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The role of Ser/Thr/Tyr phosphosignaling in the M. tuberculosis latency switch

Award Number: R01AI117023
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2016
PERIOD OF PERFORMANCE END DATE: 01/31/2022

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The role of Ser/Thr/Tyr phosphosignaling in the M. tuberculosis latency switch - DESCRIPTION (provided by applicant): A defining feature of Mycobacterium tuberculosis (Mtb) is its ability to manifest as a latent infection that can last for many years. Latent tuberculosis affects nearly 2 billion people, and in much of the world, reactivating Mtb is responsible for the vast majority of active tuberculosis (TB). In this way, latency and reactivatio shape Mtb pathogenesis and transmission and are major impediments to TB control. The bacterial signaling mechanisms and effectors driving the switch between latency and reactivation (the latency switch) are almost entirely unknown. The signal transduction that underpins transitions of this type in other bacteria propagates through phosphorylation pathways. Using a highly reproducible, defined in vitro model of hypoxia followed by reaeration to model latency and reactivation in Mtb, we now show that the Ser/Thr protein kinase PknB and its cognate phosphatase, PstP, are major regulators of replication in response to oxygen and show that PknB is regulated by a new Mtb posttranslational modification, protein Tyr phosphorylation. Based on these data, we hypothesize that Ser/Thr and Tyr phosphosignaling control the Mtb latency switch. By defining a phosphosignaling system- PknB and PstP- that controls the physiologic response of Mtb to shifting oxygen tension, we provide an opportunity to identify the relevant downstream substrates and effectors that execute hypoxia adaptations. These findings will uncover signaling pathways and effectors that control latency and reactivation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	6	4/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $470,750 )
2020	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	6	1/23/2020	NON-COMPETING CONTINUATION	$470,750
														Subtotal = $470,750

Issue Date FY: 2019 ( Subtotal = $470,750 )
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	004	5	1/24/2019	NON-COMPETING CONTINUATION	$470,750
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	006	4	5/1/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$43,330
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	4	11/19/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$169,559
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	003	4	1/10/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$14,691
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	3	11/19/2018	NON-COMPETING CONTINUATION	-$169,559
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	3	1/10/2019	NON-COMPETING CONTINUATION	$14,691
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	005	3	5/1/2019	NON-COMPETING CONTINUATION	-$43,330
														Subtotal = $470,750

Issue Date FY: 2018 ( Subtotal = $482,505 )
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	3	1/22/2018	NON-COMPETING CONTINUATION	$482,505
														Subtotal = $482,505

Issue Date FY: 2017 ( Subtotal = $482,505 )
2017	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	2	2/10/2017	NON-COMPETING CONTINUATION	$13,464
2017	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	1/16/2017	NON-COMPETING CONTINUATION	$469,041
														Subtotal = $482,505

Issue Date FY: 2016 ( Subtotal = $491,291 )
2016	2016	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	1/26/2016	NEW	$491,291
														Subtotal = $491,291

Grand Total All Awards = $2,397,801

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The role of Ser/Thr/Tyr phosphosignaling in the M. tuberculosis latency switch

Award Number: R01AI117023

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2016

PERIOD OF PERFORMANCE END DATE: 01/31/2022

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