Brian Crucian, PhD, MT(ASCP)

UPDATE ON SPACEFLIGHT IMMUNE SYSTEM DYSREGULATION, CLINICAL RISKS FOR DEEP SPACE MISSIONS, POTENTIAL COUNTERMEASURES

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

Blood and Saliva Collection- ISS

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

Spaceflight Immunologists

NASA JSC

Immunology/Virology

Laboratory