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The interplay of protein secretion and lipid virulence factors in host immune suppression by Mycobacterium tuberculosis

Award Number: R01AI197387
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: 04/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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The interplay of protein secretion and lipid virulence factors in host immune suppression by Mycobacterium tuberculosis - Mycobacterium tuberculosis (Mtb) infects one-quarter of the global population and causes more deaths annually than any other infectious disease. Despite triggering a strong immune response, Mtb evades and suppresses host immunity, establishing chronic infection. Two critical virulence factors, the ESX-1 type VII secretion system and the mycomembrane lipid phthiocerol dimycocerosate (PDIM), play a key role in this immune modulation, but their precise mechanisms remain unclear. Recent data suggest that ESX-1 and PDIM may functionally intersect, as mutants in these pathways exhibit similar virulence phenotypes. This proposal aims to investigate whether ESX-1 and PDIM operate within the same virulence pathway and how PDIM influences ESX-1. Additionally, we will explore whether their roles in virulence involve suppression of protective Th17 CD4 T cell responses and induction of immunosuppressive type I interferons (IFNs). Aim 1 will test whether ESX-1 and PDIM exhibit epistasis for virulence in mice and define how PDIM impacts ESX-1 function. We hypothesize that PDIM mutants subtly affect ESX-1 activity, which will be tested through epistasis experiments and proteomic profiling of ESX-1 function in PDIM mutants. Aim 2 will investigate whether blocking IL-23 explains the suppression of Th17 differentiation by ESX-1/PDIM mutants. We have shown that these mutants induce higher IL-23 production and a robust Th17 response, suggesting that ESX-1 and PDIM suppress this protective response. We will test the role of IL-23 suppression in Th17 differentiation and perform epistasis testing for CD4 T cell orchestration. Aim 3 will determine whether type I IFN induction is necessary for the virulence of ESX-1 and PDIM mutants. Both factors induce type I IFN, which impairs host responses to Mtb. We will test if type I IFN induction is critical for virulence by evaluating mutant strains in mice lacking type I IFN signaling. These studies will provide valuable insights into Mtb's immune evasion strategies, potentially leading to new therapeutic interventions.


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 = $756,714 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	119 CALIFORNIA HALL	BERKELEY	CA	94720	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	1	3/30/2026	NEW	$756,714
														Subtotal = $756,714

Grand Total All Awards = $756,714

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The interplay of protein secretion and lipid virulence factors in host immune suppression by Mycobacterium tuberculosis

Award Number: R01AI197387

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: 04/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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