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Scott Alper, PhD

Associate Professor of Immunology & Microbiology


 

 

1400 Jackson St., A640
Denver, CO 80045
Phone: 303-270-2659 Office, 303-270-2698 Lab
E-mail: alpers@njealth.org

Dr. Alper's National Jewish Health webpage

Overview

The human immune response has both a rapid innate component and a slower but more specific adaptive component. The adaptive immune response 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. Innate immunity regulates the inflammatory response as well as playing a key role in the activation of adaptive immunity. Thus, a robust innate immune response is critical for fighting infection.

Of course, too much of a good thing is not necessarily good. If the innate immune response becomes activated chronically, then this can contribute to the pathogenesis of many different diseases with an inflammatory component. Thus it is critical not only that innate immunity is activated when needed (upon infection) but that this response is also self-limiting and ultimately inactivated when not needed to prevent disease.

Dr. Alper's laboratory is focused on understanding the regulation of the innate immune response, particularly as it relates to the basis for these inflammatory diseases. The signaling pathways involved in the activation of innate immunity have been studied by numerous labs over the last 15 years. In contrast, the pathways that terminate this response are much less understood. We are studying two signaling pathways that terminate one class of innate immune signaling pathway, Toll-like receptor (TLR) signaling. Understanding how the maintenance of TLR signaling is regulated offers the potential to devise ways to ensure that inflammation is limited, activated to fight infection but terminated to prevent diseases with an inflammatory component such as COPD,atherosclerosis, and cancer.


Innate Immunity Gene Discovery

We used a comparative genomics screening approach in several "simple" and accessible model systems to identify novel regulators of the innate immune response. We 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. We used these assays to identify genes that control the response to Gram negative bacteria. These genes were then tested for a role in mammalian disease using knockout mice and samples from human patients.  Our overall approach is illustrated schematically below:

We have chosen to focus in detail on two signaling pathways involved in terminating TLR signaling, as outlined below.


Regulation of alternative pre-mRNA splicing in the TLR pathway to limit inflammation

LPS from Gram negative bacteria is sensed by the TLR4-MD2 co-receptors. When activated by LPS, these receptors initiate a complex signal transduction pathway (some but not all components depicted in the Figure) that ultimately leads to the activation of the pro-inflammatory transcription factors NFκB and AP1 and the resulting production of inflammatory cytokines. Remarkably, alternative splice forms of many of the signaling proteins in the TLR pathway have been identified that encode negative regulators of signaling (including TLR4, MD2, MyD88, IRAK1, and IRAK2). Production of these negatively acting splice forms is induced by prolonged LPS stimulation; thus these negatively acting splice forms mediate a negative feedback loop that limits inflammation. We are investigating the mechanisms that regulate this alternative splicing negative feedback loop with the goal of harnessing these alternative splicing mechanisms to limit inflammation and prevent chronic inflammatory disease.


Spatiotemporal regulation of TLR signaling by a novel RAB-GAP

We have found that the Tbc1d23 RAB-GAP inhibits the maintenance but not the initiation of TLR signaling, acting several hours after challenge to terminate the response to LPS. RABs are members of the RAS superfamily of small GTPases that mediate vesicle trafficking within the cell. RAB-GAPs inhibit their cognate RABs by facilitating the hydrolysis of the GTP on the RAB. Tbc1d23 inhibits TLR signaling by regulating a RAB and therefore by regulating the trafficking of key innate immune regulatory protein(s). We are currently investigating what RAB is regulated by Tbc1d23, what vesicles/proteins are trafficked by Tbc1d23, and how Tbc1d23 impacts the TLR signaling pathway. Based on our current data, we expect that inhibition of the target RAB should allow for a normal pathogen response that eventually is terminated, potentially a very attractive drug target for chronic inflammatory disease.





  • 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).
 

  • 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).
  • 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).


  • 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).
 

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

  • 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).
 

  • 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).
 

  • 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 197: 485-496 (2014).
 

  • De Arras, L, Guthrie, BS and Alper, S. Using RNAi-interference to investigate the innate immune response in mouse macrophages. J. Vis. Exp. 93:e51306 (2014).
  • O’Connor, BP, Danhorn, T, De Arras, L, Flatley, BR, Marcus, RA, Farias-Hesson, E, Leach, SM and Alper, S. Regulation of Toll-like receptor signaling by the SF3a mRNA splicing complex. PLOS Genetics. 11(2):e1004932 (2015).
  • Alper S, Warg LA, De Arras L, Flatley BR, Davidson EJ, Adams J, Smith K, Wohlford-Lenane CL, McCray PB Jr, Pedersen BS, Schwartz DA, and Yang IV. Novel Innate Immune Genes Regulating the Macrophage Response to Gram Positive Bacteria. Genetics. 204(1):327-36 (2016).
  • Blumhagen RZ, Hedin BR, Malcolm KC, Burnham EL, Moss M, Abraham E, Huie TJ, Nick JA, Fingerlin TE, and Alper S. Alternative Pre-mRNA Splicing of Toll-Like Receptor Signaling Components in Peripheral Blood Mononuclear Cells from ARDS Patients. Am J Physiol Lung Cell Mol Physiol. Epub ahead of print Aug 3, 2017.