Dr. Alan G. Goodman
Research & Interests
Innate immunity refers to the body’s initial response to curb infection upon exposure to invading organisms. While the detection of pathogen-associated molecules is an ancient form of host defense, if dysfunctional, it can cause autoimmune disease, which affects over 20 million Americans. The innate immune response is the first line of defense to microbial infection, and it is initiated through the activation of receptors recognizing conserved molecules that are signature of pathogenic infection. Following initiation of the innate immune response, a series of signaling cascades are activated which result in the recruitment of immune cells such as macrophages and dendritic cells, to the site of infection to clear the pathogen and generate antibodies against subsequent infections. Research in our lab focuses on the signaling events involved in the innate immune response.
Animal models of microbial infection
The innate immune response provides the first line of defense against pathogens by responding to foreign molecules within the cell that are a signature of pathogenic infection, such as cytosolic DNA or double-stranded RNA, by-products of bacterial and viral infections. Forward genetic screens help identify candidate genes which may be essential for an immune response. Upon identification, reverse genetics can be used to mutate the identified gene and determine if the mutant protein results in loss-of-function. My research at the University of Washington focused on the characterization of P58IPK using a knock-out mouse model.We demonstrated that P58IPK:
- Benefitted the host during influenza virus infection by protecting it from a lethal “cytokine storm,” or a hyperactive inflammatory response.
- Reduced lung pathology and prolonged survival.
- Enhanced the virus’ capacity to replicate in a longer-surviving host through its inhibition of PKR.
During my time at the University of Miami, we showed that STING (stimulator of interferon genes) function is evolutionarily conserved in Drosophila and even retains its function in the mammalian system. By knocking-down STING in the fly, we show that the protein is essential for an immune response to pathogenic infection.
Computational models for functional genomics and signaling pathways
In addition to molecular biology and animal models to study the immune response to pathogenic infection, we augment these techniques with in silico analytical techniques such as transcriptional profiling and computational modeling. For example, we use Gene Set Enrichment Analysis (GSEA) for Drosophila datasets, allowing us to functionally characterize how functional categories of genes were being regulated upon infection.
As part of our research plan, we will use next-generation sequencing (NGS) as a tool to identify sequences of pathogen-associated nucleic acids that bind to STING during infection. Additionally, NGS can be used in the fruit-fly model as a screening tool to identify novel non-coding RNAs that are essential for the induction of a robust immune response. The use of a tractable, orthogonal animal model may lead to the discovery of conserved sequences in human with similar functions.
Upon the identification of novel, discrete signaling networks, we can employ more directed mathematical methods to dissect the signaling pathway and the contributions from its distinct nodes. These powerful computational and mathematical methods are applicable to a wide range of model systems, from cells to flies to humans.
Ahlers, L.R.H., Bastos, R.G., Hiroyasu, A., Goodman, A.G. Invertebrate iridescent virus 6, a DNA virus, stimulates a mammalian innate immune response through RIG-I-like receptors. PLoS One. 2016 Nov 8; 11(11): e0166088. PMID: 27824940
Ahlers, L.R.H., Goodman, A.G. Nucleic acid sensing and innate immunity: signaling pathways controlling viral pathogenesis and autoimmunity. Curr. Clin. Microbiol. Rep. 2016 Sep; 3(3): 132-141. PMID: 27857881
Vijayan, A., Gómez, C.E., Espinosa, D.A., Goodman, A.G., Sanchez-Sampedro, L., Soranzo, C.O.S., Zavala, F., Esteban, M. Adjuvant-like effect of vaccinia virus 14K protein: a case study with malaria vaccine based on the circumsporozoite protein. J. Immunol. 2012 Jun 15; 188(12): 6407-17. PMID: 22615208
Goodman, A.G., Heinen, P.P., Guerra, S., Vijayan, A., Sorzano, C.O.S., Gomez, C.E., Esteban, M. A human multi-epitope recombinant vaccinia virus as a universal T-cell vaccine candidate against influenza virus. PLoS One. 2011 Oct 5; 6(10): e25938. PMID: 21998725
Goodman, A.G., Tanner, B.C.W., Chang, S.T., Esteban, M., Katze, M.G. Virus infection rapidly activates the P58IPK pathway, delaying peak kinase activation to enhance viral replication. Virology. 2011 Aug 15; 417(1): 27-36. PMID: 21612809
Cillóniz, C., Pantin-Jackwood, M., Ni, C., Goodman, A.G., Peng, X., Proll, S.C., Carter, V.S., Rosenzweig, E.R., Szretter, K.J., Katz, J.M., Korth, M.J., Swayne, D.E., Tumpey, T.M., Katze, M.G. Differential regulation of inflammatory gene expression and interferon signaling in mouse models of highly pathogenic H1N1 and H5N1 influenza virus infection. J. Virol. 2010 Aug; 84(15): 7613-24. PMID: 20504916
Datta, R., Shah, G.N., Rubbelke, T.S., Waheed, A., Rauchman, M., Goodman, A.G., Katze, M.G., Sly, W.S. Progressive renal injury from transgenic expression of human carbonic anhydrase IV folding mutants is enhanced by deficiency of p58IPK. Proc. Natl. Acad. Sci. USA. 2010 Apr 6; 107(14): 6448-52. PMID: 20308551
Goodman, A.G., Zeng, H., Proll, S.C., Peng, X., Cillóniz, C., Carter, V.S., Korth, M.J., Tumpey, T.M., Katze, M.G. The interferona/b receptor provides protection against influenza virus replication but is dispensable for inflammatory response signaling. J. Virol. 2010 Feb; 84(4): 2027-37. PMID: 19939913
Billharz, R., Zeng, H., Proll, S.C., Korth, M.J., Lederer, S., Albrecht, R., Goodman, A.G., Rosenzweig, E., Tumpey, T.M., García-Sastre, A., Katze, M.G. The NS1 protein of the 1918 pandemic influenza virus blocks host interferon and lipid metabolism pathways. J. Virol. 2009 Oct; 83(20): 10557-70. PMID: 19706713
Goodman, A.G., Fornek, J.L., Medigeshi, G.R., Perrone, L.A., Peng, X., Dyer, M.D., Proll, S.C., Knoblaugh, S.E., Carter, V.C., Korth, M.J., Nelson, J.A., Tumpey, T.T., Katze, M.G. P58IPK: a novel “CIHD” member of the host innate defense response against pathogenic virus infection. PLoS Pathog. 2009 May; 5(5): e1000438. PMID: 19461876
Rutkowski, D.T., Kang, S.W., Goodman, A.G., Garrison, J.L., Taunton, J., Katze, M.G., Kaufman, R.J., Hegde, R.S. The role of P58IPK in protecting the stressed endoplasmic reticulum. Mol. Biol. Cell. 2007 Sep; 18(9): 3681-3691. PMID: 17567950
Goodman, A.G., Smith, J.A., Balachandran, S., Perwitasari, O., Proll, S.C., Thomas, M.J., Korth, M.J., Baber, G.N., Schiff, L.A., Katze, M.G. The cellular protein, P58IPK, regulates influenza virus mRNA translation and replication through a PKR mediated mechanism. J. Virol. 2007 Mar; 81(5): 2221-2230. PMID: 17166899
Oyadomari, S., Yun, C., Fisher, E.A., Kreglinger, N., Kreibich, G., Oyadomari, M., Harding, H.P., Goodman, A.G., Harant, H., Garrison, J.L., Taunton, J., Katze, M.G., Ron, D. Cotranslocational degradation protects the stressed endoplasmic reticulum from protein overload. Cell. 2006 Aug 25; 126(4):727-39. PMID: 16923392
Kash, J.C., Goodman, A.G., Korth, M.J., Katze, M.G. Hijacking of the host-cell response and translational control during influenza virus infection. Virus Res. 2006 Jul; 119(1):111-20. PMID: 16630668
Ladiges, W.C., Knoblaugh, S.E., Morton, J.F., Korth, M.J., Sopher, B.L., Baskin, C.R., MacAuley, A., Goodman, A.G., LeBoeuf, R.C., Katze, M.G. Pancreatic b-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK. Diabetes. 2005 Apr;54(4):1074-81. PMID: 15793246
Goodman A., Tseng Y., Wirtz D. Effect of length, topology, and concentration on the microviscosity and microheterogeneity of DNA solutions. J. Mol. Biol. 2002 Oct 18;323(2):199-215. PMID: 12381315
Franco, A.A., Cheng, R.K., Goodman, A., Sears, C.L. Modulation of bft expression by the Bacteroides fragilis pathogenicity island and its flanking region. Mol Microbiol. 2002 Aug; 45(4): 1067-77. PMID: 12180925