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Role of the solute carrier 15A4 in anti-microbial inflammatory responses and autophagy in dendritic cells

Award Number: R01AI196199
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: 08/11/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Role of the solute carrier 15A4 in anti-microbial inflammatory responses and autophagy in dendritic cells - Summary Solute sensing and transport are evolutionarily conserved mechanisms essential for organismal defense and survival. The importance of controlling nutrient transport in maintaining cellular and immune fitness is evidenced by the association between dysfunctions in many nutrient transporters, like solute carriers (SLCs), and metabolic and inflammatory diseases. However, the molecular mechanisms that connect nutrient transport and sensing with anti-bacterial inflammatory responses are unclear. Our studies are focused on the lysosomal histidine (His) transporter SLC15A4, which is preferentially expressed in immune cells and is associated with human inflammatory disorders. In plasmacytoid dendritic cells (pDCs), SLC15A4 plays His transport-independent functions associated with the adaptors TASL/ TASL2 (TASL). In conventional DCs (DCs), we showed that SLC 15A4 not only maintains nutrient homeostasis by transporting His to the cytosol, but also promotes anti-bacterial immune responses and inhibits autophagy – a major anti-inflammatory process – by activating mTORC1, the master regulator of cell fitness. While mTORC1 has been studied in other cell types, our data suggest that it plays unique functions in DCs, the main instructors of adaptive immune responses. Specifically, we hypothesize that the SLC15A4→mTORC1 pathway in DCs (1) promotes antigen (Ag) processing and presentation, by stimulating the activity of the motor protein KIF5B; (2) promotes NLRC4 inflammasome perinuclear positioning and activity, essential for mounting heightened immune responses to pathogenic bacteria, by inhibiting the motor protein KIF1C; and (3) inhibits autophagy by preventing the nuclear translocation of the transcription factor TFEB, the master regulator of autophagy. By using a mouse model of non-functional SLC15A4 (Feeble), TASL double knockout mice and Salmonella infections, our studies will provide mechanistic links between impaired nutrient transport and dysregulated immune responses both in vitro and in vivo. Fulfilling the following Specific Aims will shed light on the mechanisms that link solute transport by SLC15A4 to Ag processing and presentation, the escalation of immune responses by NLRC4 inflammasomes and the control of bacterial infections in DCs. 1. To determine how SLC15A4 promotes phagosome maturation to favor Ag processing and presentation in DCs. 2. To determine how SLC15A4 promotes NLRC4 inflammasome perinuclear positioning and activity in DCs. 3. To determine whether SLC15A4 modulates anti-microbial and autophagy programs to control bacterial infection in vivo. Elucidating the mechanisms that link nutrient transport to optimal anti-microbial immunity and inflammatory responses may provide valuable insights for future treatment of both infectious and inflammatory diseases.


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 = $712,776 )
2026	2026	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	8/11/2026	NEW	$712,776
														Subtotal = $712,776

Grand Total All Awards = $712,776

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Role of the solute carrier 15A4 in anti-microbial inflammatory responses and autophagy in dendritic cells

Award Number: R01AI196199

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: 08/11/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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