Lethal Influenza in Two Related Adults with Inherited GATA2 Deficiency

Abstract

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.

Human genetics of life-threatening influenza pneumonitis

“…Four IEIs-GATA2 (Bigley et al 2011;Pasquet et al 2013;Sologuren et al 2018), IRF7 (Ciancanelli et al 2015), IRF9 (Hernandez et al 2018), and TLR3 (Lim et al 2019) deficiencies-have been shown to cause life-threatening influenza pneumonitis (Table 1). Autosomal dominant (AD) GATA2 deficiency is the only one of these IEIs leading to a pleiotropic syndromic disorder that manifests as a lack of multilymphoid and granulocyte-macrophage progenitors in the bone marrow, smaller numbers of dendritic cells (DCs), monocytes, T, B and NK lymphocytes in peripheral blood, and higher susceptibility to viral, mycobacterial, and fungal infections.…”

“…Autosomal dominant (AD) GATA2 deficiency is the only one of these IEIs leading to a pleiotropic syndromic disorder that manifests as a lack of multilymphoid and granulocyte-macrophage progenitors in the bone marrow, smaller numbers of dendritic cells (DCs), monocytes, T, B and NK lymphocytes in peripheral blood, and higher susceptibility to viral, mycobacterial, and fungal infections. However, the severity of each manifestation varies between patients, and relatives with at-risk genotypes can be asymptomatic (Bigley et al 2011;Pasquet et al 2013;Sologuren et al 2018;Dickinson et al 2011Dickinson et al , 2014Spinner et al 2014;Collin et al 2015;Donadieu et al 2018). The deaths of four adults from severe infections despite the presence of IAV-neutralizing antibodies in the serum have been reported (Bigley et al 2011;Pasquet et al 2013;Sologuren et al 2018).…”

“…Surprisingly, forward genetics approach identified inherited Mx1 deficiency as a strong determinant of vulnerability to IAV in mice years before human patients (Ciancanelli et al 2016;Haller et al 1979Haller et al , 1980Zhang et al 2019). Recently discovered inborn errors of immunity (IEIs) have demonstrated that life-threatening influenza pneumonitis or encephalitis can be caused by monogenic defects of innate/intrinsic immunity (Bigley et al 2011;Pasquet et al 2013;Sologuren et al 2018;Ciancanelli et al 2015;Hernandez et al 2018Hernandez et al , 2019Picard et al 2018). Here, we discuss the human genetic determinism of life-threatening influenza pneumonitis, which is rapidly changing our understanding of both clinical influenza and the basic principles of antiviral immunity.…”

Mx genes: host determinants controlling influenza virus infection and trans-species transmission

“…Interestingly, genetic susceptibility to devastating influenza does not appear to be a polygenic trait, but is determined by defects in single genes that govern non-redundant pathways of type I (α/β) and type III (λ) interferon (IFN) responses. Critical genes identified so far are either involved in induction of type I and type III IFNs (TLR3, IRF7) (Ciancanelli et al 2015;Lim et al 2019), IFN production by plasmacytoid dendritic cells (GATA2) (Sologuren et al 2018) or are part of the IFN signaling pathway required for antiviral action (IRF9) . Surprisingly, however, no clear defects have yet been found in type I and type III IFN-stimulated genes (ISGs).…”

RNF144A shapes the hierarchy of cytokine signaling to provide protective immunity against influenza

“…6g), when predicting severe versus moderate influenza. We next compared the performance of RNF144A against those of published genes associated with influenza severity, IFITM3 39 , TLR3 40 , MX1 (in mice) 41 , IRF7 42 , GATA2 43 and CD177 (a neutrophil-specific marker) 38 , as well as CD8A. Only CD177, IFITM3, TLR3 and RNF144A expressions were able to predict influenza severity.…”