Key Dates

Related Announcements

• May 07, 2020 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed). See NOFO PA-20-195.
• May 05, 2020 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed). See NOFO PA-20-185. 

Issued by

National Institute of Allergy and Infectious Diseases (NIAID)

Purpose

This Notice of Special Interest (NOSI) solicits research aimed at gaining a comprehensive understanding of the expression, function, and regulation of DEAD/H-box helicases in immune homeostasis, activation, and/or function.

Knowledge obtained from such studies may be applied to the design of improved vaccines and immunotherapies to combat pathogenic infections, inflammation, or treat/prevent immune-mediated diseases.

Research to understand the immune function of DEAD/H-box helicases  was previously supported by NIAID through the expired NOSI NOT-AI-21-066  (Understanding the Immune Functions of DEAD/H-box Helicases). The intent of this NOSI is to emphasize NIAID’s continued interest in this research area, as described below.

Background

DEAD/H-box helicases contain the conserved amino acid motifs Asp-Glu-Ala-Asp (DEAD) or Asp-Glu-Ala-His (DEAH). In humans, 42 DEAD-box and 16 DEAH-box helicases have been described. They are essential for RNA metabolism (e.g., RNA synthesis, processing, pre-mRNA splicing, modification, transport, translation, and turnover) and participate in almost every cellular process that involves RNA. Individual DEAD/H-box helicases exhibit critical roles in pro- or anti-microbial responses. Various DEAD/H-box helicases (e.g., DHX15) can serve as cytosolic sensors for viral RNAs and DNAs to initiate anti-viral responses. Other DEAD/H-box helicases have a direct negative impact on viral replication by binding and inhibiting viral polymerase assembly or by participating in the degradation process of a viral RNA to restrict viral reproduction (e.g., inhibition of HBV by DDX3), or exert a positive impact by suppressing the IFN signaling pathway to enhance viral infection. Thus, a better understanding of the role of DEAD/H-box (DDX) helicases in response to pathogens can aid in the development of novel anti-virals and other therapeutics to combat infectious disease.

DEAD/H-box helicases also play an important role in inflammation, which may link to autoimmune and allergic diseases. It has been reported that DDX3X and DHX33 can interact with NLRP3 to drive inflammasome activation, whereas DHX9 can induce MyD88-dependent activation of NF-kB in plasmacytoid dendritic cells by sensing class B CpG motifs. NF-kB signaling also is modulated by DDX3, which promotes inflammation by enhancing the phosphorylation of the protein phosphatase PP2A. Some DEAD/H-box helicases are involved in immune tolerance and susceptibility to autoimmune disease. DDX39B has been shown to manipulate the expression of many genes that either link to the susceptibility to Multiple Sclerosis or relate to immune tolerance, including Forkhead Box P3 (Foxp3). Knock-down of DDX39B changes the gene expression signatures from an immune tolerance state to an immune effective state. In contrast, an immunohistochemistry study on the synovial tissues from two different arthritis patients ( rheumatoid arthritis vs. osteoarthritis) revealed that DDX60 protein expression was more profound in the patients with rheumatoid arthritis, suggesting that DDX60, and maybe other DEAD/H-box helicases, could serve as biomarkers for autoimmune diseases.

While contributing to pro- or anti-microbial responses, inflammation, immune tolerance or autoimmunity, DEAD/H-box helicases also play a role in immune cell production, differentiation, composition, proliferation, and migration. For example, absence of DDX3X results in reduced hematopoiesis and abnormal composition of the leukocyte compartment in the bone marrow and spleen. Similarly, DDX46 facilitates the differentiation of hematopoietic stem cells (HSCs) into the various leukocyte lineages. DDX58 (RIG-I) can promote myelopoiesis via regulation of TRIM 25-dependent protein ISGylation. DDX18 is required for the proliferation of hematopoietic cells in animal models, and dysregulation of some DEAD/H-box helicases is linked to hematological malignancy.

Although DEAD/H-box helicases have broad functions in microbial infections and immune regulation and function, their expression, function, and regulation remain poorly understood. A better characterization of DEAD/H-box helicases will provide foundational knowledge for understanding their roles in immune systems development and function, allergic and autoimmune diseases (immune-mediated diseases), and infectious disease, and for developing novel biomarkers and therapeutics for infectious and immune-mediated diseases.

Research Objectives

This NOSI encourages innovative research on the role of DEAD/H-box helicases in immune homeostasis and activation/function at steady state and in response to immune-mediated or infectious diseases.

The scientific objectives of this NOSI include:

• Supporting the investigation of the role of DEAD/H-box helicases in innate immune sensing and in the modulation of innate and adaptive immune signaling pathways and gene expression; and
• Improving our understanding of the mechanisms by which DEAD/H-box helicases control immune cell development, proliferation, migration, composition, and function.

Applicants are encouraged to establish collaborations among immunologists, systems biologists, microbiologists, virologists, hematologists, and infectious disease experts to expand our knowledge of the function of DEAD/H-box helicases in the immune system.

Research areas of interest include, but are not limited to:

• Studies of the role of DEAD/H-box helicases in immune system development, regulation, and function during homeostasis and in response to antigenic challenge (e.g., pathogens, vaccines, adjuvants, allergens, or autoantigens).
• Examination of small molecule probes or agents targeting DEAD/H-box helicases to further define how these helicases modulate immune system development and homeostasis, anti-microbial immunity, vaccine responsiveness, immune-mediated diseases, inflammation, and/or immune tolerance.
• Examination of the role and underlying mechanism of DEAD/H-box helicases in HSC self-renewal and differentiation, immune cell production, proliferation, composition, migration, and activation and function.
• Discovery of the role and mode of action of DEAD/H-box helicases in regulating innate and adaptive immune signaling pathways and gene expression.
• Studies of the exploitation and modification of DEAD-box proteins by pathogens to circumvent immune surveillance or protection.

Application and Submission Information

This notice applies to due dates on or after October 5, 2024, and subsequent receipt dates through July 16, 2027.

Submit applications for this initiative using one of the following notices of funding opportunity (NOFOs) or any reissues of these announcements through the expiration date of this notice.

• PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
• PA-20-195– NIH Exploratory/Developmental Research Project Grant (Parent R21 Clinical Trial Not Allowed)

All instructions in the SF424 (R&R) Application Guide and the notice of funding opportunity used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-AI-24-058” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

Scientific/Research Contact(s)

Qian “Joy” Liu, M.D., MSc.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-6621
Email: liujoy@niaid.nih.gov