Notice of Special Interest (NOSI): Complement in Fundamental Immunology
Notice Number:

Key Dates

Release Date:

November 25, 2022

First Available Due Date:
February 05, 2023
Expiration Date:
January 08, 2026

Related Announcements

NOT-AI-23-003 - Notice of Early Expiration of "Notice of Special Interest (NOSI): Complement in Basic Immunology (CIBI)", NOT-AI-21-008

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

Issued by

National Institute of Allergy and Infectious Diseases (NIAID)



The complement system is an evolutionarily conserved component of innate immunity that serves as a first line of defense against infection. Complement-associated molecules, known as C1 through C9, operate in a cascade of enzymatic reactions that can ultimately lead to lysis of infected cells and opsonization of pathogens to aid in phagocytic clearance. Three major pathways of complement activation have been described that are triggered independently, namely the classical, the lectin, and the alternative pathways, all of which merge at the step of C3 activation.

Although most complement is produced by the liver to act systemically, complement may act locally within cells or in tissues. Complement components can also be produced in a broad range of immune and other cell types, such as endothelial cells. In addition to functioning in the above-mentioned enzymatic cascades, individual complement components have been shown to play other critical roles in immune responses. Examples of non-canonical roles of complement include: C3 can serve as a damage-associated molecular pattern (DAMP) that enhances intracellular innate immunity and acts as a controller of T lymphocyte survival; intracellular C5 activation appears to be essential for NLRP3 inflammasome assembly in CD4+T cells; and C1q has been reported to enhance phagocytosis and efferocytosis in human monocytes and suppress inflammatory responses. There are additional reports of interaction between individual complement components and innate signaling pathways, including Toll-Like Receptors.

While the protective benefits of complement have been, and continue to be, described, dysregulation of complement can have deleterious effects. Immune sensing of pathogens or foreign objects can induce local and systemic complement activation and subsequent inflammation at early timepoints during infection. These inflammatory responses typically resolve; however, over-activation or dysregulation of the complement cascade can cause collateral damage of cells and tissues. For example, complement dysregulation has been observed in severe COVID-19 disease where over-activation of the complement system induces endothelial cell injury and death, leading to initiation of clotting cascades. These complications can lead to life-threatening illness and multi-organ failure.

The mechanisms by which complement components, receptors, and pathways contribute to protective immune responses or pathogenesis remain to be fully elucidated. A better understanding of complement’s role in fundamental immunology is critical for harnessing its positive effects and avoiding deleterious effects caused by dysregulation.

Research Objectives

NIAID conducts and supports basic and applied research to better understand, treat, and ultimately prevent infectious and immune-mediated diseases. This mission includes support of fundamental immunology research that aims to understand host/pathogen interactions and immune regulation that can be later applied to developing safe and effective treatments and vaccines.

The main objective of this program is to support studies that accelerate our understanding of the roles of complement components and/or receptors in the initiation, magnitude, maintenance, and quality of immune responses involved in pathogenic infections, vaccination, post-infection sequelae, autoimmunity, allergy, or transplantation. The results of such studies will inform the development of vaccines or therapeutics that target complement components.

The work to be encouraged includes studies of the roles of complement components (molecules and/or receptors) during immune responses. Research areas of interest include, but are not limited to:

  • Studies of the role of complement during adaptive or innate immune cell activation, differentiation, function, homeostasis, and memory;
  • Mechanisms regulating the crosstalk of complement with other innate receptor systems;
  • The role of complement components in immune pathogenesis;
  • Interactions between vaccines/therapeutics and complement components;
  • Development of in vivo animal models or cell/tissue-specific in vitro systems for studying the roles of complement in regulating immune responses.

Application and Submission Information

This notice applies to due dates on or after February 5, 2023 and subsequent receipt dates through January 7, 2026.

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 Grant Program (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-23-012 (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.


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

Ari Joffe, PhD
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-5084