Key Dates

Related Announcements

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

Issued by

National Institute of Allergy and Infectious Diseases (NIAID)

Purpose

This Notice of Special Interest (NOSI) solicits research on the immunologic characterization of mice with diverse microbial experience (commonly referred to as “dirty mice”) to determine their usefulness as research tools for advancing understanding of human immune status and function during homeostasis or in infectious or immune-mediated (e.g., allergy, autoimmunity, transplant rejection) diseases.

Background

Mouse models have been critical in the study of immune system development and function, microbial pathogenesis, allergic and autoimmune diseases, providing mechanistic insights that have been foundational for the development of therapeutics and vaccines. Despite the value of mice in advancing these areas, multiple differences in immune responses between laboratory mice and humans have limited their utility for predicting human responses to candidate vaccines and immunotherapies. This discrepancy has been partially attributed to inter-species microbiota differences, as humans live in open environments with diverse microorganisms that shape the maturation of their immune system, whereas laboratory mice live in controlled specific pathogen-free (SPF) facilities that maintain their immune system in a naïve state.

To confirm the important role of the microbiome, researchers intentionally expose  laboratory mice to complex microbiota and pathogens, resulting in mouse colonies with diverse microbial experiences to mimic human living conditions. To date, in addition to wild mice, there are five types of microbial experienced mouse models that have been generated as follows:

• WildR mice: Created by transfer of ileocecal material orally from wild mice into pregnant germ-free inbred recipients
• Wildling: Created by implanting lab-strain embryos into wild mice
• Cohoused or cross-fostered mice: Created by housing inbred laboratory mice with pet-store mice and/or exposed to fomites or by transferring inbred laboratory mouse pups to a cage with a dirty outbred dam and its pups)
• Re-wilded lab mice: Created by releasing inbred laboratory mice in an outdoor enclosure that permits movement and social interactions while exposing animals to microorganisms present in soil, such as fungi
• Mice sequentially infected with selected pathogens: Created from inbred laboratory mice sequentially infected with mouse Gammaherpes Virus 68 (MHV68), Mouse Cytomegalovirus (MCMV), influenza or Sendai virus, and Heligmosomoides polygyrus

Comparison of these mice with those maintained under standard SPF conditions shows that SPF mice poorly recapitulate mature human immune responses and exhibit immune responses more like human neonates. In contrast, mice with diverse microbial experience react to immune stimuli more like human adults and recapitulate immune responses to vaccines and immunotherapeutics seen in human clinical trials. For example, all the models, except the WildR model, exhibit human-like levels of granulocytes, monocytes, and effector and memory T cells under homeostatic conditions, and most of the models demonstrate better protection after challenge with certain bacteria, viruses, and worms when compared with SPF mice. WildR mice develop immune-related adverse events (irAE) after checkpoint inhibitor cancer immunotherapy similar to those observed in human patients. Wildling mice recapitulate the cytokine storm in response to CD28-superagonist (CD28SA) seen in a clinical trial to treat autoimmune and inflammatory disease, which was absent in previous studies using standard laboratory mouse strains. These observations support the hypothesis that microbial experience significantly influences the development and function of both the innate and adaptive immune system, making these mice better research tools that more closely mimic human immune status and function.

Currently, mice with diverse microbial experience are underused by the immunology research community due to the increased animal husbandry and housing costs needed to prevent microbiota spread to animal colonies in neighboring SPF facilities. These requirements have limited the willingness of some institutions to invest in the establishment of mouse colonies with diverse microbial experience, curtailing the insights that these mouse models may impart.

Research Objectives and Scope

This NOSI aims to stimulate research to characterize immune system development, regulation, and function in mice with diverse microbial experience. Research approaches include, but are not limited to:

• Comparison of SPF mice to animals with a diverse microbial exposure to assess immune homeostasis or in response to various infectious or immune-mediated diseases;
• In vitro and ex vivo comparative assessment, between human primary cells/samples and mice with diverse microbiome exposures, of immune profiles, disease status, and/or response to an adjuvant, vaccine, or immune-based therapeutic;
• Evaluation of the influence of diverse microbial experiences on immune responses to a pathogen, antigen, adjuvant, vaccine, or therapeutic;
• Assessment of the impact of diverse microbiome exposure in early life on immune system maturation and disease development;
• Head-to-head comparison of the immune profile and response of microbial experienced mouse colonies established using different approaches; 
• Identification of the factors that may affect the mouse’s response to microbial exposure, such as the duration of exposure, sequence of exposure to infectious agents, prior infections, and mouse age, sex, or genetic background. 
   

These studies will advance our understanding of the impact of a host’s microbial experience on the development and function of host immunity and provide the necessary data to encourage broader use of the mouse models in immunologic and microbiologic research.

Research areas of interest include:

• Fundamental Immunology: Define the properties, interactions, development, and function of innate and adaptive components (cells, molecules pathways) of the immune system during homeostasis, or in response to pathogenic infections or vaccination.
• Allergic Diseases, with a focus on asthma, rhinitis and rhinosinusitis, food allergy, and atopic dermatitis: Determine elements associated with disease, including development and persistence, genetics, identification of targets for new preventive, and therapeutic approaches.
• Autoimmunity: Define the immunologic basis of disease, e.g., 1) develop a greater understanding of the fundamental immunologic principles underlying disease onset and progression, 2) develop improved animal models of disease and diagnostic tools, and 3) identify and evaluate more effective immune-based treatment and prevention strategies.
• Transplant Immunology: Elucidate immunological mechanisms and pathways that contribute to 1) allograft rejection or tolerance in models of pancreatic islet, solid organ, or vascularized composite allograft transplantation, or 2) graft-versus-host disease in models of bone marrow/hematopoietic stem cell transplantation.
• Vaccinology: Understand how broad microbial exposure impacts safety, immunogenicity, and efficacy of adjuvants and vaccines.

Application and Submission Information

This notice applies to due dates on or after February 5, 2025 and subsequent receipt dates through November 16, 2027.

Submit applications for this initiative using one of the following notice of funding opportunity (NOFOs) 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 NOFO used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-AI-24-078” (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, MSc, M.D.
Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Diseases (NIAID) 
Telephone: 301-761-6621
Email: [email protected] 

Financial/Grants Management Contact(s)

Tamia Carter
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2982
Email: [email protected]