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The thrust and parry of host pathogen interactions OR Host defense from a pathogens point of view

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Expansion of germinal center reactions involving B and T cells in Peyer's ... Pleurocidin from skin mucous secretions of the winter flounder. LL37 from humans. ... – PowerPoint PPT presentation

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Title: The thrust and parry of host pathogen interactions OR Host defense from a pathogens point of view


1
The thrust and parry of host pathogen
interactionsORHost defense from a pathogens
point of view
2
Infection via an Epithelial Surface
3
The epithelial barrier
  • Normal Flora
  • Mucus Layer
  • Secreted IgA
  • Antimicrobial peptides
  • Tight Junctions
  • Intraepithelial Lymphocytes

4
Protection by normal flora
5
Normal flora are necessary forintestinal immunity
6
Bacterial Contributions to Gut Adaptive Immunity
  • Formation of anatomical structures, including
    Peyers patches, which harbor developing B and T
    cells
  • Expansion of germinal center reactions involving
    B and T cells in Peyers patches
  • Increased IgA production by intestinal B cells
  • Generation of antibody diversity (in rabbits)
  • Expansion of intraepithelial lymphocyte
    populations (abTCR-bearing)

7
Antimicrobial peptides
  • Small polypeptides secreted at all mucosal
    surfaces
  • Also in phagocytes
  • Direct bactericidal properties
  • Insertion into biological membranes
  • Inhibited by cholesterol

8
Varieties of antimicrobial peptides
  • Anionic peptides
  • Dermcidin from humans.
  • Linear cationic a -helical peptides
  • Cecropins.
  • Magainin
  • Pleurocidin from skin mucous secretions of the
    winter flounder.
  • LL37 from humans.
  • Cationic peptides enriched for specific amino
    acids
  • Anionic and cationic peptides that contain
    cysteine and form disulphide bonds
  • Peptides with 3 disulphide bonds include a and b
    -defensins.
  • Peptides with gt3 disulphide bonds include
    drosomycin in fruit flies and plant antifungal
    defensins.
  • Anionic and cationic peptide fragments of larger
    proteins
  • Lactoferricin from lactoferrin.
  • Casocidin I from human casein.
  • Antimicrobial domains from bovine -lactalbumin,
    human haemoglobin, lysozyme and ovalbumin.

9
Mechanisms for antimicrobial peptide bactericidal
activity
10
Bacterial resistance mechanisms
Alteration of net surface charges Staphylococcus
aureus reduces the net negative charge by
introducing basic amino groups. Capsule
polysaccharide of Klebsiella pneumoniae limits
the interaction of antimicrobial peptides with
membrane targets Alterations in Lipid
A Salmonella species reduce the fluidity of their
outer membrane forming hepta-acylated Lipid A by
adding palmitate. The increased hydrophobic
moment is though to retard or abolish
antimicrobial peptide insertion and pore
formation. Changes in membrane proteins In
Yersinia enterocolitica, alteration in the
production of outer membrane proteins correlates
with resistance to killing by antimicrobial
peptides. Role of transporters ATP-binding
cassette transporters import antimicrobial
peptides and the resistance-nodulation
cell-division efflux pump exports antimicrobial
peptides. Both transporters have been associated
with antimicrobial peptide resistance. Proteolytic
enzymes Bacteria produce proteolytic enzymes,
which may degrade antimicrobial peptides. LL-37
is cleaved and inactivated by S. aureus
metalloproteinase aureolysin.
11
Not all gut epithelial cells make antimicrobial
peptides
12
Epithelial cells make IL-8 in response to bacteria
13
Breaching the epithelial barrier
14
Peyers Patches are an easier way through the
epithelial barrier
15
Dendritic cells
16
The Dendritic Cell Paradigm
  • DC are present at all epithelial barriers, where
    they are sentinels for infection
  • DC ingest invading pathogens
  • Upon this stimulus, DC migrate to local lymph
    nodes, where they present pathogen antigens to T
    cells, which initiate specific immunity
  • Thus DC are critical for crosstalk between innate
    and adaptive immunity

17
Mast cells in host defense
18
Mast cells in intra-abdominal abscess
PMN recruitment
19
Neutrophils are key cells in host defense at
epithelial barriers
  • For humans with PMN lt500, rate of systemic
    infection proportional to length of neutropenia
  • Without prophylaxis, 7days 100
  • Infections are generally with organisms from GI
    tract (including mouth, gums, oropharynx) gt lung

20
How do epithelial cells, dendritic cells, mast
cells (etc.) get activated by pathogens?
Toll-like Receptors (TLR) recognize
Pathogen-Associated Molecular Patterns (PAMPS)
21
PRR are ancient host defense receptors
Cell membrane
Nuclear membrane
22
TLR signaling
23
Complement System Overview
24
Mechanisms of evasion of complement killing
  • Thick cell wall (Gram positive)
  • Dont support alternative pathway initiation
    (sialic acid capsules)
  • Activation far from cell wall (smooth LPS)
  • Make inhibitors of complement activation or
    membrane insertion

25
Complement Opsonization
Deposition of C3b and particularly iC3b on
pathogen iC3b does not continue complement
cascade
26
Complement Receptors
27
Zipper Hypothesis
Phagocytosis Ingestion of solid material ? 1m
in diameter
Phagocytosis requires repeated sequential
interactions between the phagocyte membrane and
target particle
Implications Cell changes and signaling events
are very local Exquisite cellular discrimination
among surface receptors
28
PhagocytosisDictyostelium Genetics
Cardelli, Traffic, 2000
29
Phagocyte recognition of targets-Nonopsonic-
?PAMPs and PRRs (but TLRs probably dont mediate
phagocytosis, just signaling from the
phagosome) ?CR3 ?CD66, CD36 ?Mannose receptor and
other lectins
30
Opsonins
  • IgG, IgA
  • C3 fragments C3b and iC3b
  • Collectins and C1q
  • Pentraxins

31
Zippering, Sinking, and Coiling
Pathogens can regulate mode of phagocytosis
32
Distinct GTPase Effectors in Different Modes of
Phagocytosis
GTPase modulators are common TyIII effectors and
affect pathogen phagocytosis
33
The Virtual Phagosome
Pathogens can regulate targeting of host proteins
to the phagosome
Garin, et al JCB 2001
34
Effector mechanisms resulting from phagocytic
receptor engagement
Fc receptor engagement- proinflammatory CR3-
partially inflammatory Proinflammatory effector
mechanisms NADPH Oxidase (CGD) iNOS PLA2
Recruitment of TLRs TNFa, IL-1, etc.
Recruitment of effector mechanisms can be
blocked by pathogens
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