Identifying Host Cell Death Pathway Targets for Host-Directed Therapies for Treatment of Mtb and Mtb/HIV Co-Infection (R01 Clinical Trial Not Allowed) | PAR 22 223

Opportunity Information: Apply for PAR 22 223

This grant opportunity, PAR 22-223, is an NIH R01 funding announcement focused on tuberculosis and TB/HIV co-infection, with an emphasis on understanding how host cell death pathways shape immune responses during infection. The central goal is to fund mechanistic, hypothesis-driven research that clarifies how different forms of host cell death influence the course of Mycobacterium tuberculosis (Mtb) disease and Mtb/HIV co-infection, and then uses those insights to identify promising immune or pathway targets for host-directed therapies. In practical terms, the FOA is looking for studies that move beyond descriptive observations and instead explain cause-and-effect relationships: which host pathways are engaged, how they are regulated, how they alter bacterial control or persistence, and how they could be manipulated to improve outcomes when used alongside standard antimicrobial treatment.

A key theme is “host-directed therapy,” meaning interventions that aim to improve disease outcomes by modifying the patient’s immune or cellular responses rather than directly targeting the pathogen. For TB, this approach is especially attractive because it can potentially shorten treatment duration, reduce lung tissue damage and inflammation, improve bacterial clearance, and help address challenges like drug resistance by working through host mechanisms. For TB/HIV co-infection, host-directed approaches may also help address immune dysregulation associated with HIV, including altered macrophage and T cell function, chronic immune activation, and vulnerability to severe or disseminated TB. The FOA’s emphasis on host cell death pathways reflects the idea that infected cells’ fate, whether they undergo apoptosis, necrosis, pyroptosis, necroptosis, ferroptosis, or other regulated death programs, can strongly influence both bacterial survival and the quality of downstream immune responses.

The research scope centers on identifying and validating specific host cell death-related mechanisms and immunologic processes that could serve as actionable targets. Projects responsive to this opportunity would typically examine how Mtb (and in co-infection scenarios, HIV) modulates cell death decisions in relevant host cells such as macrophages, dendritic cells, neutrophils, and possibly epithelial or other lung-resident cells. Competitive applications would be expected to tie cell death pathways to measurable consequences for infection biology, such as intracellular bacterial replication, granuloma dynamics, antigen presentation and T cell priming, inflammatory mediator production, immune cell recruitment, and tissue pathology. Because the FOA explicitly supports mechanistic studies, it favors proposals that use rigorous experimental strategies to dissect pathways, for example through pathway perturbation, genetic or pharmacologic manipulation, well-justified model systems, and clearly defined readouts that connect molecular events to immunologic and disease-relevant outcomes.

This is an R01 mechanism, which generally supports substantial multi-year research projects with well-developed aims and a strong rationale, and it is designated “Clinical Trial Not Allowed.” That means the funded work should not include prospective assignment of human participants to interventions to evaluate health-related outcomes in a way that meets the NIH definition of a clinical trial. The announcement is still compatible with a wide range of non-trial human research approaches, such as analysis of clinical specimens, observational cohort-derived samples, ex vivo functional assays using patient cells, or integrative studies that combine human biospecimens with animal or in vitro mechanistic work, as long as the project does not cross into an interventional clinical trial design.

Eligibility is broad and includes many types of organizations. In addition to typical academic and research institutions, eligible applicants include state, county, and local governments; special district governments; independent school districts; public housing authorities and Indian housing authorities; federally recognized Native American tribal governments and other tribal organizations; nonprofits (with or without 501(c)(3) status); private institutions of higher education; for-profit organizations (other than small businesses) and small businesses; and other entities. The FOA also explicitly calls out additional eligible applicants such as Alaska Native and Native Hawaiian Serving Institutions, AANAPISIs, Hispanic-serving institutions, HBCUs, tribally controlled colleges and universities, faith-based or community-based organizations, eligible federal agencies, U.S. territories or possessions, and non-U.S. (foreign) organizations and regional organizations. This breadth signals interest in supporting scientifically strong proposals from a wide range of settings, including those with direct relevance to TB-endemic regions and communities disproportionately affected by TB and HIV.

Administrative details in the source information place this opportunity under the NIH, with a health-related activity classification and CFDA number 93.855. The opportunity is listed as discretionary funding using the grant instrument. The posting date is August 9, 2022, and the original closing date provided is December 7, 2024. The award ceiling and expected number of awards are not specified in the excerpt, which often means applicants should refer to the full FOA text and NIH institute-specific guidance for budget expectations, project period limits, and any priorities or preferences in review.

Overall, this FOA is aimed at advancing the basic and translational immunology of TB by zeroing in on how host cell death programs intersect with protective immunity and immunopathology, especially under the added complexity of HIV co-infection. The intended deliverable is not a clinical intervention study, but a set of validated, mechanistically grounded targets and pathways that could later be developed into host-directed therapeutic strategies to improve TB and TB/HIV outcomes.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Identifying Host Cell Death Pathway Targets for Host-Directed Therapies for Treatment of Mtb and Mtb/HIV Co-Infection (R01 Clinical Trial Not Allowed)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.855.
• This funding opportunity was created on 2022-08-09.
• Applicants must submit their applications by 2024-12-07. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

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