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ポストイムノバイオティクスの呼吸器免疫調節機能の解明に関する基礎的研究

友清, 帝 東北大学

2023.03.24

概要

2022 年度

博士論文

ポストイムノバイオティクスの
呼吸器免疫調節機能の解明に関する基礎的研究

東北大学大学院農学研究科
生物産業創成科学専攻
食品機能健康科学講座
動物食品機能学分野 博士課程後期 3 年
C0AD1303 友清 帝
指導教員 北澤 春樹 教授

目次
第1章

諸論

第2章

抗ウイルス性ポストイムノバイオティクスの選抜とブタ肺胞マクロファージ

2

を用いた評価
第 1 節 緒言

9

第 2 節 材料と⽅法

12

第 3 節 結果

22

第 4 節 考察

39

第 5 節 ⼩括

45

第3章

ポストイムノバイオティクスの免疫調節機構の解明

第 1 節 緒言

47

第 2 節 材料と⽅法

49

第 3 節 結果

52

第 4 節 考察

66

第 5 節 ⼩括

70

第4章

ポストイムノバイオティクスによるウイルス感染低減効果の実証試験

第 1 節 緒言

72

第 2 節 材料と⽅法

74

第 3 節 結果

83

第 4 節 考察

90

第 5 節 ⼩括

93

第5章

総括

94

謝辞

98

引用文献

99

1

第1章
諸論
近年、新型コロナウイルスによる新興感染症が世界的に蔓延し、人類を脅かす感染
症のパンデミックに発展している。WHO によると、全世界において累計 6 億 5000 万
人以上がコロナウイルスに感染し、死者数は 665 万人以上に達すると報告されている
(WHO, 2022 年 12 月時点)。このような突発的な新興・再興感染症による甚大な被害が
問題となる一方で、呼吸器疾患をはじめとした慢性感染症の蔓延も解決すべき社会問
題となっている。とりわけ、呼吸器合胞体ウイルス(Respiratory Syncytial Virus:RSV)
によるウイルス性肺炎は、乳児や高齢者において重篤な呼吸器症状を引き起こす重大
な感染症と位置付けられている。これらの対策としてワクチンなどの開発が進められ
ているが、未だ実用化には至っておらず、また有効な対策方法も確立されていない。
RSV は、パラミクスウイルス科に属する RNA ウイルスであり、1956 年にアメリカ
のウイルス学者である Morris らによって呼吸器疾患を患ったチンパンジーから初めて
分離された(Morris et al., 1956)。その後、重症下気道疾患の乳児からも分離され、ヒト
への感染性が明らかにされた(Chanock et al., 1957; Chanock & Finberg, 1957)。特に乳幼児
の気管支炎や肺炎の主要な原因病原体として知られており(Breese Hall et al., 2009)、軽
度の風邪症状から喘息、重度の気管支炎、肺炎などの下気道疾患に至るまで、様々な
症状を誘発する(Bont et al., 2004; Henderson et al., 2005; Nair et al., 2010; Sigurs et al., 2000,
2005, 2010; Stein et al., 1999) 。RSV に感染すると数日間の潜伏期間の後、発熱、鼻汁、
咳などの上気道炎を発症するが、そのうち約 7 割は上気道炎のみの症状にとどまり数
日で回復する。一方、残りの 3 割は 2〜3 日後に感染が下気道に及び、気管支炎、細気
管支炎または肺炎といった重篤な下気道炎を発症する。RSV は世界中に分布しており、
2 歳までにほとんどの乳児が RSV に感染すると言われている(Griffiths et al., 2017)。5 歳

2

以 下 の 子 ど も の う ち 、RSV に よ る 急 性 下 気 道 感 染 症 (Acute Lower Respiratory
Infection:ALRI)の患者数は推定 3,380 万人で(ALRI の全症例の 22 %を占める)
、そ
のうち 340 万人以上が入院を必要とし、年間 66,000〜99,000 人が死亡していると報告さ
れている(Nair et al., 2010)。また、RSV 感染症関連の死亡率は、インフルエンザの死亡
率よりも高いと言われている(Robin A Weiss & Anthony J McMichael, 2004)。
RSV はエンベロープを有しており、その表面には宿主細胞への吸着および膜融合を
担う約 10 nm のスパイクが存在する(Fig. 1)
。RSV は約 15.2 kb の一本鎖 RNA(single
strand RNA:ssRNA)をゲノムとして有しており、そのゲノムには 11 個のタンパク質
をコードする 10 個の遺伝子が存在する(Bawage et al., 2013; Taleb et al., 2018)。RSV が感
染性を獲得するためには、G タンパク質を介した宿主細胞への接着が重要とされ、そ
の後 F タンパク質(fusion protein:F protein)に構造変化が起こり、それを介してウイ
ルスエンベロープが宿主細胞膜と融合することにより細胞内に侵入する(Smith et al.,
2009; Zhao et al., 2000)。侵入後、L タンパク質(Large protein :L protein)と P タンパク
質(Phosphoprotein:P protein)から成る RNA 依存性 RNA ポリメラーゼが、ゲノム
RNA-N タンパク質(nucleoprotein:N protein)複合体を鋳型としてウイルス RNA の転
写と複製の両過程を担い(Grosfeld et al., 1995)、F タンパク質を介した細胞-細胞融合に
よりウイルスが拡散し合胞体が形成される(Merz et al., 1980)(Fig. 2)

この複製過程で生じるウイルス RNA に対して宿主は TLR3 や TLR7 などの細胞質内
レセプターを介して感知し、抗ウイルス性免疫応答を誘導するが、RSV は宿主の自然
免疫機構の活性化に関与するシグナル分子を標的とすることで IFN 経路を阻害する生
存戦略を有することが知られている。具体的には、RSV の非構造タンパク質である
NS1 が IFN の産生に重要な interferon regulatory factor(IRF)3 および IRF7 を、NS2 が
TNF receptor-associated factor 3(TRAF3)の発現を減少させ、IFN 及び IFN 誘導遺伝子
群(IFN-Stimulated genes;ISGs)の産生を阻害する(Sedeyn et al., 2019)。

3

我々の体内には、ウイルス・細菌などの病原体や、癌細胞などの異物から身体を守
る、免疫系と呼ばれる生体防御システムが備わっている。免疫系は様々な細胞や分子
からなり、極めて複雑なネットワークを形成することで非自己である異物を排除する。
それらは、「自然免疫系」と「獲得免疫系」に大別することができ、この組み合わせに
より恒常性が維持されている(Gasteiger & Rudensky, 2014)。特に、自然免疫系は、病原
体の侵入門戸である呼吸器などの粘膜組織において生体防御の最前線として重要な役
割を果たしている。呼吸器における自然免疫系は上皮細胞や NK 細胞、補体系などの
様々な細胞から構成されるが、特にその中心を担う代表的な細胞としてマクロファー
ジが挙げられる。マクロファージは白血球の一種に分類され、自然免疫反応の誘導に
おいて重要な役割を果たす免疫担当細胞であり、単独あるいは他の細胞との相互作用
によって生体の恒常性維持を担っている。マクロファージはパターン認識受容体
(PRRs)を有しており、病原体が特異的に保有する病原体分子パターン(PAMPs)や
微生物関連分子パターン(MAMPs)を認識すると、貪食やサイトカインの誘導を介し
て病原体を排除する。
一方で、乳酸菌やビフィズス菌に代表されるプロバイオティクス(probiotics)は、
抗 生 物 質 (antibiotics) に 対 比 さ れ る 言 葉 で 、 共 生 を 意 味 す る プ ロ バ イ オ シ ス
(probiosis : pro 共に、〜のために、 biosiss 生命)を語源としている。1989 年に英国の
微生物学者である Fuller により「腸内フローラのバランスを改善することにより人に
有益な作用をもたらす生きた微生物」として定義されたが(Fuller R., 1989)、2002 年の
FAO/WHO 合同会議において「十分量摂取した時に宿主に有益な効果をもたらす生き
た微生物」に再定義され(Joint FAO/WHO Working Group, 2002)、今日では世界中で広く
受け入れられている。プロバイオティクスの一例として Lactobacillus、Streptococcus、
Enterococcus、Lactococcus、Bifidobacterium、Bacillus、Clostridium、Saccharomyces、
Aspergillus などに分類される微生物種を挙げることができる。また、大腸内の特定の細

4

菌の増殖および活性を選択的に変化させることで宿主の健康増進に寄与する難消化性
食品成分(オリゴ糖や食物繊維等)はプレバイオティクス(prebiotics)、プロバイオテ
ィクスとプレバイオティクスの複合物はシンバイオティクス(synbiotics)と定義され
ている(Gibson & Roberfroid, 1995; Roberfroid, 1998)。2003 年には Clancy によってプロバ
イオティクスの中でも特に高い粘膜免疫調節作用を有する生きた微生物を「イムノバ
イオティクス」(Clancy, 2003)、2005 年には当研究室の北澤らによってイムノバイオテ
ィクス由来の免疫調節因子を「イムノジェニクス」とそれぞれ定義され(下里 & 北澤,
2010)、その詳細な解析が進められている。
近年、健康志向の高まりに伴い、イムノバイオティクスの保健効果に関する研究が
精力的に進められている。とりわけ、イムノバイオティクスがウイルスや病原細菌に
対して感染防御作用を発揮することが明らかとなり、それを契機に感染症の予防およ
び軽減に向けた食品や飼料さらには製剤への利活用が期待されている。一方で、最近
になって、その安定的実用性の観点から、イムノバイオティクス由来の不活化菌体で
ある非生存型イムノバイオティクス(ポストイムノバイオティクス)が提案された
(Tomokiyo et al., 2022)。興味深いことに、一部のポストイムノバイオティクスも生菌体
と 同 様 に 感 染 防 御 作 用 を 示 す こ と が 報 告 さ れ た こ と か ら(Clua et al., 2017, 2020;
Tomosada et al., 2013)、病原体に対する新規予防および治療方法の確立に向けたポスト
イムノバイオティクスの積極的利用が期待されている。しかしながら、ポストイムノ
バイオティクスの感染防御に至る詳細な機構はほとんど明らかにされておらず、その
利活用が著しく遅れている。
そこで本研究では、ポストイムノバイオティクスの利用性拡大に向けて、新規抗ウ
イルス性ポストイムノバイオティクスを選抜し、その詳細な免疫調節作用および機構
を細胞生物学および分子生物学的手法を用いて in vitro 及び in vivo の両面から解明する
ことを目的とした。

5

or chronic lung-diseased) [20–22]. This antisk (e.g., immune-compromised, premature, conin use for adults and elderly. Hence, vaccinaor chronic lung-diseased) [20–22]. This antiient
method
to protect
immune-compromised
d in use
for adults
and elderly.
Hence, vaccinaV
illness
and
complications.
Still,
to date, no
cient method to protect immune-compromised
en
licensed,
specifically
after
the
failure
of difSV illness and complications. Still, to date,
no
rials
such
as
formalin-inactivated
RSV
vaccine
een licensed, specifically after the failure of difntrials
enhanced
illness in theRSV
vaccinated
such asdisease
formalin-inactivated
vaccine
in enhanced disease illness in the vaccinated
].tein, a target for neutralizing antibodies, is
variable
making
challenging
to createisa
otein,
a target
for itneutralizing
antibodies,
tive
vaccine.
On the
other hand, Ftoglycoprovariable
making
it challenging
create a
arget vaccine.
for neutralizing
antibodies,
is highly
ctive
On the other
hand, F glycoproit is present
in two forms
on the virion
surtarget
for neutralizing
antibodies,
is highly
et
it is present
in two
forms
on the virion
surastable
structure
called
pre-fusion
(pre-F),
tastable
structure
called pre-fusion
(pre-F),
sed
to switch
unpredictably
to another
stable
osed tostructure
switch unpredictably
another
stable
ost-F)
[25]. Despitetothe
fact that
G
post-F)
structure
[25].
Despite
the
fact
that
G
oteins provoke neutralizing antibody producoteinsvaccine
provokedevelopment
neutralizing antibody
producmajor
target since
it is
major
vaccine
development
target
since
it
is
nter host cells, and presents more epitopes
enter
host cells,
and presents
more
epitopes
utralizing
antibodies
[26–28].
To date,
six
eutralizing
antibodies
[26–28].
To
date,
six
for neutralization have been identified on
s for neutralization have been identified on

me and proteins.
ome andRNA
proteins.
e-sense
ve-sense
RNA
and aa indicate
t
and
aa
indicate
mino acid
amino
acid
ely.
b Mapping
vely.
b
Mapping
RSV virion
and
ngRSV
virion
classes and
ng classes

15,000 nucleotides and encodes for 11 proteins. F, G, and SH
RSV genome is a negative sense ssRNA containing more than
are the only glycoproteins located at virion surface, where F
15,000 nucleotides and encodes for 11 proteins. F, G, and SH
andthe
G only
are the
main targetslocated
for neutralization
and vaccine
are
glycoproteins
at virion surface,
where Fdevelopment
[11].
and G are the main targets for neutralization and vaccine development [11].

Fusion protein (F)
Fusion protein (F)

F protein is a class I fusion protein composed of 574 amino
(AA).
weight
of a 50 of
kDa
Facids
protein
is aWith
class aI molecular
fusion protein
composed
574C-terminal
amino
fragment
and
a 20 kDaweight
N-terminal
F2, the
acids
(AA).F1
With
a molecular
of a 50 fragment
kDa C-terminal
protein
acquires
a
trimer
of
heterodimers
[9].
At
AA
posifragment F1 and a 20 kDa N-terminal fragment F2, the
tions 109
and a136,
twooffurin
cleavages
place.
This
protein
acquires
trimer
heterodimers
[9].take
At AA
positions
109releases
and 136,
two furin cleavages
place.
feature
a glycopeptide
and thus take
reveals
the This
hydrofeature
a glycopeptide
andF1
thus
hydrophobicreleases
site at F1
fragment [32].
andreveals
F2 arethe
linked
by a
phobic
site
at
F1
fragment
[32].
F1
and
F2
are
linked
by
cysteine-rich region at two positions: between AA70 aand
cysteine-rich
at two
positions:
between [9].
AA70
and FAA212, andregion
between
AA37
and AA439
Other
AA212,
and
between
AA37
and
AA439
[9].
Other
related features involve N-glycosylation in F1 at AA Fposirelated
features
at AA
tion 500,
and involve
in F2 atN-glycosylation
AA positionsin27F1and
70 posi[33]. F
tion
500,isand
in F2
at AA positions
27 25
andAA
70 differences
[33]. F
protein
highly
conserved,
with only
protein
highlysubtypes
conserved,
withB only
25 AA differences
betweenis RSV
A and
[9, 11].
between RSV subtypes A and B [9, 11].

3’

5’

Taleb et al., 2018を一部改変

Figure 1.

RSVのゲノムと構造

6

10

Advances in Virology
RSV

Life cycle of RSV

Budding RSV
ready to infect
adjacent cell

接着 (Gタンパク質)

Merging with the cell membrane

融合 (Fタンパク質)
Antigenome

Transcription

F protein

転写・複製
Replication
(Lタンパク質・Nタンパク質)

G protein

Protein synthesis

タンパク質合成

ウイルス粒子
Assembly

SH protein

P protein

形成

N protein

L protein

Golgi
complex

Endoplasmic
reticulum

Nucleus

Bawage et al., 2013を一部改変
Figure 4: A schematic representation of RSV life cycle.

F protein

Figure
2. ofRSV
Modes
RSVのライフサイクル
inhibition

G protein
+

RSV

No binding
to the cell

Gold nanoparticles

No infection

Cell
No infection

+
RSV

No binding
to the cell

Antibodies
Drug

No infection

+
RSV

No binding
to the cell

Peptide
Fusion inhibitors

Fusion

No treatment

Infection

Binding

RSV

7

Figure 5: A schematic representation of various compounds inhibiting RSV binding to the cell. ...

この論文で使われている画像

参考文献

Albarracin, L., Garcia-Castillo, V., Masumizu, Y., Indo, Y., Islam, M. A., Suda, Y., GarciaCancino, A., Aso, H., Takahashi, H., Kitazawa, H., & Villena, J. (2020). Efficient Selection

of New Immunobiotic Strains With Antiviral Effects in Local and Distal Mucosal Sites by

Using Porcine Intestinal Epitheliocytes. Frontiers in Immunology, 11.

https://doi.org/10.3389/fimmu.2020.00543

Albarracin, L., Kobayashi, H., Iida, H., Sato, N., Nochi, T., Aso, H., Salva, S., Alvarez, S.,

Kitazawa, H., & Villena, J. (2017). Transcriptomic analysis of the innate antiviral immune

response in porcine intestinal epithelial cells: Influence of immunobiotic lactobacilli.

Frontiers in Immunology, 8(FEB). https://doi.org/10.3389/fimmu.2017.00057

Andrade, B. G. N., Cuadrat, R. R. C., Tonetti, F. R., Kitazawa, H., & Villena, J. (2022). The role

of respiratory microbiota in the protection against viral diseases: Respiratory commensal

bacteria as next-generation probiotics for COVID-19. Bioscience of Microbiota, Food and

Health, 41(3), 94–102. https://doi.org/10.12938/bmfh.2022-009

Battles, M. B., & McLellan, J. S. (2019). Respiratory syncytial virus entry and how to block it.

Nature Reviews Microbiology, 17(4), 233–245. https://doi.org/10.1038/s41579-019-0149-x

Bawage, S. S., Tiwari, P. M., Pillai, S., Dennis, V., & Singh, S. R. (2013). Recent advances in

diagnosis, prevention, and treatment of human respiratory syncytial virus. In Advances in

Virology (Vol. 2013). https://doi.org/10.1155/2013/595768

Bohmwald, K., Espinoza, J. A., Pulgar, R. A., Jara, E. L., & Kalergis, A. M. (2017). Functional

impairment of mononuclear phagocyte system by the human respiratory syncytial virus.

Frontiers in Immunology, 8(NOV). https://doi.org/10.3389/fimmu.2017.01643

Bont, L., Steijn, M., van Aalderen, W. M. C., & Kimpen, J. L. L. (2004). Impact of Wheezing

after Respiratory Syncytial Virus Infection on Health-Related Quality of Life. Pediatric

Infectious

Disease

Journal,

23(5),

414–417.

https://doi.org/10.1097/01.inf.0000122604.32137.29

Breese Hall, C., Weinberg, G. A., Iwane, M. K., Blumkin, A. K., Edwards, K. M., Staat, M. A.,

Auinger, P., Griffin, M. R., Poehling, K. A., Erdman, D., Grijalva, C. G., Zhu, Y., & Szilagyi,

P. (2009). The Burden of Respiratory Syncytial Virus Infection in Young Children A bs tr ac

t. The New England Journal of Medicine, 6, 588–598.

Chanock, R., & Finberg, L. (1957). Recovery from infants with respiratory illness of a virus

related to chimpanzee coryza agent (CCA): Epidemiologic aspects of infection in infants

and

young

children.

American

Journal

of

Epidemiology,

66(3),

291–300.

https://doi.org/10.1093/oxfordjournals.aje.a119902

Chanock, R., Roizman, B., & Myers, R. (1957). Recovery from infants from with respiratory

99

illness of a virus related to chimpanzee coryza agent (CCA). American Journal of

Epidemiology, 66(3), 281–290. https://doi.org/10.1093/oxfordjournals.aje.a119901

Chi, H., Barry, S. P., Roth, R. J., Wu, J. J., Jones, E. A., Bennett, A. M., & Flavell, R. A. (2006).

Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1

(MKP-1) in innate immune responses. Proceedings of the National Academy of Sciences of

the United States of America, 103(7), 2274–2279. https://doi.org/10.1073/pnas.0510965103

Clancy, R. (2003). Immunobiotics and the probiotic evolution. FEMS Immunology and Medical

Microbiology, 38(1), 9–12. https://doi.org/10.1016/S0928-8244(03)00147-0

Clua, P., Kanmani, P., Zelaya, H., Tada, A., Humayun Kober, A. K. M., Salva, S., Alvarez, S.,

Kitazawa, H., & Villena, J. (2017). Peptidoglycan from immunobiotic lactobacillus

rhamnosus improves resistance of infant Mice to respiratory syncytial viral infection and

secondary

pneumococcal

pneumonia.

Frontiers

in

Immunology,

8(AUG).

https://doi.org/10.3389/fimmu.2017.00948

Clua, P., Tomokiyo, M., Raya Tonetti, F., Islam, M. A., García Castillo, V., Marcial, G., Salva, S.,

Alvarez, S., Takahashi, H., Kurata, S., Kitazawa, H., & Villena, J. (2020). The Role of

Alveolar Macrophages in the Improved Protection against Respiratory Syncytial Virus and

Pneumococcal Superinfection Induced by the Peptidoglycan of Lactobacillus rhamnosus

CRL1505. Cells, 9(7). https://doi.org/10.3390/cells9071653

de Almeida Nagata, D. E., Demoor, T., Ptaschinski, C., Ting, H.-A., Jang, S., Reed, M., Mukherjee,

S., & Lukacs, N. W. (2014). IL-27R-mediated regulation of IL-17 controls the development

of respiratory syncytial virus-associated pathogenesis. American Journal of Pathology,

184(6), 1807–1818. https://doi.org/10.1016/j.ajpath.2014.02.004

Eguchi, K., Fujitani, N., Nakagawa, H., & Miyazaki, T. (2019). Prevention of respiratory syncytial

virus infection with probiotic lactic acid bacterium Lactobacillus gasseri SBT2055.

Scientific Reports, 9(1). https://doi.org/10.1038/s41598-019-39602-7

Fiore, W., Arioli, S., & Guglielmetti, S. (2020). The neglected microbial components of

commercial

probiotic

formulations.

Microorganisms,

8(8),

1–8.

https://doi.org/10.3390/microorganisms8081177

Fuller R. (1989). Probiotics in man and animals. In Journal of Applied Bacteriology (Vol. 66,

Issue 5, pp. 365–378). https://doi.org/10.1111/j.1365-2672.1989.tb05105.x

Gasteiger, G., & Rudensky, A. Y. (2014). Interactions between innate and adaptive lymphocytes.

In Nature Reviews Immunology (Vol. 14, Issue 9, pp. 631–639). Nature Publishing Group.

https://doi.org/10.1038/nri3726

Ghadimi, D., Fölster-Holst, R., de Vrese, M., Winkler, P., Heller, K. J., & Schrezenmeir, J. (2008).

Effects of probiotic bacteria and their genomic DNA on T<inf>H</inf>1/T<inf>H</inf>2cytokine production by peripheral blood mononuclear cells (PBMCs) of healthy and allergic

100

subjects. Immunobiology, 213(8), 677–692. https://doi.org/10.1016/j.imbio.2008.02.001

Gibson, G. R., & Roberfroid, M. B. (1995). Dietary modulation of the human colonic microbiota:

Introducing the concept of prebiotics. Journal of Nutrition, 125(6), 1401–1412.

https://doi.org/10.1093/jn/125.6.1401

Goritzka, M., Makris, S., Kausar, F., Durant, L. R., Pereira, C., Kumagai, Y., Culley, F. J., Mack,

M., Akira, S., & Johansson, C. (2015). Alveolar macrophage-derived type I interferons

orchestrate innate immunity to RSV through recruitment of antiviral monocytes. Journal of

Experimental Medicine, 212(5), 699–714. https://doi.org/10.1084/jem.20140825

Griffiths, C., Drews, S. J., & Marchant, D. J. (2017). Respiratory syncytial virus: Infection,

detection, and new options for prevention and treatment. Clinical Microbiology Reviews,

30(1), 277–319. https://doi.org/10.1128/CMR.00010-16

Grosfeld, H., Hill, M. G., & Collins, P. L. (1995). RNA Replication by Respiratory Syncytial

Virus (RSV) Is Directed by the N, P, and L Proteins; Transcription Also Occurs under These

Conditions but Requires RSV Superinfection for Efficient Synthesis of Full-Length mRNA.

Journal of Virology, 69(9), 5677–5686. https://journals.asm.org/journal/jvi

Harata, G., He, F., Hiruta, N., Kawase, M., Kubota, A., Hiramatsu, M., & Yausi, H. (2010).

Intranasal administration of Lactobacillus rhamnosus GG protects mice from H1N1

influenza virus infection by regulating respiratory immune responses. Letters in Applied

Microbiology, 50(6), 597–602. https://doi.org/10.1111/j.1472-765X.2010.02844.x

Harker, J. A., Yamaguchi, Y., Culley, F. J., Tregoning, J. S., & Openshaw, P. J. M. (2014). Delayed

sequelae of neonatal respiratory syncytial virus infection are dependent on cells of the innate

immune system. Journal of Virology, 88(1), 604–611. https://doi.org/10.1128/JVI.02620-13

Henderson, J., Hilliard, T. N., Sherriff, A., Stalker, D., al Shammari, N., & Thomas, H. M. (2005).

Hospitalization for RSV bronchiolitis before 12 months of age and subsequent asthma, atopy

and wheeze: A longitudinal birth cohort study. Pediatric Allergy and Immunology, 16(5),

386–392. https://doi.org/10.1111/j.1399-3038.2005.00298.x

Hiscott, J., Nguyen, T.-L. A., Arguello, M., Nakhaei, P., & Paz, S. (2006). Manipulation of the

nuclear factor-κB pathway and the innate immune response by viruses. Oncogene, 25(51),

6844–6867. https://doi.org/10.1038/sj.onc.1209941

Hori, T., Kiyoshima, J., Shida, K., & Yasui, H. (2001). Effect of intranasal administration of

Lactobacillus casei shirota on influenza virus infection of upper respiratory tract in mice.

Clinical

and

Diagnostic

Laboratory

Immunology,

8(3),

593–597.

https://doi.org/10.1128/CDLI.8.3.593-597.2001

Hou, N., Du, X., & Wu, S. (2022). Advances in pig models of human diseases. Animal Models

and Experimental Medicine, 5(2), 141–152. https://doi.org/10.1002/ame2.12223

Hussell, T., & Bell, T. J. (2014). Alveolar macrophages: Plasticity in a tissue-specific context. In

101

Nature Reviews Immunology (Vol. 14, Issue 2, pp. 81–93). https://doi.org/10.1038/nri3600

Indo, Y., Kitahara, S., Tomokiyo, M., Araki, S., Islam, M. A., Zhou, B., Albarracin, L., Miyazaki,

A., Ikeda-Ohtsubo, W., Nochi, T., Villena, J., & Kitazawa, H. (2021). Ligilactobacillus

salivarius Strains Isolated From the Porcine Gut Modulate Innate Immune Responses in

Epithelial Cells and Improve Protection Against Intestinal Viral-Bacterial Superinfection.

Frontiers in Immunology, 12. https://doi.org/10.3389/fimmu.2021.652923

Inoue, R., Nagino, T., Hoshino, G., & Ushida, K. (2011). Nucleic acids of Enterococcus faecalis

strain EC-12 are potent Toll-like receptor 7 and 9 ligands inducing interleukin-12 production

from murine splenocytes and murine macrophage cell line J774.1. FEMS Immunology and

Medical Microbiology, 61(1), 94–102. https://doi.org/10.1111/j.1574-695X.2010.00752.x

Ishizuka, T., Kanmani, P., Kobayashi, H., Miyazaki, A., Soma, J., Suda, Y., Aso, H., Nochi, T.,

Iwabuchi, N., Xiao, J.-Z., Villena, J., & Kitazawa, H. (2016). Immunobiotic bifidobacteria

strains modulate rotavirus immune response in porcine intestinal epitheliocytes via pattern

recognition

receptor

signaling.

PLoS

ONE,

11(3).

https://doi.org/10.1371/journal.pone.0152416

Izumo, T., Maekawa, T., Ida, M., Noguchi, A., Kitagawa, Y., Shibata, H., Yasui, H., & Kiso, Y.

(2010). Effect of intranasal administration of Lactobacillus pentosus S-PT84 on influenza

virus infection in mice. International Immunopharmacology, 10(9), 1101–1106.

https://doi.org/10.1016/j.intimp.2010.06.012

Joint FAO/WHO Working Group. (2002). Guidelines for the Evaluation of Probiotics in Food.

http://www.fao.org/es/ESN/Probio/probio.htm

Joshi, N., Walter, J. M., & Misharin, A. V. (2018). Alveolar Macrophages. Cellular Immunology,

330, 86–90. https://doi.org/10.1016/j.cellimm.2018.01.005

Kadooka, Y., Tominari, K., Sakai, F., & Yasui, H. (2012). Prevention of rotavirus-induced diarrhea

by preferential secretion of IgA in breast milk via maternal administration of lactobacillus

gasseri SBT2055. Journal of Pediatric Gastroenterology and Nutrition, 55(1), 66–71.

https://doi.org/10.1097/MPG.0b013e3182533a2b

Kanmani, P., Albarracin, L., Kobayashi, H., Hebert, E. M., Saavedra, L., Komatsu, R., Gatica, B.,

Miyazaki, A., Ikeda-Ohtsubo, W., Suda, Y., Villena, J., & Kitazawa, H. (2018). Genomic

characterization of Lactobacillus delbrueckii TUA4408L and evaluation of the antiviral

activities of its extracellular polysaccharides in porcine intestinal epithelial cells. Frontiers

in Immunology, 9(SEP). https://doi.org/10.3389/fimmu.2018.02178

Kawashima, T., Kosaka, A., Yan, H., Guo, Z., Uchiyama, R., Fukui, R., Kaneko, D., Kumagai, Y.,

You, D.-J., Carreras, J., Nishimura, I., & Tsuji, N. (2013). Double-Stranded RNA of

Intestinal Commensal but Not Pathogenic Bacteria Triggers Production of Protective

Interferon-β. Immunity, 38(6), 1187–1197. https://doi.org/10.1016/j.immuni.2013.02.024

102

Kitazawa, H., Ueha, S., Itoh, S., Watanabe, H., Konno, K., Kawai, Y., Saito, T., Itoh, T., &

Yamaguchi, T. (2001). AT oligonucleotides inducing B lymphocyte activation exist in

probiotic Lactobacillus gasseri. International Journal of Food Microbiology, 65(3), 149–

162. https://doi.org/10.1016/S0168-1605(00)00500-6

Kolli, D., Gupta, M. R., Sbrana, E., Velayutham, T. S., Chao, H., Casola, A., & Garofalo, R. P.

(2014). Alveolar macrophages contribute to the pathogenesis of human metapneumovirus

infection while protecting against respiratory syncytial virus infection. American Journal of

Respiratory

Cell

and

Molecular

Biology,

51(4),

502–515.

https://doi.org/10.1165/rcmb.2013-0414OC

Koppe, U., Suttorp, N., & Opitz, B. (2012). Recognition of Streptococcus pneumoniae by the

innate

immune

system.

Cellular

Microbiology,

14(4),

460–466.

https://doi.org/10.1111/j.1462-5822.2011.01746.x

Laiño, J., Villena, J., Kanmani, P., & Kitazawa, H. (2016). Immunoregulatory effects triggered by

lactic acid bacteria exopolysaccharides: New insights into molecular interactions with host

cells. Microorganisms, 4(3). https://doi.org/10.3390/microorganisms4030027

Lang, R., Hammer, M., & Mages, J. (2006). DUSP meet immunology: Dual specificity MAPK

phosphatases in control of the inflammatory response. Journal of Immunology, 177(11),

7497–7504. https://doi.org/10.4049/jimmunol.177.11.7497

LeVine, A. M., Gwozdz, J., Stark, J., Bruno, M., Whitsett, J., & Korfhagen, T. (1999). Surfactant

protein-A enhances respiratory syncytial virus clearance in vivo. Journal of Clinical

Investigation, 103(7), 1015–1021. https://doi.org/10.1172/JCI5849

MacPherson, C., Audy, J., Mathieu, O., & Tompkins, T. A. (2014). Multistrain probiotic

modulation of intestinal epithelial cells’ immune response to a double-stranded RNA ligand,

Poly(I·C).

Applied

and

Environmental

Microbiology,

80(5),

1692–1700.

https://doi.org/10.1128/AEM.03411-13

Mejias, A., Rodríguez-Fernández, R., Oliva, S., Peeples, M. E., & Ramilo, O. (2020). The journey

to a respiratory syncytial virus vaccine. Annals of Allergy, Asthma and Immunology, 125(1),

36–46. https://doi.org/10.1016/j.anai.2020.03.017

Merz, D. C., Andreas, A., & Choppin, P. W. (1980). Importance of antibodies to the fusion

glycoprotein of paramyxoviruses in the prevention of spread of infection. The Journal of

Experimental Medicine, 2, 275–288.

Mizuno, H., Arce, L., Tomotsune, K., Albarracin, L., Funabashi, R., Vera, D., Islam, M. A.,

Vizoso-Pinto, M. G., Takahashi, H., Sasaki, Y., Kitazawa, H., & Villena, J. (2020).

Lipoteichoic Acid Is Involved in the Ability of the Immunobiotic Strain Lactobacillus

plantarum CRL1506 to Modulate the Intestinal Antiviral Innate Immunity Triggered by

TLR3 Activation. Frontiers in Immunology, 11. https://doi.org/10.3389/fimmu.2020.00571

103

Morris, J. A., Blount, R. E., & Smadel, J. E. (1956). Recovery of Cytopathogenic Agent from

Chimpanzees with Coryza. Proceedings of the Society for Experimental Biology and

Medicine, 92, 544–549.

Moue, M., Tohno, M., Shimazu, T., Kido, T., Aso, H., Saito, T., & Kitazawa, H. (2008). Toll-like

receptor 4 and cytokine expression involved in functional immune response in an originally

established porcine intestinal epitheliocyte cell line. Biochimica et Biophysica Acta General Subjects, 1780(2), 134–144. https://doi.org/10.1016/j.bbagen.2007.11.006

Nair, H., Nokes, D. J., Gessner, B. D., Dherani, M., Madhi, S. A., Singleton, R. J., O’Brien, K. L.,

Roca, A., Wright, P. F., Bruce, N., Chandran, A., Theodoratou, E., Sutanto, A., Sedyaningsih,

E. R., Ngama, M., Munywoki, P. K., Kartasasmita, C., Simões, E. A., Rudan, I., … Campbell,

H. (2010). Global burden of acute lower respiratory infections due to respiratory syncytial

virus in young children: a systematic review and meta-analysis. The Lancet, 375(9725),

1545–1555. https://doi.org/10.1016/S0140-6736(10)60206-1

Nakase, J., Ukawa, Y., Takemoto, S., Kubo, T., Sagesaka, Y. M., Aoki-Yoshida, A., & Totsuka, M.

(2017). RNA and a cell wall component of Enterococcus faecalis IC-1 are required for

phagocytosis and interleukin 12 production by the mouse macrophage cell line J774.1.

Bioscience,

Biotechnology

and

Biochemistry,

81(6),

1099–1105.

https://doi.org/10.1080/09168451.2017.1295799

Nakayama, Y., Moriya, T., Sakai, F., Ikeda, N., Shiozaki, T., Hosoya, T., Nakagawa, H., &

Miyazaki, T. (2014). Oral administration of Lactobacillus gasseri SBT2055 is effective for

preventing influenza in mice. Scientific Reports, 4. https://doi.org/10.1038/srep04638

Nataraj, B. H., Ali, S. A., Behare, P. v., & Yadav, H. (2020). Postbiotics-parabiotics: The new

horizons in microbial biotherapy and functional foods. In Microbial Cell Factories (Vol. 19,

Issue 1). BioMed Central. https://doi.org/10.1186/s12934-020-01426-w

Nishibayashi, R., Inoue, R., Harada, Y., Watanabe, T., Makioka, Y., & Ushida, K. (2015). RNA of

Enterococcus faecalis strain EC-12 is a major component inducing interleukin-12

production

from

human

monocytic

cells.

PLoS

ONE,

10(6).

https://doi.org/10.1371/journal.pone.0129806

Onishi, K., Mochizuki, J., Sato, A., Goto, A., & Sashihara, T. (2020). Total RNA and genomic

DNA of Lactobacillus gasseri OLL2809 induce interleukin-12 production in the mouse

macrophage cell line J774.1 via toll-like receptors 7 and 9. BMC Microbiology, 20(1).

https://doi.org/10.1186/s12866-020-01900-w

Piedimonte, G., & Perez, M. K. (2014). Respiratory syncytial virus infection and bronchiolitis.

Pediatrics in Review, 35(12), 519–530. https://doi.org/10.1542/pir.35-12-519

Pot, C., Apetoh, L., Awasthi, A., & Kuchroo, V. K. (2011). Induction of regulatory Tr1 cells and

inhibition of T<inf>H</inf>17 cells by IL-27. Seminars in Immunology, 23(6), 438–445.

104

https://doi.org/10.1016/j.smim.2011.08.003

Pyle, C. J., Uwadiae, F. I., Swieboda, D. P., & Harker, J. A. (2017). Early IL-6 signalling promotes

IL-27 dependent maturation of regulatory T cells in the lungs and resolution of viral

immunopathology. PLoS Pathogens, 13(9). https://doi.org/10.1371/journal.ppat.1006640

Qin, M., Chen, W., Li, Z., Wang, L., Ma, L., Geng, J., Zhang, Y., Zhao, J., & Zeng, Y. (2021).

Role of IFNLR1 Gene in PRRSV Infection of PAM Cells. Journal of Veterinary Science,

22(3), 1–18. https://doi.org/10.4142/JVS.2021.22.E39

Qin, M., Li, C., Li, Z., Chen, W., & Zeng, Y. (2020). Genetic Diversities and Differentially

Selected Regions Between Shandong Indigenous Pig Breeds and Western Pig Breeds.

Frontiers in Genetics, 10. https://doi.org/10.3389/fgene.2019.01351

Roberfroid, M. B. (1998). Prebiotics and synbiotics: Concepts and nutritional properties. British

Journal of Nutrition, 80(SUPPL. 2). https://doi.org/10.1017/s0007114500006024

Robin A Weiss, & Anthony J McMichael. (2004). Social and environmental risk factors in the

emergence of infectious diseases. Nature Medicine, 10, S70–S76.

Sadler, A. J., & Williams, B. R. G. (2008). Interferon-inducible antiviral effectors. Nature Reviews

Immunology, 8(7), 559–568. https://doi.org/10.1038/nri2314

Saitoh, T., Yamamoto, M., Miyagishi, M., Taira, K., Nakanishi, M., Fujita, T., Akira, S.,

Yamamoto, N., & Yamaoka, S. (2005). A20 is a negative regulator of IFN regulatory factor

signaling.

Journal

of

Immunology,

174(3),

1507–1512.

https://doi.org/10.4049/jimmunol.174.3.1507

Salminen, S., Collado, M. C., Endo, A., Hill, C., Lebeer, S., Quigley, E. M. M., Sanders, M. E.,

Shamir, R., Swann, J. R., Szajewska, H., Szajewska, H., & Vinderola, G. (2021). The

International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus

statement on the definition and scope of postbiotics. Nature Reviews Gastroenterology and

Hepatology, 18(9), 649–667. https://doi.org/10.1038/s41575-021-00440-6

Sato, N., Garcia-Castillo, V., Yuzawa, M., Islam, M. A., Albarracin, L., Tomokiyo, M., IkedaOhtsubo, W., Garcia-Cancino, A., Takahashi, H., Villena, J., Villena, J., & Kitazawa, H.

(2020). Immunobiotic Lactobacillus jensenii TL2937 Alleviates Dextran Sodium SulfateInduced Colitis by Differentially Modulating the Transcriptomic Response of Intestinal

Epithelial Cells. Frontiers in Immunology, 11. https://doi.org/10.3389/fimmu.2020.02174

Sato, N., Yuzawa, M., Aminul, M. I., Tomokiyo, M., Albarracin, L., Garcia-Castillo, V., IdekaOhtsubo, W., Iwabuchi, N., Xiao, J.-Z., Garcia-Cancino, A., Villena, J., & Kitazawa, H.

(2021). Evaluation of Porcine Intestinal Epitheliocytes as an In vitro Immunoassay System

for the Selection of Probiotic Bifidobacteria to Alleviate Inflammatory Bowel Disease.

Probiotics and Antimicrobial Proteins, 13(3), 824–836. https://doi.org/10.1007/s12602020-09694-z

105

Schneider, C., Nobs, S. P., Heer, A. K., Kurrer, M., Klinke, G., van Rooijen, N., Vogel, J., & Kopf,

M. (2014). Alveolar Macrophages Are Essential for Protection from Respiratory Failure and

Associated Morbidity following Influenza Virus Infection. PLoS Pathogens, 10(4).

https://doi.org/10.1371/journal.ppat.1004053

Sedeyn, K., Schepens, B., & Saelens, X. (2019). Respiratory syncytial virus nonstructural proteins

1 and 2: Exceptional disrupters of innate immune responses. In PLoS Pathogens (Vol. 15,

Issue 10). Public Library of Science. https://doi.org/10.1371/journal.ppat.1007984

Sengupta, R., Altermann, E., Anderson, R. C., McNabb, W. C., Moughan, P. J., & Roy, N. C.

(2013). The role of cell surface architecture of lactobacilli in host-microbe interactions in

the

gastrointestinal

tract.

Mediators

of

Inflammation,

2013.

https://doi.org/10.1155/2013/237921

Shibolet, O., & Podolsky, D. K. (2007). TLRs in the Gut. IV. Negative regulation of Toll-like

receptors and intestinal homeostasis: Addition by subtraction. American Journal of

Physiology

Gastrointestinal

and

Liver

Physiology,

292(6).

https://doi.org/10.1152/ajpgi.00531.2006

Shimosato, T., Kimura, T., Tohno, M., Iliev, I. D., Katoh, S., Ito, Y., Kawai, Y., Sasaki, T., Saito,

T., & Kitazawa, H. (2006). Strong immunostimulatory activity of AT-oligodeoxynucleotide

requires a six-base loop with a self-stabilized 5′-C...G-3′ stem structure. Cellular

Microbiology, 8(3), 485–495. https://doi.org/10.1111/j.1462-5822.2005.00640.x

Sigurs, N., Aljassim, F., Kjellman, B., Robinson, P. D., Sigurbergsson, F., Bjarnason, R., &

Gustafsson, P. M. (2010). Asthma and allergy patterns over 18 years after severe RSV

bronchiolitis

in

the

first

year

of

life.

Thorax,

65(12),

1045–1052.

https://doi.org/10.1136/THX.2009.121582

Sigurs, N., Bjarnason, R., Sigurbergsson, F., & Kjellman, B. (2000). Respiratory Syncytial Virus

Bronchiolitis in Infancy Is an Important Risk Factor for Asthma and Allergy at Age 7.

American Journal of Respiratory and Critical Care Medicine, 161(5), 1501–1507.

https://doi.org/10.1164/ajrccm.161.5.9906076

Sigurs, N., Gustafsson, P. M., Bjarnason, R., Lundberg, F., Schmidt, S., Sigurbergsson, F., &

Kjellman, B. (2005). Severe Respiratory Syncytial Virus Bronchiolitis in Infancy and

Asthma and Allergy at Age 13. American Journal of Respiratory and Critical Care Medicine,

171(2), 137–141. https://doi.org/10.1164/rccm.200406-730OC

Smith, E. C., Popa, A., Chang, A., Masante, C., & Dutch, R. E. (2009). Viral entry mechanisms:

The increasing diversity of paramyxovirus entry. In FEBS Journal (Vol. 276, Issue 24, pp.

7217–7227). https://doi.org/10.1111/j.1742-4658.2009.07401.x

Stein, R. T., Sherrill, D., Morgan, W. J., Holberg, C. J., Halonen, M., Taussig, L. M., Wright, A.

L., & Martinez, F. D. (1999). Respiratory syncytial virus in early life and risk of wheeze and

106

allergy by age 13 years. The Lancet, 354(9178), 541–545. https://doi.org/10.1016/S01406736(98)10321-5

Stumhofer, J. S., & Hunter, C. A. (2008). Advances in understanding the anti-inflammatory

properties

of

IL-27.

Immunology

Letters,

117(2),

123–130.

https://doi.org/10.1016/j.imlet.2008.01.011

Takeda, K., & Akira, S. (2005). Toll-like receptors in innate immunity. International Immunology,

17(1), 1–14. https://doi.org/10.1093/intimm/dxh186

Taleb, S. A., al Thani, A. A., al Ansari, K., & Yassine, H. M. (2018). Human respiratory syncytial

virus: pathogenesis, immune responses, and current vaccine approaches. In European

Journal of Clinical Microbiology and Infectious Diseases (Vol. 37, Issue 10, pp. 1817–1827).

Springer Verlag. https://doi.org/10.1007/s10096-018-3289-4

Tobita, K., Hoshi, F., Ohki, T., & Watanabe, I. (2021). Protein denature extracts of Lactobacillus

crispatus KT-11 strain promote interleukin 12p40 production via Toll-like receptor 2 in

J774.1 cell culture. Journal of Food Biochemistry, 45(2). https://doi.org/10.1111/jfbc.13599

Tomokiyo, M., Tonetti, F. R., Yamamuro, H., Shibata, R., Fukuyama, K., Gobbato, N., Albarracin,

L., Rajoka, M. S. R., Kober, A. K. M. H., Ikeda-Ohtsubo, W., Villena, J., & Kitazawa, H.

(2022). Modulation of Alveolar Macrophages by Postimmunobiotics: Impact on TLR3Mediated

Antiviral

Respiratory

Immunity.

Cells,

11(19),

2986.

https://doi.org/10.3390/cells11192986

Tomosada, Y., Chiba, E., Zelaya, H., Takahashi, T., Tsukida, K., Kitazawa, H., Alvarez, S., &

Villena, J. (2013). Nasally administered Lactobacillus rhamnosus strains differentially

modulate respiratory antiviral immune responses and induce protection against respiratory

syncytial virus infection. BMC Immunology, 14(1). https://doi.org/10.1186/1471-2172-1440

Tsukida, K., Takahashi, T., Iida, H., Kanmani, P., Suda, Y., Nochi, T., Ohwada, S., Aso, H.,

Ohkawara, S., Makino, S., Villena, J., & Kitazawa, H. (2016). Immunoregulatory effects

triggered by immunobiotic Lactobacillus jensenii TL2937 strain involve efficient

phagocytosis

in

porcine

antigen

presenting

cells.

BMC

Immunology,

17(1).

https://doi.org/10.1186/s12865-016-0160-1

Turner, M. W. (2003). The role of mannose-binding lectin in health and disease. Molecular

Immunology, 40(7), 423–429. https://doi.org/10.1016/S0161-5890(03)00155-X

Wang, D., Fang, L., Zhao, F., Luo, R., Chen, H., & Xiao, S. (2011). Molecular cloning, expression

and antiviral activity of porcine interleukin-29 (poIL-29). Developmental and Comparative

Immunology, 35(3), 378–384. https://doi.org/10.1016/j.dci.2010.11.003

Wang, L., Hu, S., Liu, Q., Li, Y., Xu, L., Zhang, Z., Cai, X., & He, X. (2017). Porcine alveolar

macrophage polarization is involved in inhibition of porcine reproductive and respiratory

107

syndrome virus (PRRSV) replication. Journal of Veterinary Medical Science, 79(11), 1906–

1915. https://doi.org/10.1292/jvms.17-0258

Wei, J., Xu, M., Chen, X., Zhang, P., Li, P., Wei, S., Yan, Y., & Qin, Q. (2015). Function analysis

of fish Tollip gene in response to virus infection. Fish and Shellfish Immunology, 47(2),

807–816. https://doi.org/10.1016/j.fsi.2015.10.008

Weingartl, H. M., Sabara, M., Pasick, J., van Moorlehem, E., & Babiuk, L. (2002). Continuous

porcine cell lines developed from alveolar macrophages: Partial characterization and virus

susceptibility.

Journal

of

Virological

Methods,

104(2),

203–216.

https://doi.org/10.1016/S0166-0934(02)00085-X

Wright, J. R. (2005). Immunoregulatory functions of surfactant proteins. Nature Reviews

Immunology, 5(1), 58–68. https://doi.org/10.1038/nri1528

Yoda, K., He, F., Miyazawa, K., Kawase, M., Kubota, A., & Hiramatsu, M. (2012). Orally

administered heat-killed Lactobacillus gasseri TMC0356 alters respiratory immune

responses and intestinal microbiota of diet-induced obese mice. Journal of Applied

Microbiology, 113(1), 155–162. https://doi.org/10.1111/j.1365-2672.2012.05316.x

Zhao, X., Singh, M., Malashkevich, V. N., & Kim, P. S. (2000). Structural characterization of the

human respiratory syncytial virus fusion protein core. Proceedings of the National Academy

of Sciences of the United States of America, 97, 14172–14177. www.rcsb.org

下里剛士, & 北澤春樹. (2010). イムノジェニクスとしての免疫刺激性DNA研究の最前線.

北 信 越 畜 産 学 会 報 = Hokushinetsu Journal of Animal Science, 100, 1–9.

https://cir.nii.ac.jp/crid/1523951030489339520.bib?lang=ja

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