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.
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 (https://cittadellasperanza.org/), Associazione di Promozione Sociale “Genitori in fuga” (https://www.genitoriinfuga.org/), Associazione sportiva dilettantistica “NCO Crew” and Associazione ONLUS “Aiutami a crescere” (https://www.aiutamiacrescere.it/) for their support to our scientific work. Our most heart-felt thanks go to the little patients and their families.
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Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
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