Key Dates

Related Announcements

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)

Issued by

National Institute of Allergy and Infectious Diseases (NIAID)

Purpose

This Notice of Special Interest (NOSI) supports 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 or treat/prevent immune-mediated diseases.

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. In addition, individual DEAD/H-box helicases exhibit critical roles in pro- or anti-microbial responses. Various DEAD/H-box helicases (e.g., DHX15) in cells can serve as cytosolic sensors for viral RNAs and DNAs to initiate anti-viral responses; others have 1) 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 2) a positive impact by suppressing IFN signaling pathway and, thus, enhancing viral infection. In conclusion, a better understanding of the role of DEAD/H-box (DDX) helicases in response to pathogens can aid in the development of novel 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.

While contributing to pro- or anti-microbial responses and inflammation, 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 of the bone marrow and spleen. Similarly, DDX46 contributes to 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 zebrafish, and dysregulation of some DEAD/H-box helicases is linked to hematological malignancy, such as reduced DDX32 expression in acute lymphoblastic leukemias. Several DEAD/H-box helicases also have been implicated in cancer growth and metastasis.

Although DEAD/H-box helicases have broad functions in microbial infections, immune regulation, immune cell production, differentiation and composition of both myeloid and lymphoid cells, and cell cycle progression, their expression, function, and regulation remain poorly understood. A better characterization of DEAD/H-box helicases will provide foundational knowledge for understanding innate immune sensing, anti-microbial immunity, inflammation, and immune cell homeostasis, 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.

The scientific objectives of this NOSI include:

1. 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
2. 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, allergens, or autoantigens)
• Examination of small molecule probes or agents targeting DEAD/H-box helicases to further define how these helicases modulate anti-microbial immunity, vaccine responsiveness, immune-mediated diseases, inflammation, immune system development, 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-boxproteins by viruses to avoid immune surveillance

Application and Submission Information

This notice applies to due dates on or after October 5, 2021 and subsequent receipt dates through September 7, 2024,

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement 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 funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-AI-21-066” (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

Scientific/Research Contact(s)

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