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Brian Crucian, PhD, MT(ASCP)
UPDATE ON SPACEFLIGHT IMMUNE SYSTEM DYSREGULATION, CLINICAL RISKS FOR DEEP SPACE MISSIONS, POTENTIAL COUNTERMEASURES
https://ntrs.nasa.gov/search.jsp?R=20190000086 2019-08-04T20:09:25+00:00Z
The Immune System
I Plurlpotent Stem Cell
Myelold Stem Cell
/
T Lymphocyte _ ... ADAPTIVE IMMUNITY • Secondary defense • Delayed • Antigen-specific • Results in memory
• y >- -< -(
B Lymphocyte Plasma Cell TA >-
Erythrocyte
• Monocyte
Megakaryocyte (blood clottlng)
Macrophage
INNATE IMMUNITY • Primary defense • Immediate • Non-specific • Does not result in memory
Cell mediated immunity: Mediated by cytotoxic T lymphocytes which destroy viral infected cells , transplant cells , some tumor cells
Humoral immunity: Mediated by B cells/ Plasmacytes. Antibodies bind specific antigens, signals other cells to engulf and remove that target from the body.
MAST CELL
WHITE BLOOD CELLS
RED BLOOD CELLS
Nai·ve Plasma Memory B Cell ,. Cell : B Cell
tTreg
pTreg
Eat microbes
Cause
Allergy
Kill
Infected
Cells
Fight
Cancer
Make
Antibodies
Fight Parasites Direct
‘Right’
Kind of
Response
Protect you for life!Keep
‘Control’
Inflammation
Pathogen-specific Response
CYTOKINE NETWORK
Innate/Inflammatory
Adaptive/regulatory
Humoral
Chemokines
Growth Factors
Th1/Th2
IL-1 0
IL-12~ TNFCX TNFf3
\ .
IL-1 IL-6 IL-10 IL-12 IL-15 TNFO.
' IL-1 IFNa. IL-2 IFN'3
IL-4 IFN~Y......__ • ._ IL- 6 11.-10 -IL-13
,
IL-1 IF:a IL-8 TNFa.
TNF\ ) ~ 1',
IL-6, IFNy IL-8 TNFa. IL-10 IL-12 IL-15 IL-18
IL-1 IFNO. r • • :• IL-3 IFN'3 ,. _; • __ , •• IL-4 ' IFNy •• Neutr~ phil .._ IL-1~ TNFO. • - . ' • -~
1/IL-13 T:LNF-1 F: IFN•y , ~ ~: _;~ ..... ··•• , •..
• • .. (._ II> • .. • • • • . · - ~ · . ·:-· ..... · .. : ·: : ··· . .... . ~ L -3 TNFU • • • \. ... IL
A TNF A. -. •~ sophil t• 4 - p ... . ' ~ - ".·.
--i L -8 -: . ~ IL~ '• I• -• .. . ..... ...
4 . . IL-14 / -,. .
IL-2 IL-16✓· . .£ \_ \ :t~ IL-4
IL- 8/ :~=: :~~~ I IL-8 IFN'3 IL-3 IL-9 IFNy IL-g
IL-10
IL-4 ~ .
•• ..- ,;~
ALTERED MICROBIAL
HYPOXIA/CO2 VIRULENCE
RADIATION
PHYSIOLOGICAL STRESS
PSYCHOLOGICAL STRESS
ALTERED IMMUNOCYTE DISTRIBUTION & FUNCTION
ALTERED NUTRITION
MICROGRAVITY
ALTERED MICROBIOME
CIRCADIAN MISALIGNMENT
LATENT VIRUS REACTIVATION
CLINICAL INCIDENCE
ALLERGY
SHINGLES
CANCER
Immunity and Disease
VIRAL INFECTIONBACTERIAL INFECTION
AUTOIMMUNE DISEASE
meningitis - JC virus - Measles • LCM virus - Arbovirus - Rabies
Pharyngitis • Adenovirus - Epstein-Barr virus - Cytomegalovirus
Eye infections - Herpes simplex virus - Adenovlrus - Cytomegalovirus
Pneumonia - Influenza virus,
Types A and B - Parainfluenza
virus • Respiratory
syncytial vi rus Cardiovascular-----'"----4-~::' - Adenovirus - Coxsackie B virus
Hepatitis,-------' - Hepatitis virus
types A, B, C, D, E
Skin infections----..;;... - Varicella zoster virus - Human herpesvirus 6 • Smallpox - Molluscum contagiosum - Human papillomavirus - Parvovirus B19 - Rubella
virus
Nerve fiber
Blisters develop
l-"--'--1---4-- ~~~~~~i~:x ond n11 w,th pus
Blisters eventuelly
- Adenovirus • Rotavirus - Norovirus - Astrovirus - Coronavirus
burst , crust over and heel
Nerve deimage can cause postherpetic neuralgia
Blood
Brain M<Jl'iple5clefosis
Gulloto-Borre Syndrome Au'lsm
L9Ul.emla wpusE!yttl
HemolyllC Oy,glycemlO , I
Thyroid -Hosltno!o's Dtseose G1""8S' °"""'8
Over 100 GI Tract
ce1oc-,lllleose OOhn's Dlsea5e IJlcero!tve COIi!!$ Diabetes lype I
Different Types of Autoimmune
Disorders
lun Rb< la
Wegonc<'s Gionuomatoos
Plasma Collection - ISS
Early~2 weeks
Mid2-4 mos
LateR-1-2 days
FD15FD30
FD60
FD120
FD180
Return Ambient – 45h Delay
Frozen on Orbit
• Innate immunocyte function dysregulated during spaceflight• Plasma cytokine concentrations are altered in astronauts• Astronauts experience persistent reactivation of latent herpesviruses, biomarker of
reduced immunity• Astronauts demonstrate elevated stress hormones and dysregulated circadian
rhythms during spaceflight
• Astronauts have some degree of clinical incidence, primarily dermatitis, allergy and infections
• Dermatitis may be associated with viral etiology• Some crew experience persistent symptoms requiring prolonged management
• Peripheral leukocyte distribution in astronauts is relatively normal
• T cell, NK cell function is inhibited by microgravity• T cell function is reduced in astronauts; appears to be
a shift in the activation threshold• NK cells are disarmed, reduction in lytic molecule
content• B cell function in astronauts appears unaltered
(limited data)
SPACEFLIGHT IMMUNE DYSREGULATION
MODELED
MICROGRAVITY1xG CONTROL
Red: Actin localization
Green: Microtubules/MTOC Mayra Nelman-Gonzalez
Microgravity Cell
Culture
T Cell Function
... C:
so ................ ..
40
~ 30 Q)
Q.
20
10
0
L-180 L-45
... CD4/69+
* _.CD4/69/25+
Early Mid Late R+O
T cell
One method of the " co-stimulation" needed to activate T cells . II the T cell falls to receive "signal two", It dies by ru>oc:im~~J~7<_~~~g:r6~~ in two forms: B7 -1
aCD3/aCD28
-vCD8/69+
~CDS/69/25+
R+30
... C:
80
70
60
~ so Q) Q.
40
30
20
10
*
L-180 L-45 Early
n-=17
... CD4/69+ -<?CD8/69+
_.CD4/69/25+ ~CDS/69/25+
Mid Late R+O R+30
NK Cell Function
5% 31%11%
.. _ .. , f :ii .. ~
~ ~-0:
TARGET CELLS ONLY
FORWARD SCATTER
...... , ..
U-.ltC •..
,I
CD71 (Target Cells)
1X PBMC
(NK:target = 1 :6)
.. ,~----------~ w;. c:uu. 11 rcc;ow,~• ,,.
..
...... .. .. .,
.,
..
..
10X PBMC
(NK:target = 1 :1)
..
..
20X PBMC
(NK:target = 3:1)
...... . .. ., •' ,I
Data expressed as % change from baseline (L-180). NK-cell function did
not differ between astronauts and controls at baseline
Controls (n=6)
Astronauts (n=6)
Pre-Flight In-Flight Post-Flight
K562 (Leukemia)
Pre-Flight In-Flight Post-Flight
U266 (Multiple Myeloma)
Pre-Flight In-Flight Post-Flight
221.AEH (HLA-E Transfected)
Pre-Flight In-Flight Post-Flight
721.221 (Lymphoma)
Baseline NKCA
Dr. Richard Simpson
Spaceflight Reduces NK Cell Function
NK Cell Function
0 180 0 180 .. .. ~ 160 ~ 160
s 140 s 140
~ 120 ~ 120 "" "" .. .. ! 100 ! 100
.; 80 .; 80 u u ~ ~
CII 60 CII 60 C. C.
iS 40 iS 40 .. .. z 20 z 20
0 0
0 180 .. :::: 160
140 s 140
~ 120 .:: .. ! 100
.; 80 u ~
60 CII 60 C.
iS 40 iS 40 .. .. z 20 z 20
0 0
Table 1: Twenty two cytokines for analysis by category
Inflammatory
Anti-
Inflammatory
Adaptive/
Regulatory
Growth
Factors Chemokines
IL-1α IL-1ra IFNγ G-CSF CCL2/MCP-1
IL-1β IL-2 GM-CSF CCL3/MIP-1 alpha
TNFα IL-17 FGF basic CCL4/MIP-1 beta
IL-6 IL-4 Tpo CCL5/RANTES
IL-8 IL-5 VEGF CXCL5/ENA-78
IL-10
Plasma Cytokine AnalysisPhysical Triggers of Immune Response:
• Infections -Bacterial, viral -Fungal. paras,t,c
• Toxins -Exogenous -Endogenous
• Food peptides •Allergens • Medications • Auto antigens
ThO: NaiVe T cells Th: Helper T cells
Treg: Regulatory T cells IL: Interleukin
Th17 • Extracellular bacteria
(slon, llfWl!I of r,tes!Jne)
• Fungi • Autoimmunity
Antigen Presenting Cells
TNF-a: Tumor necrosis factor-alpha IFN-y: Interferon-gamma
Treg • Immune tolerance • Lympocyte homeostasis TGF-p: Transforming growth factor-beta • Regulation of immune
responses
IL-17 IL-21 IL-22
Th1 • Cell,mediated Immunity and
inflammation • Intracellular pathogens
• Viruses, bactena • Autoimmunity • Inflammation
• Antibody-mediated Immunity • Extracellular parasites • Asthma, allergy
Cytokine
IL-1a 0.3 ± 0.1 0.4 ± 0.3 0.9 ± 0.5 0.3 ± 0.1 2.4 ± 1.9 0.6 ± 0.2 0.3 ± 0.1 0.3 ± 0.1 0.3 ± 0.1
IL-1b 0.4 ± 0.1 0.7 ± 0.3 1.5 ± 1.0 0.8 ± 0.3 0.9 ± 0.5 1.3 ± 0.9 1.1 ± 0.8 0.5 ± 0.2 0.8 ± 0.3
TNFa 1.4 ± 0.1 1.4 ± 0.1 3.2 ± 1.0 2.0* ± 0.3 2.1 ± 0.4 2.2 ± 0.5 2.0 ± 0.4 1.3 ± 0.1 1.7 ± 0.2
IL-6 0.3 ± 0.1 0.3 ± 0.1 0.5 ± 0.2 0.3 ± 0.1 0.4 ± 0.1 0.3 ± 0.1 0.3 ± 0.1 1.1* ± 0.2 0.3 ± 0.1
IL-8 2.0 ± 0.3 2.1 ± 0.3 8.1* ± 2.1 7.9* ± 2.3 7.7* ± 1.7 7.3* ± 2.1 6.9* ± 2.3 2.1 ± 0.3 2.3 ± 0.4
IL-1ra 383 ± 40 370 ± 35 567* ± 65 563* ± 80 638* ± 101 728* ± 129 661* ± 85 682* ± 118 568 ± 146
IFNg 0.8 ± 0.2 0.8 ± 0.2 0.6 ± 0.1 0.7 ± 0.2 0.8 ± 0.2 0.9 ± 0.2 0.7 ± 0.3 0.5* ± 0.1 0.7 ± 0.2
IL-2 2.2 ± 0.6 1.8* ± 0.5 1.7* ± 0.5 2.6 ± 0.8 2.4 ± 0.7 2.5 ± 0.7 2.4 ± 0.8 2.4 ± 0.7 2.7 ± 0.9
IL-17 1.3 ± 0.3 1.1 ± 0.3 0.9 ± 0.2 1.0 ± 0.2 1.1 ± 0.3 1.1 ± 0.2 0.9 ± 0.3 0.9* ± 0.2 0.9 ± 0.2
IL-4 0.3 ± 0.1 0.5 ± 0.3 3.2 ± 1.7 0.3 ± 0.2 1.4 ± 0.7 2.1 ± 1.5 1.6 ± 1.2 0.4 ± 0.2 0.2 ± 0.1
IL-5 0.1 ± 0.0 0.1 ± 0.0 0.1 ± 0.0 0.1 ± 0.0 0.1 ± 0.0 0.1 ± 0.0 0.1 ± 0.0 0.1 ± 0.0 0.1 ± 0.0
IL-10 0.2 ± 0.0 0.2 ± 0.1 0.4 ± 0.2 0.2 ± 0.0 0.2 ± 0.0 0.4 ± 0.2 0.2 ± 0.0 0.3 ± 0.1 0.4 ± 0.1
G-CSF 7.2 ± 1.9 7.0 ± 1.7 7.0 ± 1.8 4.5 ± 0.8 7.6 ± 2.0 14.7 ± 7.8 9.8 ± 3.2 10.3* ± 2.8 5.9 ± 1.4
GM-CSF 0.6 ± 0.3 0.3 ± 0.1 3.4 ± 1.9 1.9* ± 0.8 2.7 ± 1.3 2.8 ± 1.9 2.7 ± 1.9 0.7 ± 0.4 0.7 ± 0.4
FGFb 13.7 ± 5.4 15.4 ± 5.7 11.8 ± 3.3 21.9 ± 5.7 18.5 ± 4.9 12.1 ± 3.7 10.8 ± 2.7 11.7 ± 3.8 12.3 ± 4.3
Tpo 140 ± 16 146 ± 18 184* ± 18 189* ± 30 191* ± 22 196* ± 28 221* ± 24 141 ± 17 133 ± 16
VEGF 5.8 ± 0.9 6.2 ± 1.3 10.9* ± 1.9 15.8* ± 4.9 11.3* ± 1.7 12.5* ± 3.5 11.7* ± 1.9 5.1 ± 1.0 5.5 ± 0.9
CCL2/MCP-1 72.4 ± 6.8 78.5 ± 7.7 71.7 ± 5.4 66.0 ± 5.8 77.0 ± 7.0 84.0 ± 7.0 87.0 ± 7.7 124* ± 18.1 90* ± 7.5
CCL3/MIP-1a 20.3 ± 5.0 16.6 ± 5.0 25.9 ± 8.1 15.0 ± 4.4 19.1 ± 6.6 22.7 ± 7.4 21.7 ± 8.6 19.4 ± 6.3 18.1 ± 5.5
CCL4/MIP-1b 16.2 ± 2.2 16.7 ± 2.7 22.3* ± 2.9 20.2* ± 2.5 22.2* ± 2.8 24.3 ± 5.1 21.6* ± 3.3 17.3 ± 2.3 19.3 ± 4.0
CCL5/RANTES 3613 ± 263 3292 ± 246 3618 ± 202 3746 ± 195 3575 ± 185 3818 ± 217 4030 ± 202 3410 ± 266 3623 ± 219
CXCL5/ENA-78 231 ± 58 367 ± 219 2065* ± 371 1858* ± 310 2015* ± 360 1749* ± 309 1860* ± 388 190 ± 48 202 ± 55
L-180 L-45
Spaceflight
FD180 R+0 R+30FD120FD30 FD60FD15
Table 2: Mean plasma cytokine levels for ISS astronauts before, during, and following spaceflight. Data are expressed as mean concentration pg/ml ± SEM. Bold indicates statistically significant difference p≤0.05; n=28.
Plasma Cytokine Analysis
I I
I I
I I
I I
I I
0
500
1000
1500
2000
2500
3000
L-180 L-45 FD15 FD30 FD60 FD120 FD180 R+0 R+30
Chemokines
CXCL5/ENA-78
** *
**
0
100
200
300
400
500
600
700
800
900
L-180 L-45 FD15 FD30 FD60 FD120 FD180 R+0 R+30
Anti-Inflammatory Cytokines
IL-1ra
**
Plasma Cytokine Analysis
.a.
T ~ V' ~ V ~ I ~ .,
/I
T / -
.Ac V I l
-+-
Stress Hormones/Circadian Rhythm
Circadian rhythm of Salivary Cortisol in 27 healthy adults
:i: fij12 a)
.§. .... -TIMES .J 10
:::, 0 E C: 8 0 (II
'€ 6 0 u
~ 4 > 1 Cl)
2 Waking Wake + 30
PRE-FLIGHT FLIGHT POST-FLIGHT
- 180 - 45 Earh• !\lid Lat Ea1·lv Late
W W+30m W+Sh W+IOh W W+30m W+6h W+IOh W W+30m W+6h W+10h W W+30m W+6h W+10h W W+30m W+6h W+IOh W W+30m W.Sh W+10h W W+30m W+6h W+10h
Latent Herpesvirus
Herpes Simplex
Primary Infection
Cold Sore
Latent virus
Virus transit up
peripheral nerve
peripheral nerve
Latent Herpesvirus
1200
<{ z 1000 0 ~ co 800 .?: ro (/)
0 600
--(/) Q)
400 ·5.. 0 u > 200 (1) w
0
-300
1200 <{ z 0 1000 ~ co ~ 800 (J)
0 600 en Q) ·5.. o 400 0
>~ 200
0
-300
Reactivation in 65% of the crewmembers
-200 -100 0 100
Sample Collection Days
200 300
Latent Herpesvirus
Zoster Patients (n=42) 100% positiveAstronauts (n=23) 2-3 samples per crew= 59 total samples – 29/59 positive (49%)
No VZV DNA was detected pre-flight for any crew (L-180 or L-45)
Zoster PatientsAstronauts
1000000000
100000000
10000000 -_J
E .............. 1000000
V)
QJ
0.. 100000 0 u -
<( 10000
z 0
> 1000
N > 100
10
• -----------------ll·L----------1 •
• •
• • • • • •
• •
• A • • •- • [l_ • ._ • c1u •• ~ • • c:]19• ~ --u \.l• O • • • • •• •
•
•
Clinical Incidence
Total Events/
events person year
Allergic Reaction 1 0.06
Anaphylaxis 0 ---
Upper Respiratory Infection (combination of rhinitis, nasal
stuffiness and sneezing)5 0.301
Eye Infection 0 ---
Herpes Zoster 5 0.301
Otitis Media/Externa (ear pain, or ear stuffiness+congestion) 17 1.022
Pharyngitis (sore throat) 1 0.06
Sepsis 0 ---
Sinus Infection 0 ---
Skin Infection (including scalp pruritis, pus forming wounds on
wrist, finger)5 0.301
Skin Rash/Hypersensitivity (including skin conditions such as
tinea versicolor, dermatitis, rosacea) 23 1.383
Urinary Tract Infection 1 0.06
Malignancies* 0 ---
Autoimmunity* 0 ---
Infections, Other*# 11 0.666
Total: 69 4.18
Medical Conditions
Table II: Incidence data, ISS Program, Expeditions 1 to 28/29; 37 ISS crewmembers; total flight duration 6072 days/16.63 person years.
Source JSC Epidemiology Group: A. Babiak-Vazquez, Sara Mason and Jessica Garcia.
*Indicates additional conditions or symptoms categorized, beyond the original 13 IMM conditions.
#Additional infectious processes not characterized within other categories such as lymphadenitis, lymphadenopathy, mild fever and intestinal problems with such symptoms as diarrhea, excessive intestinal gas and bloating.
Clinical IncidenceCase Study ISS Astronaut
-Allergic symptoms in a non-allergicsubject
-Subject developed an AtopicDermatitis on mission day 17
-Rash was bothersome, at timessevere
-A variety of treatments employed
-At times the medications of choicewere exhausted
-Rash never resolved for the duration of the mission, although it was successfully managed to a tolerable level
-Rash spikes generally correlated well with operational stressors
-Research findings confirm immune dysregulation persisted for the duration of the mission
Cliukal Commu111ieatiou
Acass ,of persistent isk i'n rash and rh initis, with immune :syst,e.m dr'y.uegulati:on o nb0:a1d the tnter narti:ona1 .s,p,ace .Stati on Bri a Oruci an , "; Dr", Smith Jd ·· :sto· , MD,~
S:arl!lsh Me a,, F\h D'I', Raiv nd Stowai, "; 01i, Pate r l!Jcl'i,ai<Jin, P [),a, He · her Ouinia- M.", Duane, Pie .o· , ", 'IJ,", Ma k L. Laude· slar,e , FfrD11, ,and
C1i11fc:al, lnrplicalia11s
• · nc:c,r~ . iruQi wilh ~i:gb:c. indudiag m ~roi(;,l'a:\rity a nd ~ r~ . ind~ d~qi;rla:oio Cl · ·db:(; l:LLLmaa, immune ~ cem. lin !i;lme a.scr..,;mll. 1;1.1$, 1thi$ pheru:, men oC1 .may ~ .;:ia:ri;: wi:dl:i ad~ d irl M;il 0 1;1.ri;onl.e,$ o~ du~iag Hi:g,h:c ~udi a:s I'll$,:~ o r per'$~~nc rchinioi.$.
Clinical Incidence
• Rashes were observed to occur in the following locations: scalp, face, neck, chest, back, trunk, abdomen, arms and hands.
• The appearance of the rashes generally consists of bumps/nodules and/or small brown scaly patches, with or without petechiae, redness/hyperemia and itching.
Clinical Incidence
ANTI-HISTAMINE C C C C C C C C C C C C C C C C
STEROID H as needed throughout mission ---->
ANTI-VIRAL T
12
11
10 10
9 9
8 8
7 7
6 6
5 5
4 4
3 3
2 2
1 1
1 2 3 4 5 6 7 8 9 10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
ANTI-HISTAMINE C C C C Z C C C C C C B C C C C C C C C C C C C C C C C C C C Z C
STEROID M P P
ANTI-VIRAL
12
11
10 10
9 9
8 8
7 7
6 6
5 5
4 4
3 3
2 2
1 1
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
10
0
10
1
10
2
10
3
10
4
10
5
10
6
10
7
10
8
10
9
11
0
11
1
11
2
11
3
11
4
11
5
11
6
11
7
11
8
11
9
12
0
12
1
12
2
12
3
12
4
12
5
12
6
12
7
12
8
ANTI-HISTAMINE C C CZ C C C C C C Z C C C C C C C C C C C C C C C C C C C C C C
STEROID
ANTI-VIRAL X
12
11
10 10
9 9
8 8
7 7
6 6
5 5
4 4
3 3
2 2
1 1
12
8
12
9
13
0
13
1
13
2
13
3
13
4
13
5
13
6
13
7
13
8
13
9
14
0
14
1
14
2
14
3
14
4
14
5
14
6
14
7
14
8
14
9
15
0
15
1
15
2
15
3
15
4
15
5
15
6
15
7
15
8
15
9
16
0
16
1
16
2
16
3
16
4
16
5
16
6
16
7
16
8
16
9
17
0
17
1
17
2
17
3
17
4
17
5
17
6
17
7
17
8
17
9
18
0
18
1
18
2
18
3
18
4
18
5
18
6
18
7
18
8
18
9
19
0
19
1
HO
UR
S SL
EEP
SH
IFT
FLIGHT DAY
FLIGHT DAY
FLIGHT DAY
HO
UR
S SL
EEP
SH
IFT
HO
UR
S SL
EEP
SH
IFT
RA
SH S
EVER
ITY
RASH SEVERITY
Shuttle Dock to ISS
Soyuz Dock to ISS
EVA
Urine Collection
EVA
EVA
* * * *
Urine Collection
Blood/Saliva Collection
Shuttle Crew EVA*Subject EVA
Hours Subject Sleep Shift
Shuttle Dock
Progress Docking
Progress Docking
EVA
EVA
* * *
Urine CollectionUrine
Collection
to
ISS
Shuttle Dock to ISSBlood/Saliva Collection
Blood/Saliva Collection
Soyuz Dock to ISS
ATV Docking
* * * * *Urine
Collection
Significant On Orbit Ops
RASH SEVERITY
RASH SEVERITY
RA
SH S
EVER
ITY
RA
SH S
EVER
ITY
Significant Psychological Stress Event
Oral
Herpesviral Reactivation
Oral
Herpesviral Reactivation
Claratin C
Zyrtec Z
Benedryi B
Prednosone P
Medrol M
Hydrocortisone Cream H
Valtrex X
MEDICATIONS KEY
Clinical Incidence
The Herpes Simplex Virus type-1 reactivation associated with a case of persistent dermatitis during Spaceflight
43rd International Herpesvirus Workshop; Vancouver, Canada; July 21-25, 2018
Clinical Incidence
Tertiary infection using the cells and media from the secondary infection. Negative control (left), Serial dilution 10-1 (center), and serial dilution 10-6 (right).
In-Flight R+0 R+14
VZV Negative Negative
HSV1Positive
(CT-22; 5.4x10(6) copies per ng total DNA)
Positive
(CT-15; 1.4x10(9) copies per ng total DNA)Negative
VZV Negative N/A N/A
HSV1Positive
(CT-29; 2.4x10(4) copies per ng total DNA)N/A N/A
Saliva
Skin Lesion
• Peripheral leukocyte distribution in astronauts is relatively normal• T cell function is inhibited by microgravity• T cell function is reduced in astronauts; appears to be a shift in the
activation threshold• NK cell function is reduced in astronauts• NK cells are disarmed, reduction in lytic molecule content• B cell function in astronauts appears unaltered (limited data)• Plasma cytokine concentrations are altered in astronauts• Astronauts experience persistent reactivation of latent
herpesviruses, biomarker of reduced immunity• Astronauts demonstrate elevated stress hormones and dysregulated
circadian rhythms during spaceflight• Astronauts have some degree of clinical incidence, primarily
dermatitis, allergy and infections• Some crew experience persistent symptoms requiring prolonged
management
Summary
Operational ProceduresFunctional FoodsNutritional SupplementsNutraceuticalsProbioticsPharmacologicalExerciseVaccinationBehavioral CountermeasuresBone Countermeasures
Personalized/Precision Medicine
Frontiers in Immunology ; June 2018; doi: 10.3389/fimmu.2018.01437
Immune Countermeasures
OPEN ACCESS
Edited by: VidaAbed,
G,isirg,,1-IBalth System, Unitoo States
Roviewedby: Da'/ideflogo,
Univor.lita Ca~oica d<J Saao Cooro, ttay
Lj!Jafl\!al, ~ Tech, Unitoo States
"Com,spondooco, Brian E Crucian
~CflJCia>-1@rnsa.gov:
-0',o,Jkk achouksr@moo.<mi-mJ6flChen.oo
REVIEW ptt,19100; 28 ..kn> 2018
dot 10.338Mmr11J2018.01437
Immune System Dysregulation During Spaceflight: Potential Countermeasures for Deep Space Exploration Missions Brian E. Crucian' 't, Alexander Chouket''t, Richard J. Simpson•", Satish Mehta•, Gailen Marshall ', Scott M. Smith ', Sara R. Zwart •, Martina Heer•, Sergey Ponomarev••, Alexandra Whitmire", Jean P. Frippiat 12, G. Douglas", H. Lorenzi ", Judith-Irina Buchheim", George Makedonas•, Geoffrey S. Ginsburg", C. Mark Ott ', Duane L. Pierson ', Stephanie S. Krieger " , Natalie Baecker• and Clarence Sams 1
' fliomedt:a Reseair:hand Envnnnoota/ ScmcGs avism, J\lolSI\ .kh=n Spaa, C.,,ter. Hoostm. TX. t.kiitoo States. ' Laboratory ot Transationll -di 'Stmss Bfld Immunity'. Depat1mont of Anos~ f/ospila/ of th<> Ltxfwjg
Ma>imliaos-Vnivarsity. Munich, G"""""" ' Dopa<tment of Nutritima/ Sderloos, Too Unitersity of Atizona. Ti,:;son, AZ; Uniloo stat°" 'Depa1manf of Pe<iafrics. n., u,,;w,,;;ty of Atizona. Tuc,on. AZ; Lnroo stat°" ' IJGpattmenf of lmmunobiology, 11» Univt>rsilyof Arizona. Tucsoo, AZ LntedStates. ' JfS Tech. llouston. TX. Uniled States. ' Utwetsityof Mississ.ppi Modica C.,,tor; Jackson. MS. United Statos. ' Urwetsity of Tw:as Medea/ Branch. Galv6Slon. TX. United states, ' Institute of Milmiona/,nd Food Sdoncos. Univt>rsilyof Bonn. Bom, German)< " tnslRUtoof fliomedt:af Problems, Moscow. fllJssia, " KBR wi,fo, Houston. TX. Unitoo States, " Slross Immunity Pathogons t..atx.ato,r, EA7:l00. t..omine Univ""1ify Noocy, Franc6. " Human Systems £nginooting /3fld IJ<Mlklpmoot avison, J\lolSI\ Jo/Jnson Sp,cs C.,,ta; Hoostm, TX. United sta/9S, "J. Gra\J Venter tns/itufo, La.-. CA, United States, " llikB C.,,ter frx Appfoo Ger>anics and Pr<rism
MGdciio, fulml, NC. United Slatos
Recent studies have established that dysregulation of the human immune system and the reactivation of latent herpesviruses persists for the duration of a 6-month orbita spaceflight. It appears certain aspects of adaptive immunity are dysregulated during flight, yet some aspects of innate immunity are heightened. Interaction between adaptive and innate immunity also seems to be altered. Some crews experience persistent hypersensitivity reactions during flight. This phenomenon may, in synergy with extended
Immune Countermeasures
Potential Immunologic Countermeasures for Deep Space Missions
Precision Countermeasures
Pre-Mission Immunological Screen
Pre-mission immunological screen may include: Personal history of allergy/hypersensitivity, etc. Medication history (antihistamines, etc.) Leukocyte distribution (NK cell subsets) Cytokine concentration: Th1/fh2, etc. Allergy screen, patch testing Latent herpesvirus sero-positivity
Pathogen-Specific Mitigations Antiviral (VZV) vaccination
General Specific Countermeasures Countermeasures
Already in Place/Will be Optimized Pre-flight medical operations screening of crewmembers Pre-flight quarantine
Nutritional Countermeasures Diet optimized to reduce nutrient deficiency Functional foods/bioactive compounds Nutritional supplements:
Microbial screening of vehicle/payloads/foods Environmental control
• Antioxidants • Probiotics
Optimized exercise equipment Radiation shielding
Multisystem Countermeasures Optimized exercise regimen Adequate sleep schedules Psychological support - family communication Stress relieving techniques
Pharmacological Intervention Beta blockers Anti-cortisol Antibiotics Antiviral Anti-inflammatory Cytokine therapy
•
• Omega 3 fatty acids • Supplemental nucleotides • AHCC • Pegylated-lL-2
In-flight Monitoring of Immune Parameters?
PRE-FLIGHT LAUNCH TRANSIT PHASE CIS-LUNAR STATION/ LUNAR SURFACE OPS
MARS FLYBY or ORBIT/ MARS SURFACE OPS
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