Immune response to infectious agents

1. Georgia M. Dunston, Ph.D.
Department of Microbiology
October 2, 2015
Immune Responses to
Infectious Agents
FALL
2015
Biology of Pathogens I

2. References
 Kuby Immunology Seventh Edition, 2013
Owen JA, Punt J and Stranford SA with contributions
by Jones PP. W.H. Freeman and Company.
Chapter 5 Innate Immunity 141-185 and Chapter
17 Infectious Disease and Vaccines, 553-591.
 Immune Attack: Video Game that teaches
immunology by Colleen Smith, Published: Jul 24,
2008 http://fas.org/immuneattack/download

3. Objectives
1. Distinguish between innate and adaptive immunity.
2. Identify cells and molecules of the innate immune system.
3. Describe the process of phagocytosis.
4. Describe the inflammatory response.
5. Show cooperation between innate and adaptive immunity

4. Innate Immunity
We live in a microbial world and our bodies
are constantly exposed to bacteria, fungi,
parasites, and viruses. Innate immunity
consists of the defenses against infection
that are ready for immediate action when a
host is attacked by a pathogen.

5. Nonspecific Host Defenses

6. Skin and other epithelial barriers to infection

8. Effectors of Innate Responses to Infections

11. DIAPEDESIS

15. Other Proteins of Innate Resistance
 Complement proteins: These are a group of serum proteins that upon
activation results in the generation of many powerful biologically active
substances and lysis of microbial cells and viruses containing membranes.
The so called alternate pathway of complement is a nonspecific response to
many different pathogens
 Acute phase proteins: The level of these proteins in serum are usually
relatively low but may increase 1000 fold during infections They are
products of the liver and include mannose-binding protein, C-reactive
protein and serum amyloid protein P. Inducers of these hepatic proteins
include cytokines IL-1,IL-6,Tnf and bacterial component LPS
 Interferons(IFNs): A class of similar antiviral proteins produced by several
different types of cells in the mammalian host in response to viral infection.
They appear early during infection. They are host-cell- specfic but not virus-
specific (IFNs of a species are active against a number of different viruses)

16. TOLL-LIKE RECEPTORS (TLR)
Toll-like receptors are a family of
receptors involved in the recognition
of a wide range of microbial molecules
(e.g. lipopolysaccharide (LPS) from
Gram-negative bacteria and
peptidoglycan from Gram positive
bacteria).

17. TOLL-LIKE RECEPTORS (TLR)

18. TOLL-LIKE RECEPTORS (TLR)

19. INFLAMMATORY RESPONSE
 Inflammation is the body’s response to tissue injury caused
by trauma of infection
 The most important signs of inflammation are rubor, calor
(redness and heat due to increased blood flow to the area), tumor (
swelling due to edema and influx of cells to the injured area) dolor
(pain) and functio laesa ( lost of function)
 The response is characterized by:
 Vasodilation ( increase in the diameter of blood vessels)
 Vascular permeability ( increase capillary permeability)
 Influx of phagocytes and blood proteins from the more
permeable vessels to the injured area
 Tissue repair involves regeneration of new connective tissue
and blood vessels

20. Summary of the Innate Immunity

21.  Basic barrier mechanisms and simple biochemical defenses are
the frontline of immunity
 Innate immune responses depend on recognition of “general”
pathogen molecules
 Responses are varied, but include:
 Phagocytosis
 Triggering of inflammatory responses
 Direct destruction by natural killer cells
 Initiation of adaptive immune responses
 Learning the first defense strategies of immunity helps to better
understand the later adaptive methods
Summary of Innate Immunity

22. Lecture Outline Cont’d
Primary and Secondary Lymphoid Organs
Color code: Primary/red; Secondary/blue

23. Lecture Outline Cont’d
IMMUNE SYSTEM CELLS
Hematopoietic stem cells (HSC) in bone marrow >
progenitor cell > immune cells.
- Myeloid lineage gives rise to the phagocytic
and inflammatory cells of the innate immune
system.
- Lymphoid lineage gives rise to the T and B
lymphocytes of the adaptive immune system
and to natural killer cells which are generally
regarded as part of the innate immune system.

24. Lecture Outline Cont’d

25. Lecture Outline Cont’d

26. HUMORAL (ADAPTIVE) IMMUNITY
Lecture Outline Cont’d

27. Lecture Outline Cont’d

28. 12
Lecture Outline Cont’d

30. A. Innate immunity consists of cells and molecules that
distinguish host cells from those of infectious agents,
in part by recognizing conserved constituents of
microorganisms.
- not acquired through contact with an antigen
- nonspecific
- does not improve after exposure to the antigen
- no memory
B. Adaptive immunity can recognize essentially an
unlimited number of different targets but becomes
effective only after a delay on first encounter with a given
microorganism.
- acquired through contact with an antigen
- specific
- increased after exposure to the antigen
- memory
Comparison of Innate and Adaptive Immunity

32. Lecture Outline Cont’d

33. Lecture Outline Cont’d

34. T Cell Activation
Lecture Outline Cont’d

35. ADAPTIVE IMMUNITY
Lecture Outline Cont’d

36. Cooperation Between Innate and Adaptive Immunity

37. Primary and Secondary Immune Response

38. 13
Summary of Immunity

39. Immunity to Infectious Diseases

40. Viral infections
 Viruses typically enter
host cells through a cell-surface receptor
 Once inside, replication can occur
 Genome replication is often error-prone, leading
to mutations
 Viruses are more likely to thrive if they don’t
kill the host
 More chance for replication and spread
 During replication, viruses trigger humoral and
cell-mediated adaptive immunity mechanisms.

41. Viral infections (cont’d)
 Many viruses are neutralized by antibodies
 By binding to the virus, antibodies can
prevent it from binding to a target cell
receptor
 This can occur on viruses when they enter a
system if the Antibody is present, preventing
productive infection
 Can also happen on viruses when they leave a
host cell after being formed, protecting adjacent
cells.

42.  Cell-mediated immunity is important for viral
control and clearance
 Antibody can’t target cells where viral genomes
have integrated into host cell chromosomes
 CD4+ helper T cells secrete cytokines that
promote antiviral activity
-IFN-γ directly induces an antiviral state in adjacent cells
- IL-2 indirectly assists via promotion of CTL differentiation
 CD8+ CTLs actively find and destroy (through
apoptosis) virally infected host cells
 Prevents production of more virus particles
Viral infections (cont’d)

43. Viral infections (cont’d)
Examples include Antibody
Preventing influenza virus from binding
to sialic acid residues in cell membranes
Production of sIgA that binds to
poliovirus, preventing its attachment to
epithelial cells of the GI tract.

44. Viral infections (cont’d)
 Viruses employ several different strategies
to evade host defense mechanisms:
1. Hepatitis C overcomes interferon antiviral effects by
blocking/inhibiting PKR
2. HSV inhibits TAP activity, effectively shutting down MHC
class I presentation to CD8+ T cells
--Adenoviruses and cytomegalovirus use a similar strategy
--Measles virus/HIV inhibit MHC class II expression and
presentation to helper T cells
 Some viruses code for anti-complement proteins
 Other viruses constantly change their surface Ag
 Influenza virus

45. Viral infections
 Influenza has been responsible for some
 of the worst pandemics in history
 Properties of the influenza virus
 --Three basic types: A (most common
 for pandemics), B, C
 --Two key viral glycoproteins
 Hemagglutinin (HA)―
 allows attachment of virus to cells
 Neuraminidase (NA)―helps new
 virus escape from host cells

46. Bacterial infections
Immune responses to extracellular and
intracellular bacteria can differ:
---Antibody provides several strong
mechanisms for elimination of
extracellular bacteria
---Intracellular bacteria are not as
strongly affected by antibody
(except while outside target cells)
---Can activate NK cells and
macrophages for clearance

47. Bacterial infections (cont’d)

48. Bacterial infections (cont’d)
Diphtheria can be controlled by immunization
with inactivated toxoid
 Human infection spread by respiratory droplets
 Can damage heart, liver, and kidneys; causes fibrous
membrane formation in respiratory tract
 Symptoms caused by a secreted exotoxin coded for by a
bacterial virus carried in C. diphtheriae
---Immunization produces antibodies that bind to the
toxin and neutralize its activity
---Combined with whooping cough and tetanus
vaccines (both formed with inactivated toxoids)

49. Parasitic infections
Protozoan parasites account for huge
worldwide disease burdens
Malaria- #1 cause of parasite-induced death worldwide
Genus Plasmodium species carried by female
Anopheles mosquitoes
• Life cycle moves through liver/RBCs
• Immunity is poor in children under 14
• Maturational changes allow Ag shifting
• Intracellular phases resist Ab-based responses
• Short blood circulation time of free parasite stage
prevents good immune stimulation
• Ab responses avoided by outer coat shedding
• Drug resistance becoming a problem

50. Parasitic infections
Protozoan parasites account for huge
worldwide disease burdens
African sleeping sickness
 Caused by two trypanosome species
 transmitted by tsetse fly bites
 Protozoan differentiates and divides every
six hours in blood
-- Moves from blood to central nervous system
•- Expresses 1 VSG gene at a time
•- Prevents effective immunity
•- Results in waves of parasite multiplication/
symptoms

51. Parasitic infections (cont’d)
A variety of diseases are caused
by parasitic worms (helminths)
 Enter hosts through intestinal tracts
 Exclusively extracellular
 Don’t replicate in hosts, limiting
immune engagement
 May decrease external Ag expression
or wrap themselves in host proteins to
further limit immunity
 Immunity may proceed via induction
of IgE production and recruitment of
eosinophils
 Induction of TH1 IFN-γ macrophage
activation is more effective

52. Parasitic infections (cont’d)
Protozoan parasites account for huge worldwide
disease burdens--Leishmaniasis
 Lives in macrophage phagosomes
 Transmitted by sandflies
 Produces one of two syndromes
 Localized cutaneous self-resolving lesion
 Systemic visceral leishmaniasis
 Nearly always fatal without treatment
 Resistance is mediated by an effective TH1 response
and IFN-γ secretion
 Individuals skewed to TH2 response are less likely to
resolve leishmaniasis infections

53. Fungal infections

54. Fungal infections (cont’d)
Innate immunity controls most fungal infections
 PRRs on innate immunity cells keep fungal cells in check
 Commensal fungal organisms also help “crowd out”
pathogenic fungi
This is why antibacterial medications may result in oral
thrush or vulvovaginal candidiasis (yeast infections)
• Commensal microbes suddenly have no competition
for resources
• Induction of phagocytosis helps destroy fungal cells
 Fungi have evolved evasion mechanisms
 Capsules that prevent PRR binding
 Fungi-induced expulsion from macrophages

55. Fungal infections (cont’d)
Immunity against fungal pathogens can be acquired.
 Can individuals acquire resistance against fungal pathogens? YES
 Evidence in HIV patients
 Control/resistance eventually lost, resulting in increased
incidence of fungal infections
 Evidence in B cell-deficient mice
 No increased susceptibility to fungal infections
 Resistance must be mediated by cellular responses
 Observations indicate strong TH1 responses are effective
at controlling fungal infections; TH2/TREG responses are
tied to increased susceptibility to such pathogens