1. Host Response to Infections
Microbial Pathogenicity 7050
Host Response to Infections
Dr Adrienne Meyers
National Laboratory for HIV Immunology
NML
October 2013

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

3. 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

4. Immune System
Goal = protection against pathogenic invasion

5. Pathogenic Organisms
Pathogens
Viruses
Bacteria
Parasites
Fungi

6. Cells of the Immune System6
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

7. 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

8. 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

9. 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

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

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

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

13. 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

14. 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

15. 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)

16. 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

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

18. 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

19. Innate Immunity – IFN Signaling

20. Transition from Innate to Adaptive Immunity

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

22. Time Course of Immune Response To Pathogen or Vaccination

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

24. 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

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

26. 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

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

28. 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

29. Adaptive Immunity – T Cell Activation
CD4+ Th sees peptide on MHC II
CD8+ CTL seees peptide on MHC I
Recognition
Replication

30. T Cell Activation, Expansion, Memory

31. Thelpers = “Directors”

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

33. 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

34. Adaptive Immunity – B Cells

35. Adaptive Immunity – B Cells

36. Adaptive Immunity – Antibody Effects

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

38. Adaptive IR to Foreign Pathogen

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

40. 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

41. 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

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

43. 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

44. 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

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

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

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

48. Intracellular Bacteria – Immune Evasion

49. 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

50. 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

51. Adaptive Immunity - Viruses

52. 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

54. 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

55. 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

56. 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