Yersinia YopH targets SKAP2-dependent and independent signaling pathways to block neutrophil antimicrobial mechanisms.
shaban, lamyaa.
2019
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Yersinia elicits a
pronounced inflammatory response in infected tissues where bacterial microcolonies are
seen directly interfacing with neutrophils. Normally neutrophils generate various
effective antimicrobial responses, yet Yersinia counteracts the different bactericidal
mechanisms by preferentially translocating neutrophils with various Yop effector
proteins by the type 3 secretion system. ... read moreThe growth of Yersinia pseudotuberculosis
(Yptb) yopH mutant is significantly restored in the absence of neutrophils
highlighting the importance of this effector in inhibiting neutrophil antimicrobial
functions. The effector YopH is a critical tyrosine phosphatase that causes
dephosphorylation of the adapters, SKAP2, PRAM-1 and SLP-76, and effector proteins Vav1
and PLC2 in neutrophils. These targets function in integrin-mediated reactive
oxygen species (ROS) production by neutrophils. Here we investigate whether inactivating
ROS and SKAP2 are essential functions of YopH in animal tissues. Growth of a
yopH mutant was restored in mice defective in NADPH oxidase indicating that YopH
is critical for protecting Yptb from ROS generated during in vivo infection. YopH was
sufficient to block ROS production and degranulation by neutrophils downstream of
integrin, Fc and G-protein coupled receptors. Growth of a yopH mutant was
partially restored in a SKAP2KO mouse suggesting that the SKAP2 signaling pathway is an
essential pathway targeted by YopH in infected tissues. SKAP2KO PMNs migrated
efficiently to infected tissues. Bone marrow derived SKAP2KO PMNs were defective for
integrin and GPCR but not Fc receptor mediated ROS production. YopH blocked
SKAP2-independent pathways to inhibit neutrophil antimicrobial mechanisms including ROS
production and degranulation. The present finding that YopH is essential in Yptb for
blocking ROS produced by neutrophils also suggests an effect on ROS dependent downstream
signaling required by neutrophils to execute various antimicrobial
mechanisms
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Molecular Microbiology.
Advisor: Joan Mecsas.
Committee: John Leong, Andrew Camilli, and Stephen Bunnell.
Keyword: Microbiology.read less - ID:
- 73666h98d
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