The complement system is a major player in innate immunity and an effector arm of the humoral immune response. Through natural Abs, lectins and the alternative pathway (AP), especially the AP's feedback loop, the complement system activates on microbes and altered self. Injured, apoptotic and necrotic cells, accumulations of debris, and microbial pathogens are targets. As we age, lipids deposit in blood vessel walls (atherosclerosis), urate in joints (gout), amyloid proteins in the brain (Alzheimer's disease - AD) and lipofuscin pigments (drusen) in the retina (age-related macular degeneration - AMD). These body """"""""wastes"""""""" or """"""""garbage"""""""" become substrates for complement activation, leading to chronic inflammation. Thus, regulation of the complement system, particularly the amplification loop, is critical to immune homeostasis and to prevent undesirable activation in vital organs. The goal of this grant proposal is to build on prior contributions relating to interactions of the complement's key C3b fragment with receptors and regulators and to further explore its role as a nidus for assembling the feedback loop by: 1) assessing C3b interactions with its regulators and receptors, with a goal of characterizing novel heterozygous mutations in C3 that predispose to atypical hemolytic uremic syndrome (aHUS) and on a polymorphism in C3 associated with age-related macular degeneration and renal transplant survival;2) further defining the structure and function of complement receptor type one (CR1;CD35), including analyzing recently identified mutations associated with human disease;and 3) employing a newly generated animal model, the Crry-single knockout (SKO) mouse, and the Crry mouse to examine complement regulation in vivo with a focus on homeostasis of the AP's feedback loop and to assess models of human disease in which the AP mediates pathologic consequences. An underlying hypothesis for proposed experiments is that the AP is continuously turning over on cells and thereby serves as a surveillance system for foreign agents and altered self.

Public Health Relevance

The innate immune system responds to microorganisms and damaged host tissue. It is involved in many common human diseases featuring deposition of altered proteins in the brain (Alzheimer Disease), lipids in vessel walls (heart attacks and strokes) and pigments in the retina (age-related macular degeneration). Chronic inflammation in such vital organs is undesirable. Also, many pathogens including the malarial parasite, a major health risk for much of the world, take advantage of innate immune players to invade, infect, and injure. These studies will enhance our understanding of how the innate immune system participates in some of the most common and lethal diseases of man.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Nasseri, M Faraz
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
Kulkarni, Hrishikesh S; Elvington, Michelle L; Perng, Yi-Chieh et al. (2018) Intracellular C3 Protects Human Airway Epithelial Cells from Stress-Associated Cell Death. Am J Respir Cell Mol Biol :
Wu, Xiaobo; Hutson, Irina; Akk, Antonina M et al. (2018) Contribution of Adipose-Derived Factor D/Adipsin to Complement Alternative Pathway Activation: Lessons from Lipodystrophy. J Immunol 200:2786-2797
Kulkarni, Hrishikesh S; Liszewski, M Kathryn; Brody, Steven L et al. (2018) The complement system in the airway epithelium: An overlooked host defense mechanism and therapeutic target? J Allergy Clin Immunol 141:1582-1586.e1
Triebwasser, Michael P; Wu, Xiaobo; Bertram, Paula et al. (2018) Timing and mechanism of conceptus demise in a complement regulatory membrane protein deficient mouse. Am J Reprod Immunol 80:e12997
Liszewski, M Kathryn; Elvington, Michelle; Kulkarni, Hrishikesh S et al. (2017) Complement's hidden arsenal: New insights and novel functions inside the cell. Mol Immunol 84:2-9
Elvington, Michelle; Liszewski, M Kathryn; Bertram, Paula et al. (2017) A C3(H20) recycling pathway is a component of the intracellular complement system. J Clin Invest 127:970-981
Wagner, Erin K; Raychaudhuri, Soumya; Villalonga, Mercedes B et al. (2016) Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD. Sci Rep 6:31531
Lintner, Katherine E; Wu, Yee Ling; Yang, Yan et al. (2016) Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases. Front Immunol 7:36
Fonseca, Maria I; Chu, Shuhui; Pierce, Aimee L et al. (2016) Analysis of the Putative Role of CR1 in Alzheimer's Disease: Genetic Association, Expression and Function. PLoS One 11:e0149792
Elvington, Michelle; Liszewski, M Kathryn; Atkinson, John P (2016) Evolution of the complement system: from defense of the single cell to guardian of the intravascular space. Immunol Rev 274:9-15

Showing the most recent 10 out of 50 publications