The microbiome represents a previously underappreciated influence on numerous biological processes. While most microbes express determinants that are distinct from self, many microbes synthesize surface antigens that resemble host-like structures as a form of molecular mimicry. Although adaptive immunity can recognize a nearly infinite range of antigenic determinants, tolerance reduces reactivity toward self-like antigens, creating a critical gap in adaptive immunity toward molecular mimicry. Thus, immunological protection against molecular mimicry likely resides within the innate arm of immunity. As molecular mimicry often reflects decoration of microbes with distinct mammalian-like carbohydrate antigens, we screened innate immune factors for carbohydrate binding activity. Our results demonstrate that several innate immune factors, in particular galectin-4 and galectin-8, bind and kill blood group B-positive microbes, providing a mechanism whereby blood group-positive individuals protect themselves against blood group molecular mimicry. As molecular mimicry is not limited to the blood group B antigen, and galectins can recognize a variety of mammalian-like structures, galectins may also provide innate immunity against a variety of microbes that utilize molecular mimicry. Furthermore, as blood group-positive microbes can stimulate naturally occurring anti-blood group antibodies and galectins target these microbes in vivo, galectin-mediated immunity may regulate the development of naturally occurring anti-blood group antibodies, which represent the most common immunological barrier to transfusion and transplantation. Thus, we hypothesize that galectins provide innate immunity against molecular mimicry, which in turn impacts the formation of naturally occurring anti-blood group antibodies. To test this, we will examine the following specific aims. 1) Examine the impact of galectins on anti-blood group antibody formation. 2) Determine whether galectins provide broad protection against molecular mimicry. 3) Define the specificity of galectin family members for microbial antigens. These studies develop new models, characterize new paradigms in immunology, and develop new tools to study host-pathogen interactions with broad implications in transfusion medicine, infectious disease and autoimmunity.

Public Health Relevance

Microbes cloaked in host-like, sugar-rich macromolecules pose a unique challenge to host immune responses and protection. We will examine several key innate immune factors, including glycan-binding proteins, which may specifically target such microbes. As immunological responses to such microbes can impact the susceptibility of an individual to a variety of processes, from hemolytic transfusion reactions to autoimmunity, these studies will uncover fundamental processes with broad implications in a variety of biomedical disciplines.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Early Independence Award (DP5)
Project #
5DP5OD019892-04
Application #
9349375
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Basavappa, Ravi
Project Start
2014-09-12
Project End
2019-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Maier, Cheryl L; Mener, Amanda; Patel, Seema R et al. (2018) Antibody-mediated immune suppression by antigen modulation is antigen-specific. Blood Adv 2:2986-3000
Patel, Seema R; Bennett, Ashley; Girard-Pierce, Kathryn et al. (2018) Recipient priming to one RBC alloantigen directly enhances subsequent alloimmunization in mice. Blood Adv 2:105-115
Mener, Amanda; Patel, Seema R; Arthur, Connie M et al. (2018) Complement serves as a switch between CD4+ T cell-independent and -dependent RBC antibody responses. JCI Insight 3:
Mener, Amanda; Arthur, Connie M; Patel, Seema R et al. (2018) Complement Component 3 Negatively Regulates Antibody Response by Modulation of Red Blood Cell Antigen. Front Immunol 9:676
Sullivan, Harold C; Gerner-Smidt, Christian; Nooka, Ajay K et al. (2017) Daratumumab (anti-CD38) induces loss of CD38 on red blood cells. Blood 129:3033-3037
Arthur, Connie M; Patel, Seema R; Smith, Nicole H et al. (2017) Antigen Density Dictates Immune Responsiveness following Red Blood Cell Transfusion. J Immunol 198:2671-2680
Kamili, Nourine A; Arthur, Connie M; Gerner-Smidt, Christian et al. (2016) Key regulators of galectin-glycan interactions. Proteomics 16:3111-3125
Kudelka, Matthew R; Hinrichs, Benjamin H; Darby, Trevor et al. (2016) Cosmc is an X-linked inflammatory bowel disease risk gene that spatially regulates gut microbiota and contributes to sex-specific risk. Proc Natl Acad Sci U S A 113:14787-14792
Arthur, Connie M; Patel, Seema R; Sullivan, H Cliff et al. (2016) CD8+ T cells mediate antibody-independent platelet clearance in mice. Blood 127:1823-7
Arthur, Connie M; Patel, Seema R; Mener, Amanda et al. (2015) Innate immunity against molecular mimicry: Examining galectin-mediated antimicrobial activity. Bioessays 37:1327-37

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