow: B cells
• Primary lymphoid organs: Bone marrow and Thymus
• T lymphocytes unlike B lymphocytes mature in the Thymus.

Secondary Lymphoid Organs

• Lymph node
• Tonsils
• Spleen
• Peyer's patches in the small intestine

Myeloid Cells

• First responders to infection
  • Neutrophils
  • Basophils
  • Eosinophils
  • Monocyte
  • Mast cell

Lymphoid Cells

• Key players of adaptive immunity
  • B cell
  • T cell
  • NK cell
• Multipotent Hematopoietic Stem Cells (HSCs) -
• Common Lymphoid Progenitor (CLP)

The Defense Mechanisms

• Innate (non-specific):
  • Present in the body at birth.
  • Recognition element is fast; response time is within minutes/hours after barrier breach.
  • It is non-specific to a particular pathogen.
  • Does not require prior exposure to pathogens.
• Adaptive (specific):
  • Acts in response to infection and adapts to better recognize and eliminate foreign agents.
  • Response time is slower, can take up to days/weeks.
  • Recognition is specific to non-self antigens.
  • Generates immunological memory

How Pathogens Activate Innate Immune Cells

• Pattern Recognition Receptors (PRRs)
• Pattern recognition
• Microbe receptors (PRRs) on immune cells
• Pathogen-associated molecular patterns (PAMPS) on pathogen
• Innate immune cell activation
• Pathogen recognition
• Pathogen-Associated Molecular Patterns (PAMPS)

Typical Example of PRR and PAMP Binding

• PRR: TLR4
• PAMP: LPS
• Example: E. coli activating an innate immune cell.

How Adaptive Immune Cells Recognize Pathogens

• T cell: TCR
• B cell: BCR

Innate Immune Cells Trigger Adaptive Immunity

• Dendritic cell is a professional “Antigen Presenting Cell” = APC
• MHC
• Pathogens
• APC
• Naïve T cell in the Lymph node
• Innate immune cells are first responders to invading pathogens
• Innate immune cells activate adaptive immune cells

Initiation of Adaptive Immune Responses

• Site of infection e.g lung
• T cell zone
• B cell zone
• Efferent lymphatics
• Afferent lymphatics
• Lymph node
• DCs
• DC-bearing antigen
• Naïve lymphocytes
• Activated lymphocytes
• Activated lymphocytes exit the LN as effector cells
• Blood stream
• Effector cells are transported to the infection site
• High endothelial venules (HEVs)

Lecture Summary

• For pathogens to infect their host, they must be able to enter the host, locate a suitable niche where they can replicate, escape from the host’s protective mechanisms, and then exit the host to spread to others.
• Multipotent haematopoietic stem cells (HSCs) give rise to two main progenitors; myeloid and lymphoid lineage.
• Primary lymphoid organs are where immune cells develop, while secondary lymphoid organs are sites where lymphocytes encounter antigens.
• B and T lymphocytes are cells of the adaptive immune system.
• DCs-bearing antigens migrate to lymph nodes to initiate the adaptive immune response.

References

• Ramamurthy, T., Nandy, R. K., Mukhopadhyay, A. K., Dutta, S., Mutreja, A., Okamoto, K., … & Ghosh, A. (2020). Virulence regulation and innate host response in the pathogenicity of Vibrio cholerae. Frontiers in Cellular and Infection Microbiology, 10, 572096.
• Murphy, Kenneth M. & Weaver, Casey (2022). Janeway's immunobiology. 10th Edition .
• Alberts, Bruce Heald, Rebecca Johnson, Alexander Morgan, David Raff, Martin Roberts, Keith Walter, Peter (2022). Molecular biology of the cell. 7th Edition.
• Mann, Z., Sengar, M., Verma, Y. K., Rajalingam, R., & Raghav, P. K. (2022). Hematopoietic stem cell factors: their functional role in self- renewal and clinical aspects. Frontiers in Cell and Developmental Biology, 10, 664261.
• Uribe-Querol, E., & Rosales, C. (2017). Control of phagocytosis by microbial pathogens. Frontiers in immunology, 8, 1368.