Life science
Medical & healthcare, Drug development

Flagellum-triggered sensory system contributing toBordetella pertussis infection
Department of Molecular Bacteriology, Research Institute for Microbial Diseases
Assistant Professor Yukihiro Hiramatsu
https://researchmap.jp/yhiramatsu?lang=en

The Gram-negative bacterium Bordetella pertussis causes ahighly contagious respiratory disease called pertussis (whoopingcough) that is characterized by severe and uncontrollable coughing. The mechanisms regulating the expression of virulence factors 英語版of B. pertussis have been studied using the organism grown invitro, but not within the hosts. In the present study, we found that B.
pertussis senses gangliosides on the host cell membrane throughflagella during host infection and up-regulates the expression of asmall RNA designated Bpr4 and subsequent filamentous hemagglutinin (FHA), a major adhesin of the bacteria, leading bacteria toA
enhance colonization. Our findings indicate that a flagellum-trig103
gered sensory system contributes to B. pertussis infection.

Pertussis has recently seen a resurgence despite high vaccination coverage, hypothetically because of the rapid waningof immunity induced by recent acellular pertussis vaccines andadaptation of the bacterium to escape vaccine-induced immunity.
Macrolides are the first-line antibiotics to treat pertussis; however,macrolide-resistant B. pertussis has emerged worldwide, which
英語版
prompts the development of novel antibiotic-free therapies to control pertussis.
We focused on the small RNA of B. pertussis as a virulence
regulator during bacterial infection and identified four small RNAs
designated Bpr4, 5, 8, and 9 that were highly expressed upontracheal colonization in mice (Fig. 1A). Among these small RNAs,
we found that a small RNA, Bpr4, which is up-regulated up to 120fold upon tracheal colonization of B. pertussis, binds to the 5’-untranslated region of fhaB mRNA encoding FHA and protects it from
RNaseE-mediated degradation, resulting in the posttranscriptional
up-regulation of FHA, which facilitates bacterial colonization (Fig.
1B). Our results also demonstrated that Bpr4 up-regulation is triggered by the interference of flagellar rotation after the interactionof flagellin and gangliosides on the host cells, which causes thedisengagement of MotAB comprising a flagellar stator, from the flagellar complex. The liberated MotA interacted with and activated adiguanylate cyclase designated DgcB to generate cyclic di-GMP,
which plays a role in Bpr4 up-regulation through the RisK/RisA
two-component system. Our findings indicate that a flagellum-triggered sensory system leads to small RNA upregulation contributing to B. pertussis infection.

▍ Significance of the research and Future perspective

Bin vitro

107

in trachea

102

CFU/trachea▍ Background & Results

Bpr expression

Life science

Abstract

101
10010-1Bpr4

Bpr5

Bpr8105
104
103

Bpr9

P <✱✱✱
0.001

106

WT

Δbpr4 Δbpr8 Δbpr9

Fig Fig.
1. Highly-expressed
small
RNAs
ininB.B.pertussis
1. Highly-expressed
small
RNAs
pertussiscolonizingcolonizing mouse
mouse tracheas.
tracheas.
(A) Inandininvivo
expressionof pertussis
B. pertussis(A)vitro
In vitro
andvivo(in(in trachea)
trachea) expressionof B.
smallsmall
RNAsRNAs(Bpr). (Bpr).
(B) Colonization
ofofB.B.pertussis
WTand
andmutantmutantstrains
in mouse
tracheas.
(B) Colonization
pertussis WTstrains
in mouse
tracheas.

A

B. pertussis
DgcB

flagellin

MotAMotB

B
Bpr4 !
RisKcyclicdi-GMP

fhaB

RisA
RNaseEFHA !

Gangliosides

Host cell

Lipid raftFig
2. The mechanism of sequential up-regulation of Bpr4 and FHA upon bacteriFig. 2. The mechanism of sequential up-regulation of Bpr4 and FHA uponaladherence
to thetohost
bacterial
adherencethe cell.
host cell.
(A)
MotABisisincorporated
incorporated
the flagellar
basal
body B.
in pertussis.
motile B. pertussis.
(A) MotAB
into into
the flagellar
basal bodyin motile(B)
Bpr4is isup-regulated
cell adherenceof B.
pertussis
through a flagel(B) Bpr4
up-regulated
upon uponcell adherenceof B. pertussis
througha flagellumlumtriggered
sensorysystem.
triggered sensorysystem.

Similar to many pathogenic bacteria, B. pertussis is also a
problem due to the spread of antibiotic-resistant strains. The circumstance prompts the development of therapeutic approaches
without antibiotics to control pertussis. The results of this study
revealed the flagellum-triggered sensory system contributing toB. pertussis infection. Our findings may lead to the developmentof therapeutic approaches to control pertussis by targeting host(gangliosides)-sensing by flagella. In addition, given that many
pathogenic bacteria produce flagella, our idea has the potential to
be useful in combating various bacterial infections.

P a t e n t
Hiramatsu, Yukihiro; Nishida Takashi; Nugraha, Krisna, Dendi et al. Interference of flagellar rotation up-regulates the expression of small RNA contributing
to Bordetella pertussis infection. Science Advances. 2022, 8(51), eade8971. doi: 10.1126/sciadv.ade8971
URL http://www.biken.osaka-u.ac.jp/en/achievement/research/2022/183
K e y w o r d Bordetella pertussis, host-sensing system, flagella, gangliosides, small RNA
Tr e a t i s e