Host Response to Infections Microbial Pathogenicity 7050 Host Response to Infections Dr Adrienne Meyers National Laboratory for HIV Immunology NML 204 789 3260 Adrienne.Meyers@phac-aspc.gc.ca October 2013

Objectives To gain an overview understanding of the functioning, physiological immune response To understand how different pathogens impact the host immune system function

Section Outline Introduction to the Immune Response Cells of the Immune System Innate vs Adaptive Immunity Immune Response to a Pathogen Accessing the host Innate and Adaptive Responses to Bacteria, Viruses Mechanisms Pathogens Use to Evade Immune Response Evasion Destruction

Immune System Goal = protection against pathogenic invasion

Pathogenic Organisms Pathogens Viruses Bacteria Parasites Fungi

Cells of the Immune System 6 Cells of the Immune System T Lymphocytes Thelper, Tcytotoxic, Tregulatory B Lymphocytes Plasma cells NK Cells Antigen Presenting Cells (APCs) Macrophage, Dendritic PolyMorphonuclear Leucocytes (PMLs) Neutrophils, Basophils, Eosinophils http://textbookofbacteriology.net/adaptive_2.html

Immune System Protection – How? 7 Immune System Protection – How? Immunity Adaptive Immunity Innate Immunity Humoral Immunity Cell-Mediated Immunity Ultimate Goal: Removal of Infectious Agent

Phagocytes (macrophages, neutrophils) Innate Immunity Adaptive Immunity Defense Immediate (natural/native) Secondary (specific/acquired) Specificity Non (“broad”) Antigen-specific Memory No Yes Cells Natural Killer (NK) Phagocytes (macrophages, neutrophils) Lymphocytes Mechanism Barriers Phagocytosis Cytotoxicity Antibodies

Innate Immunity “non-specific” immune system First line of defense Functions Recruiting immune cells to site of infection Activation of complement cascase ID/Removal of foreign substances Activation of Adaptive Immunity (Ag Presentation) Physical Barrier against infection

Innate Immunity - Barriers Skin Mucous GI tract Cells Leukocytes NK, Mast, Baso, Eos Phagocytes MΦ, DC, Neutrophils

Innate Immunity – Cells NK Mast Phagocytes MΦ DC Neutrophils γδ T cells Internal/External Receptors PRRs, NK, TCR, BCR Recognize “foreign” Nature Reviews Immunology

Innate Immunity – How Do Cells “Destroy”? Cytotoxic Molecules – Granzymes, NO Cytokines/chemokines – interferons Antibodies – neutralization/opsinization Phagocytosis

Innate Immunity – NK Cells Activated through a complex system of activating and inhibiting signals, cytokines, and Fc receptors Cytoplasmic granules Perforin, granzymes Kill adjacent cells Secrete cytokines TNF, IFN-γ

Innate Immunity – MΦ, DCs Phagocytosis Major role antigen presentation (APC) - Via major histocompatibility complex (MHC) Secretion of cytokines - IFN, IFN, TNF, IL-12 Signals the adaptive IR - Up-regulation of co-stimulatory and signalling molecules i.e. MHC http://jvi.asm.org/content/80/10.cover-expansion http://www.bluebananadesigns.com/illusMacrophageMed.html

Innate Immunity – PAMPS and PRRs Many Different Pattern Associated Molecular Patterns (PAMPs) Pattern Recognition Receptors (PRRs) PRRs act as receptors for PAMPs – recognize and bind Toll Like Receptors (TLRs), NOD-like Receptors Activate APCs and initiate important signalling cascades (i.e. cytokine production)

Innate Immunity - TLRs TLR 1,2,4-6,10: Extracellular TLR 3,7-9: Intracellular (endosomes) Membrane receptors B Cells, T Cells, APCs Recognize structural elements That are common to broad Classes of microbes http://labs.mmg.pitt.edu/sarkar/Signaling.htm

Innate Immunity – Immediate Response Inflammation The response of living tissue To injury Purpose? Repair Signal Danger Phagocytosis

Innate Immunity – Cyto/Chemokines CYTOKINE/CHEMOKINE CELL TYPE RESPONSE TNF-α IL-1, IL-6 MΦ, DC Acute phase response to infection CCL2 (MCP-1) MΦ Attracts more cells (NK, DC, T) IFN-α,-β MΦ, T cells, NK Induce Antiviral state Activate NK cells IFN-γ IL-2, IL-12 MΦ, NK, DC, Thelper Cellular IR IL-4, IL-5, IL-6 IL-10, IL-13 Thelper Humoral IR

Innate Immunity – IFN Signaling http://www.invivogen.com/review-type1-ifn-production

Transition from Innate to Adaptive Immunity

http://drrajivdesaimd. com/wp-content/uploads/2013/04/innate-vs http://drrajivdesaimd.com/wp-content/uploads/2013/04/innate-vs.-adaptive.png

Time Course of Immune Response To Pathogen or Vaccination http://en.wikipedia.org/wiki/File:Immune_response.jpg

Adaptive Immunity Activation of Adaptive IR results in Stimulation of humoral (B cell) and T-cell mediated effects Development of Ag-specific memory

Adaptive IR - Cells T Cells B Cells Cell-mediated IR, secrete cyto/chemokines T cell Receptor (TcR) recognition of pathogens via MHC Subsets: CTL (CD8+) – cytotoxic killing Thelpers (CD4+) - modulate IR Tregs (CD4+CD25+FoxP3+) - suppress activation of IR B Cells Humoral IR, secrete antibodies, cyto/chemokines B cell Receptor (BcR) recognizes pathogens

TLRs Link Innate and Adaptive IR Nature Reviews Immunology 3, 984-993 (2003); DENDRITIC-CELL CONTROL OF PATHOGEN-DRIVEN T-CELL POLARIZATION

Adaptive Immunity – CMI Cell Mediated Immunity T Cell receptors recognize peptide fragments of protein antigens When the peptides are presented by “display” molecules (MHC) on host antigen presenting cells (APCs) This antigen “presentation” is required for T cell Activation

Antigen Presenting Cells APCs internalize, process and present Ag to T cells Dendritic Cells (Professional APC) Most nb APC, very specialized Macrophages B Cells

T Cell Circulation/Function T cells develop in thymus, migrate to bloodstream and circulate b/w blood and peripheral lymphoid tissue NAÏVE T Cells – mature, haven’t yet encountered their specific antigens in the peripheral lymphoid organs EFFECTOR T cells – Naïve T cells that have encountered their antigen, proliferated and differentiated to effector T cells Role in removal of antigen

Adaptive Immunity – T Cell Activation CD4+ Th sees peptide on MHC II CD8+ CTL seees peptide on MHC I Recognition Replication http://imuthes.com/r-and-d/vaccines/t-cells

T Cell Activation, Expansion, Memory

Thelpers = “Directors”

T Cells – CD8 CTL Effectors CD8+ CTLs kills cells containing microbes or microbial proteins Eliminates the reservoir of infection

Adaptive Immunity - Humoral Via secreted antibodies – key protection against extracellular pathogens and their toxins Antibodies prevent infection prior to establishment Block binding/entry of microbes Bind toxins and prevent damage to host cells Eliminate microbes, toxins and infected cells

Adaptive Immunity – B Cells

Adaptive Immunity – B Cells

Adaptive Immunity – Antibody Effects

Adaptive IR - secondary Memory Cells (B and T) respond much faster and amplify very quickly B cells have high affinity antibodies

Adaptive IR to Foreign Pathogen

Immune Response vs Pathogen Virus, Bacteria, Parasite, Fungus, Toxin Route of Infection? Extracellular vs Intracellular Pathogen Pathogen structure Infectious dose / Virulence

Pathogens Viral Bacterial Parasitic RNA: Ebola, Influenza, Dengue DNA: Smallpox, Hepatitis B Virus Bacterial Gram +: Anthrax, Tuberculosis Gram -: Plague, Chlamydia Parasitic Multicellular: Schistosomes, Tapeworm - Single Cell: Leishmania, Giardia

Important Features of Pathogenesis Tissue injury/disease as a result of infection can be a result of the host response to the pathogen/products The ability of a pathogen to evade an effective host immune response is a critical means of survival and longevity

Mode of Entry A pathogen’s mode of entry can impact the type and strength of the host immune response

Immunity to Extracellular Bacteria Replicate outside host cells Cause disease via Induction of inflammation/tissue destruction at site Bacterial production of toxins Endotoxin, exotoxin Immune responses aim to Eliminate bacteria Neutralize effects of bacterial toxins

Adaptive IR to Extracellular Bacteria Adaptive IR to extracellular pathogens Antibody production (“humoral” immunity) Activation of CD4+ Thelper cells Humoral immunity is primary protective IR against extracellular bacteria Blocks infection Eliminates bacteria Neutralizes txoins

Immunity to Intracellular Bacteria Survive and replicate within phagocytes Good at finding “hiding spots” to avoid circulating antibodies Elimination via Cell Mediated Immunity

Intracellular Bacteria – Innate Immunity The innate immune response to intracellular bacteria is mainly mediated by: -Phagocytes (Macrophage/DC) -Natural Killer (NK) cells

Intracellular Bacteria – Adaptive Immunity Primarily via Cell-Mediated Immunity (T cells)

Intracellular Bacteria – Immune Evasion

Immunity to Viruses Obligatory intracellular pathogens Hijack host cell machinery Nucleic acid/protein synthesis Replicate within host cells Use host cell surface molecules as receptors to gain entry to new host cells

Innate Immunity - Viruses Physical/Chemical Barriers Epithelia Antimicrobial/antiviral substances at surfaces Inhibition of infection Type 1 IFNs Innate cell-mediated killing of infected cells NK

Adaptive Immunity - Viruses

Immune Evasion - Viruses Virus Infection of WBC (HIV) Impairs immune response Downregulation of MHC (Pox, Adeno, Herpes, HIV) Make infected cells less susceptible to CTL-mediated killing Interference with cytokine production Block IFN production/response Antigenic Variation Influenza, rhinovirus, HIV Production of immunosuppressive cytokines Epstein Barr Virus

Influenza Virus - Orthomyxoviridae ssRNA segmented genome Aerosol transmission Acute infection – sudden onset, short lived Fever, cough, aches, fatigue, respiratory distress Makes neutralizing antibodies to surface proteins

Influenza Virus - escape Viral Protein (NS1) blocks host PRR (RIG-1) Inhibits IFN signaling/response Antigenic Shift Emergence of new strain (via reassortment) No immunity Antigenic Drift Gradual changes in HA or NA Not recognized by antibodies

What You Should Know…. Innate vs Adaptive Immunity Cell-mediated vs Humoral Immune Response Main Cells of Immune System How Pathogens impact the Immune Response 2 examples of how Pathogens evade the Immune Response