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Host tRNA-derived small RNAs (tsRNAs) mediate interactions between host and oral microbes

Award Number: R01DE030943
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/22/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Host tRNA-derived small RNAs (tsRNAs) mediate interactions between host and oral microbes - Host mucosal surfaces are highly specialized and possess a complex array of innate and adaptive immunity. They provide the first line of protection against infectious agents by initiating protective responses to potential pathogens. Furthermore, the symbiotic relationship of the hundreds of microbial species with the host requires a fine-tuned response at the mucosal surface that prevents overgrowth of opportunistic pathogens, but sparing beneficial microbes. While small RNAs (sRNAs) have been regarded as a class of intracellular regulatory elements, emerging studies in plant-pathogen and host-gut microbiome interactions uncover that hosts can exploit sRNAs, such as transfer RNA (tRNA)-derived sRNAs (termed “tsRNAs”), via encapsulation in exosomes, as a new mode of bacterial gene modulation or defense mechanism. Yet, it remains to be elucidated whether such sRNA-mediated inter-kingdom gene modulation or defense mechanism exist in the context of host-oral microbiome interaction. To address this knowledge gap, the present R01 application will focus on host-derived, exosome-borne, salivary tsRNAs, of which the biological functions have remained largely elusive to date. Speficically, we recently demonstrated that human Normal Oral Keratinocyte- Spontaneously Immortalized (NOKSI) cells released two exosome-borne tsRNAs, tsRNA-000794 and tsRNA- 020498, when challenged with Fusobacterium nucleatum (Fn), a key oral commensal and opportunistic periodontal pathogen. Importantly, these two tsRNAs can be readily detected from saliva in healthy human subjects. Intriguingly, both tsRNAs exhibit highly selective, Fn-targeting antimicrobial activity—directly adding synthetic mimics of these two tsRNAs, but not scramble RNA, to bacterial culture inhibits the growth of Fn, but not that of Porphyromonas ginigivalis (Pg), a gram-negative periodontal pathogen or Streptococcus mitis (Sm), a health-associated oral bacterium. In preliminary work, we further took a multi-facet approach to identify a putative RNA-specific membrane transporter as well as candidate intracellular bacterial protein targets of Fn- targeting tsRNAs. Building on our comprehensive preliminary data, the goal of this application is two-fold: (Part I) achieve mechanistic understanding of the cross-kingdom trafficking of host-derived Fn-targeting tsRNAs and their modulating effect on Fn growth during NOKSI-Fn interaction, through exosome tracking and in-depth dissection of the tsRNAs transporter and intracellular targets in Fn; (Part II) expand our work to profile and compare salivary tsRNAs between healthy and periodontitis subjects, with a focus on demonstrating the broad implication of host-generated tsRNAs as a conserved mechanism to achieve host-microbial homeostasis. The realization of this application will not only address a fundamental question by defining tsRNAs as a new class of host defense molecules in maintaining host-microbiome homeostasis via targeted microbial modulation, but also will pave the way for a new therapeutic strategy against oral diseases, considering the already successful trajectory of nucleic acid therapeutics in recent years.


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: 2026 ( Subtotal = $468,431 )
2026	2026	ADA FORSYTH INSTITUTE, INC.	100 CHESTNUT ST FL 4	SOMERVILLE	MA	02143	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	5	8/11/2026	NON-COMPETING CONTINUATION	$468,431
														Subtotal = $468,431

Issue Date FY: 2025 ( Subtotal = $524,685 )
2025	2025	ADA FORSYTH INSTITUTE, INC.	245 1ST ST 17TH FLOOR	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	001	4	5/7/2025	NON-COMPETING CONTINUATION	$52,468
2025	2025	ADA FORSYTH INSTITUTE, INC.	245 1ST ST 17TH FLOOR	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	4	1/16/2025	NON-COMPETING CONTINUATION	$472,217
														Subtotal = $524,685

Issue Date FY: 2024 ( Subtotal = $481,381 )
2024	2024	ADA FORSYTH INSTITUTE, INC.	245 1ST ST 17TH FLOOR	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	3	1/24/2024	NON-COMPETING CONTINUATION	$442,083
2024	2024	ADA FORSYTH INSTITUTE, INC.	245 1ST ST 17TH FLOOR	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	001	3	6/18/2024	NON-COMPETING CONTINUATION	$39,298
														Subtotal = $481,381

Issue Date FY: 2023 ( Subtotal = $496,111 )
2023	2023	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	001	2	2/22/2023	NON-COMPETING CONTINUATION	$49,610
2023	2023	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	2	1/6/2023	NON-COMPETING CONTINUATION	$446,501
														Subtotal = $496,111

Issue Date FY: 2022 ( Subtotal = $478,380 )
2022	2022	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	1	2/22/2022	NEW	$478,380
														Subtotal = $478,380

Grand Total All Awards = $2,448,988

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Host tRNA-derived small RNAs (tsRNAs) mediate interactions between host and oral microbes

Award Number: R01DE030943

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/22/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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