Susceptibility to infection in early life: a growing role for human genetics


The unique vulnerability to infection of newborns and young infants is generally explained by a constellation of differences between early-life immune responses and immune responses at later ages, often referred to as neonatal immune immaturity. This developmental view, corroborated by robust evidence, offers a plausible, population-level description of the pathogenesis of life-threatening infectious diseases during the early-life period, but provides little explanation on the wide inter-individual differences in susceptibility and resistance to specific infections during the first months of life. In this context, the role of individual human genetic variation is increasingly recognized. A life-threatening infection caused by an opportunistic pathogen in an otherwise healthy infant likely represents the first manifestation of an inborn error of immunity. Single-gene disorders may also underlie common infections in full-term infants with no comorbidities or in preterm infants. In addition, there is increasing evidence of a possible role for common genetic variation in the pathogenesis of infection in preterm infants. Over the past years, a unified theory of infectious diseases emerged, supporting a hypothetical, age-dependent general model of genetic architecture of human infectious diseases. We discuss here how the proposed genetic model can be reconciled with the widely accepted developmental view of early-life infections in humans.

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  1. Alcaïs A, Quintana-Murci L, Thaler DS et al (2010) Life-threatening infectious diseases of childhood: single-gene inborn errors of immunity? Ann N Y Acad Sci 1214:18–33.

  2. Al-Herz W, Ragupathy R, Massaad MJ et al (2012) Clinical, immunologic and genetic profiles of DOCK8-deficient patients in Kuwait. Clin Immunol 143:266–272.

  3. Asgari S, Schlapbach LJ, Anchisi S et al (2017) Severe viral respiratory infections in children with IFIH1 loss-of-function mutations. Proc Natl Acad Sci USA 114:8342–8347.

  4. Baker CJ, Kasper DL (1976) Correlation of maternal antibody deficiency with susceptibility to neonatal group B streptococcal infection. N Engl J Med 294:753–756.

  5. Baker CJ, Edwards MS, Kasper DL (1981) Role of antibody to native type III polysaccharide of group B Streptococcus in infant infection. Pediatrics 68:544–549

  6. Baker CJ, Carey VJ, Rench MA et al (2014) Maternal antibody at delivery protects neonates from early onset group B streptococcal disease. J Infect Dis 209:781–788.

  7. Barzaghi F, Amaya Hernandez LC, Neven B et al (2018) Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: an international multicenter retrospective study. J Allergy Clin Immunol 141:1036–1049.e5.

  8. Billingham RE, Brent L, Medawar PB (1953) Actively acquired tolerance of foreign cells. Nature 172:603–606.

  9. Borghesi A, Stronati M (2008) Strategies for the prevention of hospital-acquired infections in the neonatal intensive care unit. J Hosp Infect 68:293–300.

  10. Borghesi A, Stronati M, Fellay J (2017) Neonatal group B streptococcal disease in otherwise healthy infants: failure of specific neonatal immune responses. Front Immunol 8:215.

  11. Borghesi A, Stronati M, Castagnoli R et al (2018) Novel approaches to the study of neonatal infections. Am J Perinatol 35:570–574.

  12. Bruton OC (1952) Agammaglobulinemia. Pediatrics 9:722–728

  13. Bucciol G, Moens L, Bosch B et al (2019) Lessons learned from the study of human inborn errors of innate immunity. J Allergy Clin Immunol 143:507–527.

  14. Buckley RH (2004) Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu Rev Immunol 22:625–655.

  15. Candotti F (2018) Clinical manifestations and pathophysiological mechanisms of the Wiskott-Aldrich syndrome. J Clin Immunol 38:13–27.

  16. Casanova J-L (2015a) Human genetic basis of interindividual variability in the course of infection. Proc Natl Acad Sci USA 112:E7118–7127.

  17. Casanova J-L (2015b) Severe infectious diseases of childhood as monogenic inborn errors of immunity. Proc Natl Acad Sci USA 112:E7128–7137.

  18. Casanova J-L, Abel L (2007) Human genetics of infectious diseases: a unified theory. EMBO J 26:915–922.

  19. Casanova J-L, Abel L (2018) Human genetics of infectious diseases: Unique insights into immunological redundancy. Semin Immunol 36:1–12.

  20. Centers for Disease Control and Prevention (2018)

  21. Chandesris M-O, Melki I, Natividad A et al (2012) Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey. Medicine (Baltimore) 91:e1–e19.

  22. Chang DR, Toh J, de Vos G, Gavrilova T (2016) Early diagnosis in dedicator of cytokinesis 8 (DOCK8) deficiency. J Pediatr 179:33–35.

  23. Chapel H, Puel A, von Bernuth H et al (2005) Shigella sonnei meningitis due to interleukin-1 receptor-associated kinase-4 deficiency: first association with a primary immune deficiency. Clin Infect Dis 40:1227–1231.

  24. Chapgier A, Wynn RF, Jouanguy E et al (2006) Human complete Stat-1 deficiency is associated with defective type I and II IFN responses in vitro but immunity to some low virulence viruses in vivo. J Immunol 176:5078–5083.

  25. Chiriaco M, Salfa I, Di Matteo G et al (2016) Chronic granulomatous disease: clinical, molecular, and therapeutic aspects. Pediatr Allergy Immunol 27:242–253.

  26. Cirillo E, Cancrini C, Azzari C et al (2019) Clinical, immunological, and molecular features of typical and atypical severe combined immunodeficiency: report of the Italian primary immunodeficiency network. Front Immunol 10:1908.

  27. Conley ME, Dobbs AK, Farmer DM et al (2009) Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol 27:199–227.

  28. Courtois G, Smahi A, Reichenbach J et al (2003) A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J Clin Invest 112:1108–1115.

  29. Cuvelier GDE, Rubin TS, Junker A et al (2019) Clinical presentation, immunologic features, and hematopoietic stem cell transplant outcomes for IKBKB immune deficiency. Clin Immunol 205:138–147.

  30. Dangor Z, Kwatra G, Izu A et al (2015) HIV-1 Is associated with lower group B streptococcus capsular and surface-protein IgG antibody levels and reduced transplacental antibody transfer in pregnant women. J Infect Dis 212:453–462.

  31. Della Mina E, Borghesi A, Zhou H et al (2017) Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts. Proc Natl Acad Sci USA 114:E514–E523.

  32. Dommergues MA, de La Rocque F, Guy C et al (2009) Local and regional adverse reactions to BCG-SSI vaccination: a 12-month cohort follow-up study. Vaccine 27:6967–6973.

  33. Duclaux-Loras R, Charbit-Henrion F, Neven B et al (2018) Clinical heterogeneity of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: a French multicenter retrospective study. Clin Transl Gastroenterol 9:201.

  34. Dupuis S, Jouanguy E, Al-Hajjar S et al (2003) Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet 33:388–391.

  35. Engelhardt KR, Gertz ME, Keles S et al (2015) The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol 136:402–412.

  36. Esposito S, Zampiero A, Pugni L et al (2014) Genetic polymorphisms and sepsis in premature neonates. PLoS ONE 9:e101248.

  37. Etzioni A (2010) Defects in the leukocyte adhesion cascade. Clin Rev Allergy Immunol 38:54–60.

  38. Farley MM, Harvey RC, Stull T et al (1993) A population-based assessment of invasive disease due to group B Streptococcus in nonpregnant adults. N Engl J Med 328:1807–1811.

  39. Fischer A, Notarangelo LD, Neven B et al (2015) Severe combined immunodeficiencies and related disorders. Nat Rev Dis Primers 1:15061.

  40. Forsthuber T, Yip HC, Lehmann PV (1996) Induction of TH1 and TH2 immunity in neonatal mice. Science 271:1728–1730.

  41. Frank J, Pignata C, Panteleyev AA et al (1999) Exposing the human nude phenotype. Nature 398:473–474.

  42. Fujiu T, Maruyama K, Koizumi T (2002) Early-onset group B streptococcal sepsis in a preterm infant with Kostmann syndrome. Acta Paediatr 91:1397–1399.

  43. Garel D, Devictor D, Tchernia G et al (1989) Streptococcus group B tardive meningitis revealing chronic septic granulomatosis. Ann Pediatr (Paris) 36:35–37

  44. Gobin K, Hintermeyer M, Boisson B et al (2017) IRAK4 deficiency in a patient with recurrent pneumococcal infections: case report and review of the literature. Front Pediatr 5:83.

  45. Goetghebuer T, Adler C, Epalza C, Levy J (2012) High incidence of group B streptococcal infection in infants born to HIV-infected mothers. Emerg Infect Dis 18:539–540.

  46. Greenhow TL, Hung Y-Y, Herz AM (2012) Changing epidemiology of bacteremia in infants aged 1 week to 3 months. Pediatrics 129:e590–596.

  47. Gruber C, Martin-Fernandez M, Ailal F et al (2019) Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy. Immunology

  48. Guerin JM, Mofredj A, Leibinger F et al (2000) Group B streptococcus meningitis in an HIV-positive adult: case report and review. Scand J Infect Dis 32:215–217.

  49. Gundlapalli AV, Scalchunes C, Boyle M, Hill HR (2015) Fertility, pregnancies and outcomes reported by females with common variable immune deficiency and hypogammaglobulinemia: results from an internet-based survey. J Clin Immunol 35:125–134.

  50. Hambleton S, Salem S, Bustamante J et al (2011) IRF8 mutations and human dendritic-cell immunodeficiency. N Engl J Med 365:127–138.

  51. Heeg M, Ammann S, Klemann C et al (2018) Is an infectious trigger always required for primary hemophagocytic lymphohistiocytosis? Lessons from in utero and neonatal disease. Pediatr Blood Cancer 65:e27344.

  52. Holland SM (2010) Chronic granulomatous disease. Clin Rev Allergy Immunol 38:3–10.

  53. Hull R, Gay H, Giles H, Nowicki M (2008) Streptococcus agalactiae myositis in a child with perinatally acquired human immnodeficiency virus. South Med J 101:317–319.

  54. Hussain SM, Luedtke GS, Baker CJ et al (1995) Invasive group B streptococcal disease in children beyond early infancy. Pediatr Infect Dis J 14:278–281.

  55. Israel L, Wang Y, Bulek K et al (2017) Human adaptive immunity rescues an inborn error of innate immunity. Cell 168:789–800.e10.

  56. Jilling T, Ambalavanan N, Cotten CM et al (2018) Surgical necrotizing enterocolitis in extremely premature neonates is associated with genetic variations in an intergenic region of chromosome 8. Pediatr Res 83:943–953.

  57. Jindal AK, Suri D, Guleria S et al (2019) Recurrent Salmonella typhi infection and autoimmunity in a young boy with complete IL-12 receptor β1 deficiency. J Clin Immunol 39:358–362.

  58. Klein C (2011) Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes. Annu Rev Immunol 29:399–413.

  59. Kollmann TR, Kampmann B, Mazmanian SK et al (2017) Protecting the newborn and young infant from infectious diseases: lessons from immune ontogeny. Immunity 46:350–363.

  60. Krause JC, Ghandil P, Chrabieh M et al (2009) Very late-onset group B Streptococcus meningitis, sepsis, and systemic shigellosis due to interleukin-1 receptor-associated kinase-4 deficiency. Clin Infect Dis 49:1393–1396.

  61. Kwan A, Abraham RS, Currier R et al (2014) Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA 312:729–738.

  62. Lamborn IT, Jing H, Zhang Y et al (2017) Recurrent rhinovirus infections in a child with inherited MDA5 deficiency. J Exp Med 214:1949–1972.

  63. Le Doare K, Allen L, Kampmann B et al (2015) Anti-group B Streptococcus antibody in infants born to mothers with human immunodeficiency virus (HIV) infection. Vaccine 33:621–627.

  64. Leruez-Ville M, Magny J-F, Couderc S et al (2017) Risk factors for congenital cytomegalovirus infection following primary and nonprimary maternal infection: a prospective neonatal screening study using polymerase chain reaction in saliva. Clin Infect Dis 65:398–404.

  65. Leven EA, Maffucci P, Ochs HD et al (2016) Hyper IgM syndrome: a report from the USIDNET registry. J Clin Immunol 36:490–501.

  66. Levy O (2007) Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol 7:379–390.

  67. Levy J, Espanol-Boren T, Thomas C et al (1997) Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr 131:47–54.

  68. Licciardi F, Montin D, Versace A et al (2016) Familial segregation of group B streptococcal infection in a consanguineous kindred. Int J Infect Dis 51:22–24.

  69. Liu L, Okada S, Kong X-F et al (2011) Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med 208:1635–1648.

  70. Maak B, Müller E, Berbig H, Estel C (1993) Maternal deficiency of IgG 2 and IgG 4 and neonatal infection caused by B-streptococci. Zentralbl Gynakol 115:136–139

  71. Magnani A, Jouannic J-M, Rosain J et al (2019) Successful in utero stem cell transplantation in X-linked severe combined immunodeficiency. Blood Adv 3:237–241.

  72. Meuwissen MEC, Schot R, Buta S et al (2016) Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. J Exp Med 213:1163–1174.

  73. Moutsopoulos NM, Zerbe CS, Wild T et al (2017) Interleukin-12 and interleukin-23 blockade in leukocyte adhesion deficiency type 1. N Engl J Med 376:1141–1146.

  74. Nagaraja V, Stewart TE, Mackay SG et al (2015) Supraglottitis due to group B streptococcus in an adult with IgG4 and C2 deficiency: a case report and review of the literature. Laryngoscope 125:852–855.

  75. O’Connell AE (2019) Primary immunodeficiency in the NICU. Neoreviews 20:e67–e78.

  76. Olin A, Henckel E, Chen Y et al (2018) Stereotypic immune system development in newborn children. Cell 174:1277–1292.e14.

  77. Owen RD (1945) Immunogenetic consequences of vascular anastomoses between bovine twins. Science 102:400–401.

  78. Oxelius VA, Lindén V, Christensen KK, Christensen P (1983) Deficiency of IgG subclasses in mothers of infants with group B streptococcal septicemia. Int Arch Allergy Appl Immunol 72:249–252.

  79. Picard C, Puel A, Bonnet M et al (2003) Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299:2076–2079.

  80. Picard C, Bobby Gaspar H, Al-Herz W et al (2018) International union of immunological societies: 2017 primary immunodeficiency diseases committee report on inborn errors of immunity. J Clin Immunol 38:96–128.

  81. Pou C, Nkulikiyimfura D, Henckel E et al (2019) The repertoire of maternal anti-viral antibodies in human newborns. Nat Med 25:591–596.

  82. Puel A, Casanova J-L (2019) The nature of human IL-6. J Exp Med 216:1969–1971.

  83. Quinti I, Papetti C, von Hunolstein C et al (1988) IgG subclasses to group B streptococci in normals, colonized woman and IgG2 subclass-deficient patients. Monogr Allergy 23:148–155

  84. Ricci S, Romano F, Nieddu F et al (2017) OL-EDA-ID syndrome: a novel hypomorphic NEMO mutation associated with a severe clinical presentation and transient HLH. J Clin Immunol 37:7–11.

  85. Ridge JP, Fuchs EJ, Matzinger P (1996) Neonatal tolerance revisited: turning on newborn T cells with dendritic cells. Science 271:1723–1726.

  86. Saito S, Oda A, Kasai M et al (2014) A neonatal case of chronic granulomatous disease, initially presented with invasive pulmonary aspergillosis. J Infect Chemother 20:220–223.

  87. Santos N, Silva R, Rodrigues J, Torres-Costa J (2014) Sjögren’s syndrome and acquired splenic atrophy with septic shock: a case report. J Med Case Rep 8:10.

  88. Sampath V, Menden H, Helbling D et al (2015) SIGIRR genetic variants in premature infants with necrotizing enterocolitis. Pediatrics 135:e1530–1534.

  89. Sarzotti M, Robbins DS, Hoffman PM (1996) Induction of protective CTL responses in newborn mice by a murine retrovirus. Science 271:1726–1728.

  90. Shane AL, Stoll BJ (2014) Neonatal sepsis: progress towards improved outcomes. J Infect 68(Suppl 1):S24–S32.

  91. Siegrist C-A, Aspinall R (2009) B-cell responses to vaccination at the extremes of age. Nat Rev Immunol 9:185–194.

  92. Simón JL, Bosch J, Puig A, Grau M (1989) Two relapses of group B streptococcal sepsis and transient hypogammaglobulinemia. Pediatr Infect Dis J 8:729–730

  93. Sims KD, Barton TD (2006) Group B streptococcal toxic shock syndrome in an asplenic patient: case report and literature review. Eur J Clin Microbiol Infect Dis 25:208–210.

  94. Skokowa J, Dale DC, Touw IP et al (2017) Severe congenital neutropenias. Nat Rev Dis Primers 3:17032.

  95. Spencer S, Köstel Bal S, Egner W et al (2019) Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses. J Exp Med 216:1986–1998.

  96. Srinivasan L, Kirpalani H, Cotten CM (2015) Elucidating the role of genomics in neonatal sepsis. Semin Perinatol 39:611–616.

  97. Srinivasan L, Page G, Kirpalani H et al (2017a) Genome-wide association study of sepsis in extremely premature infants. Arch Dis Child Fetal Neonatal Ed 102:F439–F445.

  98. Srinivasan L, Swarr DT, Sharma M et al (2017b) Systematic review and meta-analysis: gene association studies in neonatal sepsis. Am J Perinatol 34:684–692.

  99. Sunkara B, Bheemreddy S, Lorber B et al (2012) Group B Streptococcus infections in non-pregnant adults: the role of immunosuppression. Int J Infect Dis 16:e182–186.

  100. Tazi A, Bellais S, Tardieux I et al (2012) Group B Streptococcus surface proteins as major determinants for meningeal tropism. Curr Opin Microbiol 15:44–49.

  101. Thiruppathy K, Privitera A, Jain K, Gupta S (2008) Congenital asplenia and group B streptococcus sepsis in the adult: case report and review of the literature. FEMS Immunol Med Microbiol 53:437–439.

  102. Tremlett CH, Ridgway EJ, Allen KD (1994) Fatal group B streptococcal septicaemia 16 years after splenectomy. J Infect 28:107–108.

  103. Tsujita Y, Mitsui-Sekinaka K, Imai K et al (2016) Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome-like immunodeficiency. J Allergy Clin Immunol 138:1672–1680.e10.

  104. Vetrie D, Vorechovský I, Sideras P et al (1993) The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 361:226–233.

  105. Volpi S, Cicalese MP, Tuijnenburg P et al (2019) A combined immunodeficiency with severe infections, inflammation, and allergy caused by ARPC1B deficiency. J Allergy Clin Immunol 143:2296–2299.

  106. von Bernuth H, Picard C, Jin Z et al (2008) Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321:691–696.

  107. Walkovich K, Connelly JA (2016) Primary immunodeficiency in the neonate: early diagnosis and management. Semin Fetal Neonatal Med 21:35–43.

  108. Weitkamp JH, Stüber F, Bartmann P (2000) Pilot study assessing TNF gene polymorphism as a prognostic marker for disease progression in neonates with sepsis. Infection 28:92–96.

  109. Winkelstein JA, Marino MC, Johnston RB et al (2000) Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 79:155–169.

  110. Zabsonré JT, Laoubi K, Kemiche F et al (2012) Streptococcus B septic polyarthritis revealing Good’s syndrome. Joint Bone Spine 79:412–414.

  111. Zaki M, Thoenes M, Kawalia A et al (2017) Recurrent and prolonged infections in a child with a homozygous IFIH1 nonsense mutation. Front Genet 8:130.

  112. Zhang X, Zhivaki D, Lo-Man R (2017) Unique aspects of the perinatal immune system. Nat Rev Immunol 17:495–507.

  113. Zonana J, Elder ME, Schneider LC et al (2000) A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet 67:1555–1562.

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We wish to thank Jacinta Cecilia Bustamante (Paris University, Imagine Institute, France) for critical reading of the manuscript. We are grateful to Jean-Laurent Casanova and Laurent Abel (Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York and Imagine Institute, Paris, France) for their advices in the field of human genetics of infectious diseases and their collaboration. We also thank all the colleagues and collaborators who indirectly contributed, with suggestions and critical discussions, to shaping the concepts reported in the present review. We thank the medical, nurse and research staff of the Neonatal Intensive Care Unit of Fondazione IRCCS Policlinico “San Matteo”, Pavia, Italy, scientists from the “Fellay lab” (École Polytechnique Fédérale de Lausanne, Switzerland), Alessandra Biffi (Azienda Ospedaliera -University of Padova, Padova, Italy) and Luregn Schlapbach (Mater Children’s Hospital, Brisbane, Australia) for their support in research projects on human genetics of infectious diseases and primary immunodeficiencies. We thank Fondazione Città della Speranza ONLUS (, Associazione di Promozione Sociale “Genitori in fuga” (, Associazione sportiva dilettantistica “NCO Crew” and Associazione ONLUS “Aiutami a crescere” ( for their support to our scientific work. Our most heart-felt thanks go to the little patients and their families.

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Borghesi, A., Marzollo, A., Michev, A. et al. Susceptibility to infection in early life: a growing role for human genetics. Hum Genet (2020) doi:10.1007/s00439-019-02109-2

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