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Characterizing IL-22 driven chronic immune activation in HIV/TB co-pandemic

Award Number: K01OD031898
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Characterizing IL-22 driven chronic immune activation in HIV/TB co-pandemic - Project Summary The Human Immunodeficiency Virus (HIV) and tuberculosis (TB) co-pandemic poses a major healthcare burden in resource-limited countries. HIV co-infection predisposes the host to reactivation of latent tuberculosis infection (LTBI) resulting in worsening of disease conditions and mortality. The most well characterized impact of HIV is the CD4+ T cell depletion in lymphoid tissues and peripheral blood. However, studies using the nonhuman primate (NHP) model of M. tuberculosis (Mtb)/SIV co-infection have revealed protective CD4+ T cell-independent immune responses that suppress LTBI reactivation. Recent work shows that the mere depletion of CD4+ T cells is insufficient to cause LTBI reactivation in SIV co-infected macaques. Instead, chronic immune activation appears to be the key correlate for reactivation. Further, highly effective combinatorial antiretroviral therapy (ART), while effective in reducing viral loads in the periphery and lungs of Mtb/SIV co-infected macaques, fails to reduce the rate of reactivation of LTBI. Thus, understanding the driving forces behind chronic immune activation in a relevant co-infected preclinical model underscores the discovery of key biomarkers and development of intervention strategies. We therefore aim to gain insight into the mechanism of mucosal damage, a paramount factor in chronic immune activation, during SIV/TB co-infection. Towards this end, we will investigate the role of IL-22, a key cytokine in protection from HIV and respiratory diseases including TB. We hypothesize that IL-22 protects the lung from damage during LTBI and SIV co-infection abrogates this protection by IL-22 perturbation. We aim to identify the mechanism by which IL-22 disarms the host immune response leading to SIV-driven immune activation and ultimately, the reactivation of LTBI, in a macaque model of SIV/TB co-infection. In Aim 1 we will study the functional role of IL-22 in Mtb/HIV co-infection. We will determine the levels of IL-22 production by CD4+ and CD8+ T cells as well as non-T-cell populations, NKp44+ cells, and CD103+ dendritic cells in the blood, lymph node and colorectum of co-infected macaques and in response to ART intervention (1a). We will also identify the frequency of polyfunctional Th17 cells producing IFNγ, IL-17, IL-22, TNFα, production of antimicrobial peptides; defensin-β, REG-3 proteins and S100A8/A9 proteins in the bronchoalveolar lavage fluid, colorectum, lung tissue lysates of co-infected macaques and in response to ART intervention (1b). In Aim 2, we will study the impact of SIV-induced IL-22 loss on LTBI reactivation. We will first determine whether the presence of IL- 22R expressing macrophages in non-necrotic granulomas of LTBI macaques correlates with protective control of Mtb (2a). We will then perform transcriptional profiling on sorted cell subsets and mononuclear cells isolated from blood, lymph nodes, lungs and colorectal mucosa before and after SIV infection to determine the impact of IL-22 loss on immune activation and subsequent LTBI reactivation (2b). Understanding the mechanism of IL-22 perturbation in HIV/TB will lead to identification and development of antibody-based therapeutics or use of recombinant IL-22 to prevent reactivation of LTBI in coinfected cohorts.


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: 2025 ( Subtotal = $0 )
2025	2023	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Research Infrastructure Programs	000	3	6/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $188,995 )
2023	2023	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Research Infrastructure Programs	000	3	1/14/2023	NON-COMPETING CONTINUATION	$188,995
														Subtotal = $188,995

Issue Date FY: 2022 ( Subtotal = $188,956 )
2022	2022	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Research Infrastructure Programs	001	2	5/17/2022	NON-COMPETING CONTINUATION	$18,896
2022	2022	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Research Infrastructure Programs	000	2	1/20/2022	NON-COMPETING CONTINUATION	$170,060
														Subtotal = $188,956

Issue Date FY: 2021 ( Subtotal = $188,713 )
2021	2021	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Research Infrastructure Programs	000	1	3/30/2021	NEW	$188,713
														Subtotal = $188,713

Grand Total All Awards = $566,664

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Characterizing IL-22 driven chronic immune activation in HIV/TB co-pandemic

Award Number: K01OD031898

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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