Chapter 37 : Genetics of Antibacterial Host Defenses

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This chapter reviews the well-characterized genetic syndromes of bacterial susceptibility with an eye toward specificity of the susceptibility, applicability of the defect to infections in the general population, and, where applicable, treatment. Defects in barriers involving the skin and lung and defects of leukocyte number, trafficking, and function are also considered in this chapter. The major protection afforded by the skin is due to the stratum corneum, which provides a multifunctional barrier retarding water loss and providing an antimicrobial barrier. Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), the gene that encodes the major epithelial chloride channel. This chapter focuses on examples of innate immune defects, especially those involving phagocytic cells as mutations in the genes regulating the innate immune system have been very informative regarding the specific associations of genes and infections. Inherited neutropenias can occur in both autosomal recessive and dominant forms. Chronic granulomatous disease (CGD) is caused by defects in the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Chediak-Higashi syndrome (CHS) is characterized by oculocutaneous albinism, frequent pyogenic infections, neurologic abnormalities, and a relatively late-onset lymphoma-like accelerated phase. There are a growing number of genetic syndromes that predispose an individual to bacterial infections. They dissect the biologic pathways that are required, desirable, and dispensible for protection. The complexity of bacterial susceptibility is compounded by the extraordinary variability in bacteria themselves, as well as the ways in they are encountered.

Citation: Holland S. 2011. Genetics of Antibacterial Host Defenses, p 473-482. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch37

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1. Boztug, K.,, G. Appaswamy,, A. Ashikov,, A. A. Schäffer,, U. Salzer,, J. Diestelhorst,, M. Germeshausen,, G. Brandes,, J. Lee-Gossler,, F. Noyan,, A. K. Gatzke,, M. Minkov,, J. Greil,, C. Kratz,, T. Petropoulou,, I. Pellier,, C. Bellanné-Chantelot,, N. Rezaei,, K. Mönkemöller,, N. Irani-Hakimeh,, H. Bakker,, R. Gerardy-Schahn,, C. Zeidler,, B. Grimbacher,, K. Welte, and, C. Klein. 2009. A syndrome with congenital neutropenia and mutations in G6PC3. N. Engl. J. Med. 360:3243.
2. Chapgier, A.,, S. Boisson-Dupuis,, E. Jouanguy,, G. Vogt,, J. Feinberg,, A. Prochnicka-Chalufour,, A. Casrouge,, K. Yang,, C. Soudais,, C. Fieschi,, O. F. Santos,, J. Bustamante,, C. Picard,, L. de Beaucoudrey,, J. F. Emile,, P. D. Arkwright,, R. D. Schreiber,, C. Rolinck-Werninghaus,, A. Rösen-Wolff,, K. Magdorf,, J. Roesler, and, J. L. Casanova. 2006. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease. PLoS Genet. 2:e131.
3. Collaco, J. M., and, G. R. Cutting. 2008. Update on gene modifiers in cystic fibrosis. 2008. Curr. Opin. Pulm. Med. 14:559566.
4. Devriendt,, K.,, A. S. Kim,, G. Mathijs,, S. G. Frints,, M. Schwartz,, J. J. Van Den Oord,, G. E. Verhoef,, M. A. Boogaerts,, J. P. Fryns,, D. You,, M. K. Rosen, and, P. Vandenberghe. 2001. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat. Genet. 27:313317.
5. Dorman,, S. E.,, C. Picard,, D. Lammas,, K. Heyne,, J. T. van Dissel,, R. Baretto,, S. D. Rosenzweig,, M. Newport,, M. Levin,, J. Roesler,, D. Kumararatne,, J. L. Casanova, and, S. M. Holland. 2004. Clinical features of dominant and recessive interferon gamma receptor 1 deficiencies. Lancet 364:211321.
6. Dupuis, S.,, E. Jouanguy,, S. Al-Hajjar,, C. Fieschi,, I. Z. Al-Mohsen,, S. Al-Jumaah,, K. Yang,, A. Chapgier,, C. Eidenschenk,, P. Eid,, A. Al Ghonaium,, H. Tufenkeji,, H. Frayha,, S. Al-Gazlan,, H. Al-Rayes,, R. D. Schreiber,, I. Gresser, and, J. L. Casanova. 2003. Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat. Genet. 33:388391.
7. Eapen,, M.,, C. A. DeLaat,, K. S. Baker,, M. S. Cairo,, M. J. Cowan,, J. Kurtzberg,, C. G. Steward,, P. A. Veys, and, A. H. Filipovich. 2007. Hematopoietic cell transplantation for Chediak-Higashi syndrome. Bone Marrow Transplant 39:411415.
8. Ehrenreich, M.,, M. M. Tarlow,, E. Godlewska-Janusz, and, R. A. Schwartz. 2007. Incontinentia pigmenti (Bloch-Sulzberger syndrome): a systemic disorder. Cutis. 79:355362.
9. Elhasid, R., and, J. M. Rowe. 2009. Hematopoietic stem cell transplantation in neutrophil disorders: severe congenital neutropenia, leukocyte adhesion deficiency and chronic granulomatous disease. Clin. Rev. Allergy Immunol. 38:6167.
10. Elias, P. M., and, M. Schmuth. 2009. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr. Allergy Asthma Rep. 9:265272.
11. Etzioni, A. 2009. Genetic etiologies of leukocyte adhesion defects. Curr. Opin. Immunol. 21:481–486.
12. Feld,, J. J.,, N. Hussain,, E. C. Wright,, D. E. Kleiner,, J. H. Hoofnagle,, S. Ahlawat,, V. Anderson,, D. Hilligoss,, J. I. Gallin,, T. J. Liang,, H. L. Malech,, S. M. Holland, and, T. Heller. 2008. Hepatic involvement and portal hypertension predict mortality in chronic granulomatous disease. Castroenterology 134:191726.
13. Fieschi, C.,, S. Dupuis,, E. Catherinot,, J. Feinberg,, J. Bustamante,, A. Breiman,, F. Altare,, R. Baretto,, F. Le Deist,, S. Kayal,, H. Koch,, D. Richter,, M. Brezina,, G. Aksu,, P. Wood,, S. Al-Jumaah,, M. Raspall,, A. J. Da Silva Duarte,, D. Tuerlinckx,, J. L. Virelizier,, A. Fischer,, A. Enright,, J. Bernhöft,, A. M. Cleary,, C. Vermylen,, C. Rodriguez-Gallego,, G. Davies,, R. Blütters-Sawatzki,, C. A. Siegrist,, M. S. Ehlayel,, V. Novelli,, W. H. Haas,, J. Levy,, J. Freihorst,, S. Al-Hajjar,, D. Nadal,, D. De Moraes Vasconcelos,, O. Jeppsson,, N. Kutukculer,, K. Frecerova,, I. Caragol,, D. Lammas,, D. S. Kumararatne,, L. Abel, and, J. L. Casanova. 2003. Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications. J. Exp. Med. 197:52735.
14. Foweraker, J. 2009. Recent advances in the microbiology of respiratory tract infection in cystic fibrosis. Br. Med. Bull. 89:93110.
15. Freeman, A. F., and, S. M. Holland. 2009. Antimicrobial prophylaxis for primary immunodeficiencies. Curr. Opin. Allergy Clin. Immunol. 9:525530.
16. Goldman,, M. J.,, G. M. Anderson,, E. D. Stolzenberg,, U. P. Kari,, M. Zasloff, and, J. M. Wilson. 1997. Human betadefensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 88:553560.
17. Gu, Y., and, D. A. Williams. 2002. RAC2 GTPase deficiency and myeloid cell dysfunction in human and mouse. J. Pediatr. Hematol. Oncol. 24:791794.
18. Hanson,, E. P.,, L. Monaco-Shawver,, L. A. Solt,, L. A. Madge,, P. P. Banerjee,, M. J. May, and, J. S. Orange. 2008. Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J. Allergy Clin. Immunol. 122:11691177.
19. Hansson, M.,, I. Olsson, and, W. M. Nauseef. 2006. Biosynthesis, processing, and sorting of human myeloperoxidase. Arch. Biochem. Biophys. 445:214224.
20. Horwitz,, M. S.,, Z. Duan,, B. Korkmaz,, H. H. Lee,, M. E. Mea-liffe, and, S. J. Salipante. 2007. Neutrophil elastase in cyclic and severe congenital neutropenia. Blood 109:18171824.
21. Huizing, M.,, A. Helip-Wooley,, W. Westbroek,, M. Gunay-Aygun, and, W. A. Gahl. 2008. Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics. Annu. Rev. Genomics Hum. Genet. 9:359386.
22. Kawai, T., and, H. L. Malech. 2009. WHIM syndrome: congenital immune deficiency disease. Curr. Opin. Hematol. 16:2026.
23. Klein, C.,, Grudzien,, M., Appaswamy,, G., Germeshausen,, M., Sandrock,, I., Schäffer,, A. A., Rathinam,, C., Boztug,, K., Schwinzer,, B., Rezaei,, N., Bohn,, G., Melin,, M., Carlsson,, G., Fadeel,, B., Dahl,, N., Palmblad,, J., Henter,, J. I., Zeidler,, C., Grimbacher,, B., & Welte,, K. (2007). HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat. Genet. 39:8692.
24. Knowles, M. R., and, R. C. Boucher. 2002. Mucus clearance as a primary innate defense mechanism for mammalian airways. J. Clin. Invest. 109:571577.
25. Ku,, C. L.,, H. von Bernuth,, C. Picard,, S. Y. Zhang,, H. H. Chang,, K. Yang,, M. Chrabieh,, A. C. Issekutz,, C. K. Cunningham,, J. Gallin,, S. M. Holland,, C. Roifman,, S. Ehl,, J. Smart,, M. Tang,, F. J. Barrat,, O. Levy,, D. McDonald,, N. K. Day-Good,, R. Miller,, H. Takada,, T. Hara,, S. Al-Hajjar,, A. Al-Ghonaium,, D. Speert,, D. Sanlaville,, X. Li,, F. Geissmann,, E. Vivier,, L. Maródi,, B. Z. Garty,, H. Chapel,, C. Rodriguez-Gallego,, X. Bossuyt,, L. Abel,, A. Puel, and, J. L. Casanova. 2007. Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J. Exp. Med. 204:24072422.
26. Lagresle-Peyrou,, C.,, E. M. Six,, C. Picard,, F. Rieux-Laucat,, V. Michel,, A. Ditadi,, C. Demerens-de Chappedelaine,, E. Morillon,, F. Valensi,, K. L. Simon-Stoos,, J. C. Mullikin,, L. M. Noroski,, C. Besse,, N. M. Wulffraat,, A. Ferster,, M. M. Abecasis,, F. Calvo,, C. Petit,, F. Candotti,, L. Abel,, A. Fischer, and, M. Cavazzana-Calvo. 2009. Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. Nat. Genet. 41:106111.
27. Leigh,, M. W.,, J. E. Pittman,, J. L. Carson,, T. W. Ferkol,, S. D. Dell,, S. D. Davis,, M. R. Knowles, and, M. A. Zariwala. 2009. Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome. Genet. Med. 11:473487.
28. Marciano,, B. E.,, S. D. Rosenzweig,, D. E. Kleiner,, V. L. Anderson,, D. N. Darnell,, S. Anaya-O’Brien,, D. M. Hilligoss,, H. L. Malech,, J. I. Gallin, and, S. M. Holland. 2004. Gastrointestinal involvement in chronic granulomatous disease. Pediatrics 114:462468.
29. Matute,, J. D.,, A. A. Arias,, N. A. Wright,, I. Wrobel,, C. C. Waterhouse,, X. J. Li,, C. C. Marchal,, N. D. Stull,, D. B. Lewis,, M. Steele,, J. D. Kellner,, W. Yu,, S. O. Meroueh,, W. M. Nauseef, and, M. C. Dinauer. 2009. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. Blood 114:33093315.
30. Meves, A.,, C. Stremmel,, K. Gottschalk, and, R. Fässler. 2009. The Kindlin protein family: new members to the club of focal adhesion proteins. Trends Cell Biol. 19:504513.
31. Minegishi, Y.,, M. Saito,, T. Morio,, K. Watanabe,, K. Agematsu,, S. Tsuchiya,, H. Takada,, T. Hara,, N. Kawamura,, T. Ariga,, H. Kaneko,, N. Kondo,, I. Tsuge,, A. Yachie,, Y. Sakiyama,, T. Iwata,, F. Bessho,, T. Ohishi,, K. Joh,, K. Imai,, K. Kogawa,, M. Shinohara,, M. Fujieda,, H. Wakiguchi,, S. Pasic,, M. Abinun,, H. D. Ochs,, E. D. Renner,, A. Jansson,, B. H. Belohradsky,, A. Metin,, N. Shimizu,, S. Mizutani,, T. Miyawaki,, S. Nonoyama, and, H. Karasuyama. 2006. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25:745755.
32. O’Sullivan, B. P., and, S. D. Freedman. 2009. Cystic fibrosis. Lancet 373:18911904.
33. Olivier, K., N.; NTM in CF Study Group. 2004. The natural history of nontuberculous mycobacteria in patients with cystic fibrosis. Paediatr. Respir. Rev. 5 Suppl A:S213-S216.
34. Pannicke, U.,, M. Hönig,, I. Hess,, C. Friesen,, K. Holzmann,, E. M. Rump,, T. F. Barth,, M. T. Rojewski,, A. Schulz,, T. Boehm,, W. Friedrich, and, K. Schwarz. 2009. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nat. Genet. 41:101105.
35. Paulson, M. L.,, A. F. Freeman, and, S. M. Holland. 2008. Hyper IgE syndrome: an update on clinical aspects and the role of signal transducer and activator of transcription 3. Curr. Opin. Allergy Clin. Immunol. 8:527533.
36. Renner,, E. D.,, D. Hartl,, S. Rylaarsdam,, M. L. Young,, L. Monaco-Shawver,, G. Kleiner,, M. L. Markert,, E. R. Stiehm,, B. H. Belohradsky,, M. P. Upton,, T. R. Torgerson,, J. S. Orange, and, H. D. Ochs. 2009. Comel-Netherton syndrome defined as primary immunodeficiency. J. Allergy Clin. Immunol. 124:536543.
37. Rosenzweig,, S. D.,, S. E. Dorman,, G. Uzel,, S. Shaw,, A. Scurlock,, M. R. Brown,, R. H. Buckley, and, S. M. Holland. 2004. A novel mutation in IFN-gamma receptor 2 with dominant negative activity: biological consequences of homozygous and heterozygous states. J. Immunol. 173:40004008.
38. Rosenzweig, S. D., and, S. M. Holland. 2005. Defects in the interferon-gamma and interleukin-12 pathways. Immunol. Rev. 203:3847.
39. Rowe, S. M.,, S. Miller, and, E. J. Sorscher. 2005. Cystic fibrosis. N. Engl. J. Med. 352:19922001.
40. Segal,, A. W. 2008. The function of the NADPH oxidase of phagocytes and its relationship to other NOXs in plants, invertebrates, and mammals. Int. J. Biochem. Cell Biol. 40:604618.
41. Segal,, B. H.,, T. L. Leto,, J. I. Gallin,, H. L. Malech, and, S. M. Holland. 2000. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore) 79:170200.
42. Seger,, R. A.,, T. Gungor,, B. H. Belohradsky,, S. Blanche,, P. Bordigoni,, P. Di Bartolomeo,, T. Flood,, P. Landais,, S. Müller,, H. Ozsahin,, J. H. Passwell,, F. Porta,, S. Slavin,, N. Wulffraat,, F. Zintl,, A. Nagler,, A. Cant, and, A. Fischer. 2002. Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000. Blood 100:43444350.
43. Torgerson, T. R. 2008. Immune dysregulation in primary immunodeficiency disorders. Immunol. Allergy Clin. North Am. 28:315327.
44. Uzel, G.,, E. Tng,, S. D. Rosenzweig,, A. P. Hsu,, J. M. Shaw,, M. E. Horwitz,, G. F. Linton,, S. M. Anderson,, M. R. Kirby,, J. B. Oliveira,, M. R. Brown,, T. A. Fleisher,, S. K. Law, and, S. M. Holland. 2008. Reversion mutations in patients with leukocyte adhesion deficiency type-1 (LAD-1). Blood 111:209218.
45. van den Berg,, J. M.,, E. van Koppen,, A. Ahlin,, B. H. Belohradsky,, E. Bernatowska,, L. Corbeel,, T. Español,, A. Fischer,, M. Kurenko-Deptuch,, R. Mouy,, T. Petropoulou,, J. Roesler,, R. Seger,, M. J. Stasia,, N. H. Valerius,, R. S. Weening,, B. Wolach,, D. Roos, and, T. W. Kuijpers. 2009. Chronic granulomatous disease: the European experience. PLoS ONE 4:e5234.
46. von Bernuth, H.,, C. Picard,, Z. Jin,, R. Pankla,, H. Xiao,, C. L. Ku,, M. Chrabieh,, I. B. Mustapha,, P. Ghandil,, Y. Camcioglu,, J. Vasconcelos,, N. Sirvent,, M. Guedes,, A. B. Vitor,, M. J. Herrero-Mata,, J. I. Aróstegui,, C. Rodrigo,, L. Alsina,, E. Ruiz-Ortiz,, M. Juan,, C. Fortuny,, J. Yagüe,, J. Anton,, M. Pascal,, H. H. Chang,, L. Janniere,, Y. Rose,, B. Z. Garty,, H. Chapel,, A. Issekutz,, L. Maródi,, C. Rodriguez-Gallego,, J. Banchereau,, L. Abel,, X. Li,, D. Chaussabel,, A. Puel, and, J. L. Casanova. 2008. Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321:691696.
47. Xia, J., and, D. C. Link. 2008. Severe congenital neutropenia and the unfolded protein response. Curr. Opin. Hematol. 15:17.
48. Zeidler, C.,, M. Germeshausen, and, C. Klein, K. 2009. Welte. Clinical implications of ELA2-, HAX1-, and G-CSF-receptor (CSF3R) mutations in severe congenital neutropenia. Br. J. Haematol. 144:459467.
49. Zhang,, Q.,, J. C. Davis,, I. T. Lamborn,, A. F. Freeman,, H. Jing,, A. J. Favreau,, H. F. Matthews,, J. Davis,, M. L. Turner,, G. Uzel,, S. M. Holland, and, H. C. Su. 2009. Combined immunodeficiency associated with DOCK8 mutations. N. Engl. J. Med. 361:20462055.


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Inherited neutropenias

Citation: Holland S. 2011. Genetics of Antibacterial Host Defenses, p 473-482. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch37
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Chronic granulomatous disease

Citation: Holland S. 2011. Genetics of Antibacterial Host Defenses, p 473-482. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch37
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Leukocyte adhesion defects

Citation: Holland S. 2011. Genetics of Antibacterial Host Defenses, p 473-482. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch37
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Mycobacterial susceptibility

Citation: Holland S. 2011. Genetics of Antibacterial Host Defenses, p 473-482. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch37
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IgE elevation syndromes

Citation: Holland S. 2011. Genetics of Antibacterial Host Defenses, p 473-482. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch37

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