Notice Number: NOT-HL-19-744

Key Dates
Release Date: December 13, 2019

Issued by
National Heart, Lung, and Blood Institute (NHLBI)

Purpose

The purpose of this Notice is to inform potential applicants of NHLBI's secondary participation in PAR-19-357 "Myeloid-Derived Suppressor Cells (MDSCs) as Potential Therapeutic Targets in TB/HIV (R01 Clinical Trial Not Allowed)" to support innovative research aimed at investigation of MDSCs as important elements of the host immune response to Mycobacterium tuberculosis in the context of HIV co-infection, and to investigate MDSCs' potential as a target for host-directed therapeutics for MTB in the context of HIV co-infection.

Background

HIV and Mycobacterium tuberculosis (MTB) infection represent major global health problems, with MTB remaining on the World Health Organization’s list of top 10 causes of death worldwide, and HIV having moved off the top 10 list only in the last 15 years. Each disease presents unique therapeutic challenges on its own e.g., drug resistance, complex and prolonged pharmacotherapy with significant toxicities and drug interactions. Indeed, many of the toxicities themselves contribute to heart, lung, blood, and sleep (HLBS)-related comorbidities e.g., bone marrow suppression, impairment of cardiac bioenergetics, lipodystrophy, hypertriglyceridemia, etc. When MTB infection occurs in the context of HIV co-infection, therapeutic challenges can escalate exponentially. Exploration of novel therapeutic strategies that are not pathogen-directed represents a potential way forward.

PAR-19-357 is designed to stimulate research into myeloid-derived suppressor cells (MDSCs) as a possible host-directed target for novel therapeutic development for MTB infection in the context of HIV co-infection. This is not an area of inquiry heavily represented in NHLBI’s existing portfolio and secondary participation in this program is intended to stimulate research in this important area. MDSCs are increasingly recognized as serving a suppressive role in host immunity that allows MTB to establish and maintain infection through a variety of mechanisms.

Research Examples

Examples of research topics of particular interest to NHLBI could include, but are not limited to, the following:

• Studies focused on elucidating the roles of MDSCs in mycobacterial granuloma dynamics (e.g., formation, maintenance, and breakdown) within the lung or heart, and how HIV infection shapes MDSC-dependent granuloma dynamics
• Investigations into the bone marrow-specific effects of HIV infection and/or antiretroviral therapy on MDSC biology and responses to mycobacterial infection
• Projects proposing to utilize existing resources such as the MACS/WHIS Combined Cohort Study, NHLBI BioLINCC, or other existing resources to investigate MDSC biology in the context of mycobacterial infection in HIV+ and/or HIV- individuals
• Studies focused on interactions between MDSCs and lung-specific immune components (e.g., pulmonary mucosal immunity, alveolar/tissue macrophages), and how these interactions shape host responses to mycobacterial infection in HIV+ and HIV- individuals
• Projects investigating interactions between MDSCs and HIV/TB, and how those interactions shape the development and progression of heart, lung, blood, and sleep diseases in people living with HIV

Inquiries

Please direct all inquiries to:

Josh Fessel, M.D., Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0222
Email: [email protected]