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Genetics of Innate Immunity and Host Defense


‚ÄčInnate immunity is conserved over a wide variety of species from flies to mammals.  Innate immunity uses germline-encoded receptors to aid in anti-microbial host defense, with Toll-like receptors (TLRs) being the most extensively studied family.  These receptors recognize certain patterns, rather than particular structures, thereby allowing a limited number of Pattern Recognition Receptors (PRRs) to recognize a wide variety of microbes. In the case of LPS, the PRR is directed toward the highly conserved portion of LPS known as lipid A.  As such, lipid A is considered the Pathogen Associated Molecular Pattern (PAMP) for the PRR TLR4. 

We have previously shown that polymorphisms in TLR4, the receptor for LPS, are associated with hyporesponsiveness to inhaled LPS in mice and humans.  We have also shown that these same polymorphisms predispose humans to Gram negative sepsis and protect them from atherosclerosis. However, our previous findings also demonstrate that sequence variants of TLR4 account for only a portion of the LPS phenotype in either mice or humans and that other genes are also involved in regulating the response to LPS.

One of the goals of the innate immunity project is to identify novel genes involved in innate immunity and consequently determine if polymorphisms in some of these genes regulate the innate immune response to Gram negative sepsis and other microbial infections in humans.  Novel genes are identified using genetic mapping (whole genome association and quantitative trait loci mapping) and expression studies in mice and cultured macrophages stimulated with bacterial, viral, and fungal PAMPs. Candidate innate immune genes identified using these approaches are tested functionally by RNA interference in macrophages and in mouse lines with targeted mutations.  Polymorphisms in human orthologs of candidate genes are then tested in patient cohorts.

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to see Figure 8

Figure 8

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to see Figure 9

Figure 9

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to see Figure 10

Figure 10

 

 

 

 

 

 

 

A schematic of the overall strategy for novel innate immunity gene identification.
We have performed several genomic screens to identify genes other than TLR4 that are important in the innate immune response to LPS.

Another major goal of the innate immunity project is to understand how and why environmental exposures such as air pollution alter lung host defense. To accomplish this, we are testing the hypothesis that the expression of toll-like receptors (TLRs) in the lung are influenced by environmental (ozone and/or PAMPs) and genetic factors, and the dynamic expression of TLRs has profound effects on lung host defense and consequently the development of lung infections and allergic airway disease.

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Figure 11

 

 

 

 

 

 

 

Selected Innate Immunity Publications

  1. Yang IV, Alper S, Lackford B, Rutledge H, Warg LA, Burch LH, Schwartz DA. Novel regulators of the systemic response to lipopolysaccharide. Am J Respir Cell Mol Biol. 2011; 45:393-402.
  2. Yang IV, Wade CM, Kang HM, Alper S, Rutledge H, Lackford B, Eskin E, Daly MJ, Schwartz DA.  Identification of novel genes that mediate innate immunity using inbred mice.  Genetics. 2009; 183:1535-44.
  3. Zaas AK, Liao G, Chien J, Weinberg C, Shore D, Giles SS, Marr KA, Usuka J, Burch L, Perara L, Perfect JR, Schwartz DA.  Plasminogen Alleles Influence Susceptibility to Invasive Aspergillosis.  PLOS Genetics 2008; 4:e1000101.
  4. Alper S, Laws R, Lackford B, Boyd WA, Dunlap P, Freedman JH, Schwartz DA.  Identification of innate immunity genes and pathways using a comparative genomics approach.  Proc Nat Acad Sciences 2008; 105:7016-7021.
  5. Huang YC, Li Z, Carter JD, Soukup JM, Schwartz DA, Yang IV. Fine ambient particles induce oxidative stress and metal binding genes in human alveolar macrophages. Am J Respir Cell Mol Biol. 2009;41:544-52.
  6. Hollingsworth JW, Maruoka S, Li Z, Potts EN, Foster WM, Schwartz DA.  Ambient ozone primes pulmonary innate immunity in mice.  J Immunology 2007; 179:4367-4375.
  7. Hollingsworth JW, Chen BJ, Brass DM, Berman K, Gunn MD, Cook DN, Schwartz DA. The critical role of hematopoietic cells in lipopolysaccharide-induced airway inflammation.  Am J Resp Crit Care Med 2005; 171:806-813.
  8. Cook DN, Pisetsky DS, Schwartz DA. Toll-like receptors in the pathogenesis of human disease. Nat Immunol 2004; 5:975-979.
  9. Palmer SM, Burch LH, Schwartz DA. Toll-like receptors and allograft rejection. Am J Respir Crit Care Med 2004; 169:971-972.
  10. Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Willeit J, Schwartz DA. Toll-like receptor 4 polymorphisms and atherogenesis in humans. N Engl J Med 2002; 347(3):185-192.
  11. Lorenz E, Mira JP, Frees KL, Schwartz DA. Relevance of mutations in the TLR4 receptor in patients with Gram negative septic shock. Arch Int Med 2002; 162:1028-1032.
  12. Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA. TLR4 mutation is associated with endotoxin hyporesponsiveness in humans. Nature Genetics 2000; 25:187-191.