Department of Immunology

The innate immune response & human disease:
Diseases of the immune system such as sepsis, asthma, and atherosclerosis 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 approximately 17 million people in the U.S., leading to 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.

In response to infection, humans mount an immediate innate immune response and a slower but more specific adaptive immune response. The innate response involves the action of phagocytic and cytotoxic cells, which migrate to the site of infection and produce antimicrobial compounds. The innate immune response also plays a key role in the activation of adaptive immunity and is therefore critical to host defense. However, excessive activation of innate immunity can also have detrimental consequences and can contribute to the onset and/or severity of many diseases, including sepsis, asthma, and atherosclerosis. Thus, the elucidation of the mechanisms that regulate innate immunity is critical both to our understanding of immunological disease and to the identification of potential targets for treatment of these 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:

Legend: 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 mutations to ask some key questions about how these genes regulate immunity and disease:

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 member of the Tbc family, which regulates RAB-mediated membrane traffic. What is the molecular function of this 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 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 alter NF-kB activity?

We are now addressing these questions using genetic techniques in C. elegans and biochemical techniques in mouse cells.

What about other pathogens?
Thus far, we have focused on the response to Gram negative bacteria. We are now also initiating experiments to look at the response to other pathogens, including Gram positive bacteria, fungi, and viruses. What novel genes can we identify that regulate these responses? Are these genes the same or different than the genes that regulate the response to Gram negative bacteria?

Alper, S., McElwee, M., Apfeld, J., Lackford, B., Freedman, J.H., and Schwartz, D.A. Germline Proliferation regulates distinct signaling pathways in C. elegans to control lifespan and innate immunity. Submitted (2009).

Yang, I.V., Alper, S., Lackford, B., Rutledge, H., Burch, L.H., and Schwartz, D.A. Identification of Hedgehog signaling and novel transcription factors involved in the regulation of the systemic response to LPS. Submitted (2009).

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

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