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Welcome to the Integrated Department of Immunology at the University of Colorado - School of Medicine and National Jewish Health.

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Scott Alper PhD

Assistant Professor of Immunology and Center for Genes, Environment, and Health


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Education: Harvard University – PhD (1996)
E-Mail: alpers@njhealth.org
Phone: 303-270-2659 Office, 303-270-2698 Lab
Dr. Alper's National Jewish Health webpage

 

The innate immune response & human disease:

The human immune response has both a rapid (innate) component and a slower but more specific (adaptive) component.  The adaptive immune system involves cells and immune mediators such as T cells, B cells, and antibodies.  The innate immune response involves the action of phagocytic and cytotoxic cells, which migrate to the site of infection and produce antimicrobial compounds.  The innate response also plays a key role in the activation of adaptive immunity and is therefore critical to host defense.  The innate immune response is still poorly understood, but we are beginning to unravel its mysteries.  Over the past decade, it has become clear that the innate immune system also plays a critical role in the pathogenesis of many human diseases, ranging from sepsis to asthma to cancer to atherosclerosis and many others, as depicted in the figure.  Thus, the identification of genes that regulate the body’s innate immune system can have profound consequences for the diagnosis and treatment of many common diseases.  These diseases affect millions of people worldwide, and the incidence of many of these diseases is rising. For example, sepsis affects approximately 800,000 people in the U.S. annually, with a mortality rate over 20%.  Similarly, asthma affects more than 17 million people in the U.S., leading to significant suffering and several thousand deaths annually.  We are interested in understanding the regulation of the innate immune response, particularly as it relates to the basis for such immunological diseases.

 

Innate immunity gene discovery:  

We are using a comparative genomics approach in several ‘simple’ and accessible model systems to identify novel regulators of the innate immune response.  We have developed assays to monitor the response to pathogens in two different model systems: an in vivo system using the nematode C. elegans, and an in vitro system using mouse macrophage cell culture.  Thus far, we have used these assays to identify genes that control the response to Gram negative bacteria, and we are now testing the role of these genes in several mouse disease models.  We are also examining these genes in human patient cohorts to determine whether DNA polymorphisms in these genes affect the incidence of diseases such as sepsis.  Our overall approach is illustrated schematically below:

  


 

 

 

 

 

 

 

 

  

 

We monitor the C. elegans immune response using transgenic worms harboring antimicrobial genes fused to Green Fluorescence Protien(GFP)


We have identified several novel candidate innate immune regulators.  Many of these genes fall into two broad classes:  genes that affect protein and vesicle transport within the cell and genes that regulate NF-
kB activity.  We have obtained mutations in several of these genes in both C. elegans and mice, and we are using these mutants to ask some key questions about how these genes regulate immunity and disease.

 

Membrane trafficking and the innate immune response:

When we consider the regulation of the immune response, we tend to think about signal transduction pathways and circuit diagrams that culminate in transcriptional activation.  However, the location and movement of these signaling molecules within the cell also plays a key role in regulating the immune response.  We have identified several genes that regulate trafficking of cellular proteins in our screens for innate immune regulators.  This has led us to ask several questions:

How do genes that control membrane traffic at the cellular level lead to a defect in innate immunity at the organismal level?  For example, one of the genes that we have identified is a putative RAB-GAP, which regulates RAB-mediated membrane traffic.  A knockout of this gene leads to a hyper-inflammatory phenotype in a mouse cell culture model (left panel in figure);

conversely, overexpression of this gene completely abolishes the immune response (right panel in figure).  What is the molecular function of this key regulatory gene?  What specific aspect of membrane trafficking is regulated by this gene?  How does this trafficking defect cause a defect in the organismal immune response?  We are investigating this gene and several other candidate protein trafficking genes to determine how they regulate cellular and organismal immunity.

 
A RAB-GAP switch controls inflammation in mouse macrophages.


Novel regulators of NF-kB activation:

We have also identified several genes that are either direct or indirect regulators of a key transcription factor in immunity, NF-kB.  Are these novel genes direct or indirect regulators of this transcription factor, and how do they regulate NF-kB activity?  We are now addressing these questions using genetic techniques in C. elegans and biochemical techniques in mouse cells.

Together, these avenues of investigation are allowing us to unravel the mysteries of innate immunity on a genetic and molecular level. 

1.    Alper, S, McBride, S, Lackford, B, Freedman, JH, and Schwartz, DA. Specificity and Complexity of the C. elegans Innate Immune Respone. Mol. Cell. Biol. 27: 5544-5553 (2007).

2.    Cui, Y, McBride SJ, Boyd, WA, Alper, S, and Freedman, JH. Toxicogenomic Analysis of Caenorhabditis elegans Reveals Novel Genes and Pathways in the Resistance to Cadmium Toxicity. Genome Biol. 8: R122 (2007).

3.    Alper, S, Laws, R, Lackford, B, Boyd, WA, Dunlap, P, Freedman JH, and Schwartz, DA. Identification of Novel Innate Immunity Genes and Pathways Using a Comparative Genomics Approach. Proc. Natl. Acad. Sci. USA. 105: 7016-7021. (2008).

4.  Yang, IV, Wade, CM, Kang, HM, Alper, S, Rutledge H, Lackford B, Eskin, E., Daly, MJ, and Schwartz DA. Identification of novel genes that mediate innate immunity in inbred mice. Genetics. 183: 1535-1544. (2009).

5.    Green, RM, Gally, F, Keeney, JG, Alper, S, Gao, B, Han, M, Martin, RJ, Weinberger, AR, Case, SR, Minor, MN, Chu, HW. Impact of cigarette smoke exposure on innate immunity: a Caenorhabditis elegans model. PLOS One. 4:e6860. (2009).

6.    Alper, S, Mcelwee, M, Apfeld, J, Lackford, B, Freedman, JH, and Schwartz, DA. The Caenorhabditis elegans germ line regulates distinct signaling pathways to control lifespan and innate immunity. J. Biol. Chem. 285: 1822-1828. (2010).

7.    Alper, S. Model Systems to the Rescue: the relationship between aging and innate immunity. Comm. and Integr. Biol. 3(5): 409-414. (2010).

8.    Yang, IV, Alper, S, Lackford, B, Rutledge, H, Burch, LH, and Schwartz, DA. Novel Regulators of the Systemic Response to Lipopolysaccharide (LPS). American J. Resp. Cell. Mol. Biol. 45: 393-402. (2011).

9.    Yang, IV, Jiang, W, Rutledge, HR, Lackford, B, Warg, LA, De Arras, L, Alper, S, Schwartz, DA, and Pisetsky, DS. Identification of Novel Innate Immune Genes by Transcriptional Profiling of Macrophages Stimulated with TLR Ligands. Molec Immunol. 48: 1886-95 (2011).

10.  De Arras, L, Yang, IV, Lackford, B, Riches, DWH, Prekeris, R, Freedman, JH, Schwartz, DA, and Alper, S. Spatiotemporal inhibition of innate immunity signaling by the Tbc1d23 RAB-GAP. J. Immunol. 188: 2905-13 (2012).

11.  Victorino, F, and Alper, S. Identifying novel spatiotemporal regulators of innate immunity. Immunologic Research. 55: 3-9 (2013).

12.  De Arras, L, Seng, A, Lackford, B, Keikhaee, MR, Bowerman, B, Freedman, JH, Schwartz, DA, Alper, S. An evolutionarily conserved innate immunity protein interaction network. J. Biol. Chem. 288: 1967-1978 (2013).

13.  De Arras, L and Alper, S. Limiting of the innate immune response by SF3A-dependent control of MyD88 alternative mRNA splicing. PLOS Genetics 9(10):e1003855 (2013).

14.  De Arras, L, Laws, R, Leach, S, Pontis, K, Freedman, JH, Schwartz, DA and Alper, S. Comparative genomics RNAi screen identifies Eftud2 as a novel regulator of innate immunity. Genetics published online Dec 20 (2013).

 

15.  De Arras, L and Alper, S. Using RNAi-interference to investigate the innate immune response in mouse macrophages. J. Vis. Exp. in press (2013).


View of Recent Publications in PubMed