Lethal Influenza in Two Related Adults with Inherited GATA2 Deficiency
The pathogenesis of life-threatening influenza A virus (IAV) disease remains elusive, as infection is benign in most individuals. We studied two relatives who died from influenza. We Sanger sequenced GATA2 and evaluated the mutation by gene transfer, measured serum cytokine levels, and analyzed circulating T- and B-cells. Both patients (father and son, P1 and P2) died in 2011 of H1N1pdm IAV infection at the ages of 54 and 31 years, respectively. They had not suffered from severe or moderately severe infections in the last 17 (P1) and 15 years (P2). A daughter of P1 had died at 20 years from infectious complications. Low B-cell, NK- cell, and monocyte numbers and myelodysplastic syndrome led to sequence GATA2. Patients were heterozygous for a novel, hypomorphic, R396L mutation leading to haplo-insufficiency. B- and T-cell rearrangement in peripheral blood from P1 during the influenza episode showed expansion of one major clone. No T-cell receptor excision circles were detected in P1 and P3 since they were 35 and 18 years, respectively. Both patients presented an exuberant, interferon (IFN)-γ-mediated hypercytokinemia during H1N1pdm infection. No data about patients with viremia was available. Two previously reported adult GATA2-deficient patients died from severe H1N1 IAV infection; GATA2 deficiency may predispose to life-threatening influenza in adulthood. However, a role of other genetic variants involved in immune responses cannot be ruled out. Patients with GATA2 deficiency can reach young adulthood without severe infections, including influenza, despite long-lasting complete B-cell and natural killer (NK) cell deficiency, as well as profoundly diminished T-cell thymic output.
KeywordsImmunodeficiency GATA2 influenza A virus H1N1 immunological memory
We would like to thank the patients and their families for their trust. We are highly indebted to Judith Noda, Juantxo Aróstegui, Yanira Florido, Nereida González-Quevedo, Ana Domínguez, Rafael Camacho, Mónica González-Esguevillas, and Teresa Molero for technical assistance.
I.S., M.T.M.-S., E.B.O.-J., E.B., I.C, C.O.-Q., M.M.-G., S.-Y. A., J.P., R.C., E. H.-R., C.P., M. L.-R., J.J.R.-H., C.B., M.A.-A.., M.A.F, M.J.C., J.-L.C., J.B., and C.R.-G. performed the research and analyzed and interpreted the data. J.S.V., J.M.F., F.R.C, and NF were responsible for the clinical evaluation of the patients and also collected and interpreted the data. C.R.-G. designed the research. C.R.G. and J-L.C. wrote the manuscript, and JB collaborated in writing the manuscript.
This work was supported by grants from the Instituto de Salud Carlos III, Ministry of Health [FIS PI13/01456 and FIS PI16/00759, with the funding of European Regional Development Fund-European Social Fund, FEDER-FSE] to [C.R-G.]; National Center for Research Resources and the National Center for Advancing Sciences (NCATS) [grant 8UL1TR000043]; National Institutes of Health [grant 5R01NS072381] to [J-L.C.]; the St. Giles Foundation, the French National Research Agency under the “Investments for the Future” program [grant ANR-10-IAHU-01]; the Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases [ANR-10-LABX-62-IBEID], ANR grants [ANR2014-IEIHSEER] to [S-Y.Z.]; [ANR2016-GENMSMD] to [J.B.]; INSERM, Paris Descartes University; Universidad de Las Palmas de Gran Canaria (fellowship to [E.H.R.]); and Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (fellowship [FI 11/00593] to [M.L-R.]). The sponsors of the study had no role in designing the study, collecting, analyzing, and interpreting the data, or writing of the paper.
Compliance with Ethical Standards
This research has been performed in accordance with the Declaration of Helsinki. The protocols were approved by Clinical Research Ethics Committees of hospitals involved. Written informed consent for the study was obtained from their legal representative.
Conflicts of Interest
The authors declare that they have no conflict of interest.
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