the current state of knowledge on innate and adaptive responses during fmdv infection bryan...
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The Current State of Knowledge onInnate and Adaptive Responses
during FMDV Infection
Bryan Charleston
DAYS
ME
AS
UR
EM
EN
T
14654321 87
Diagnostic windows
● ● ● ●
FMD virus in blood
Clinicallesions
antibody response
FMD virus at mucosal sites
Transmission
FMDV-sequence of events
Effect of CD4 T cell depletion onneutralising antibody response to
vaccination
T-dependent response to antigen
McHeyzer-Williams, L.J. & McHeyzer-Williams, M.G. Antigen-specific memory B cell development. Annu Rev Immunol 23, 487-513 (2005).
Short-lived plasma cells:Supposed to secrete Ab in situ for a short period of time within the lymphoid organ in which they are generated
Memory B cells:Recirculate between blood and tissues in a quiescent state (do not spontaneously secrete Ab)
Long-lived plasma cells:Spontaneously secrete Ab for a long period of time.Only detectable when transiting from the lymphoid organs towards specific niches (bone marrow, red pulp of spleen)
Day 7
Day 1 Day 7
MiceFMDV infection of mouse BMDCs is abortive, infected cells lose their ability to stimulate T-cells and differentiate towards a macrophage-like phenotype.
Generalized suppression of T-dependent responses has been observed in vivo in mice between 3 and 5 days p.i., thought to be mediated in part byMHC class II and CD40 downregulation on DCs and by IL-10.
FMDV infection induces a reduction in splenic plasmacytoid dendritic cells (pDCs) and conventional DCs (CD11c+ /CD8a+).
Antigen presentation
PigsFMDV infection of porcine pDCs, monocyte derived DCs (MODCs) and BMDCs is abortive.
Porcine MODCs respond in vitro by increasing expression of MHC class II and CD86,But data generated in vitro from cells derived from infected pigs are moreconsistent with the suppressive responses described in vitro and in vivo in mice.
Cattle FMDV infection of bovine MODCs is productive and infected cellsdie, losing their ability to stimulate T-cell proliferation in vitro.
Immune complexs induce low quantities of IFN from pDC
No reports of generalized immunosuppression during the acute phase of FMDV infection in cattle.
Antibody mediated infection/ uptake of virus and antigen
Acute FMD: naïve buffalo
Windsor et al., 2011
Reid et al., 2011
Biologically active type 1 IFN
Days post challenge
I.U./
ml I
FN
Day 0
Day 2
Day 4
Day 6
Day 8
0
10
20
30
40
50
6090
100
X1X2X3X441718192526334344476061
Acute FMD: naïve buffalo
Days post challenge
To
tal l
euco
cyte
co
un
ts x
106
/ml
Day 0
Day 2
Day 4
Day 6
Day 8
Day 1
1
Day 1
40
1
2
3
4
5
6
7
8
9
10
X1X2X3X441718192526334344476061
Buffalo leucocyte count (n = 16)
Windsor et al., 2011
Bovine B cell response to antigen
TD antigen-specific response FMDV-specific response
FMDV D46 DAPI
LZ
DZFMDV D46
80 µm
MLN 38DPCI
Budras, Bovine Anatomy
Follicles with central crypt
Casteleyn et al.,
M Hofmeyr
FMD: buffalo
Fundamental differences between cattle and human antibodies
Variable (VH)
Diversity (DH)
Junctional (JH)
Constant (CH)
Germline
κλ
Variable (VL)
Junctional (JL)
Constant (CL)
Germline
λGene segment recombination
Gene segment recombination
Translation
-S-S--S-S-
-S-S--S-S-
3.6 x 106
potential combinations of heavy and light chains
X X XXX
X
Bimodal bovine CDR3 distribution
Bovine antibodies – long CDR3
Wang et al., 2013Cell 153 1379
Oyen et al., 2011J. Mol. Biol. 407, 138
And there are revolutions in electron microscopy…
Wonderful new detectors, that collect 4k movies, and allow virus particle movements to be tracked in software … so we can see atomic detailLive virus in cryo – in a water ‘glass’ Expensive – hence a National Facility for the UK
70hrs Collection on Polara70hrs Collection on Polara
PirbrightClare GrantVeronica CarrJohn HammondClaudine PortaNick JuleffMirrie WindsorEva PerezJulian Seago
Oxford/ DiamondDave StuartLiz FryAbhay KotechaAnna FowlerMarton Munz Gerton Lunter
ReadingIan Jones
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