Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency
Open Access
- 30 January 2020
- journal article
- research article
- Published by Massachusetts Medical Society in The New England Journal of Medicine
- Vol. 382 (5), 437-445
- https://doi.org/10.1056/nejmoa1910640
Abstract
Cytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown. Inbred mice that lack the gene encoding nitric oxide synthase 2 (Nos2) are susceptible to the related murine CMV infection. We studied a previously healthy 51-year-old man from Iran who after acute CMV infection had an onset of progressive CMV disease that led to his death 29 months later. We hypothesized that the patient may have had a novel type of inborn error of immunity. Thus, we performed whole-exome sequencing and tested candidate mutant alleles experimentally. We found a homozygous frameshift mutation in NOS2 encoding a truncated NOS2 protein that did not produce nitric oxide, which determined that the patient had autosomal recessive NOS2 deficiency. Moreover, all NOS2 variants that we found in homozygosity in public databases encoded functional proteins, as did all other variants with an allele frequency greater than 0.001. These findings suggest that inherited NOS2 deficiency was clinically silent in this patient until lethal infection with CMV. Moreover, NOS2 appeared to be redundant for control of other pathogens in this patient. (Funded by the National Center for Advancing Translational Sciences and others.)Funding Information
- National Center for Research Resources (UL1TR001866)
- Investissement d’Avenir (ANR-10-IAHU-01)
- Integrative Biology of Emerging Infectious Diseases Laboratoire d’Excellence (ANR-10-LABX-62-IBEID)
- St. Giles Foundation (N/A)
- Shapiro–Silverberg Fund for the Advancement of Translational Research (N/A)
- American Philosophical Society (Daland Fellowship)
- Qatar National Research Fund (ID NPRP9-251-3-045)
This publication has 41 references indexed in Scilit:
- Defective Nitric Oxide Production by Alveolar Macrophages duringPneumocystisPneumoniaAmerican Journal of Respiratory Cell and Molecular Biology, 2011
- Cytomegalovirus in Hematopoietic Stem Cell Transplant RecipientsHematology/Oncology Clinics of North America, 2011
- Human Cytomegalovirus Induces Systemic Immune Activation Characterized by a Type 1 Cytokine SignatureThe Journal of Infectious Diseases, 2010
- Review of cytomegalovirus seroprevalence and demographic characteristics associated with infectionReviews in Medical Virology, 2010
- Immunobiology of Human Cytomegalovirus: from Bench to BedsideClinical Microbiology Reviews, 2009
- Impaired Innate Host Defense Causes Susceptibility to Respiratory Virus Infections in Cystic FibrosisImmunity, 2003
- NITRIC OXIDE AND MACROPHAGE FUNCTIONAnnual Review of Immunology, 1997
- Severe Cytomegalovirus Infection in Immunocompetent PatientsClinical Infectious Diseases, 1997
- Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis.The Journal of Experimental Medicine, 1996
- Nitric Oxide and Host Defense against Pneumocystis carinii Infection in a Mouse ModelThe Journal of Infectious Diseases, 1996