Human genetics of life-threatening influenza pneumonitis

Abstract

Influenza viruses infect millions of people around the globe annually, usually causing self-limited upper respiratory tract infections. However, a small but non-negligible proportion of patients suffer from life-threatening pulmonary disease. Those affected include otherwise healthy individuals, and children with primary infections in particular. Much effort has been devoted to virological studies of influenza and vaccine development. By contrast, the enormous interindividual variability in susceptibility to influenza has received very little attention. One interesting hypothesis is that interindividual variability is driven largely by the genetic makeup of the infected patients. Unbiased genomic approaches have been used to search for genetic lesions in children with life-threatening pulmonary influenza. Four monogenic causes of severe influenza pneumonitis-deficiencies of GATA2, IRF7, IRF9, and TLR3-have provided evidence that severe influenza pneumonitis can be genetic and often in patients with no other severe infections. These deficiencies highlight the importance of human type I and III IFN-mediated immunity for host defense against influenza. Clinical penetrance is incomplete, and the underlying mechanisms are not yet understood. However, human genetic studies have clearly revealed that seemingly sporadic and isolated life-threatening influenza pneumonitis in otherwise healthy individuals can be genetic.

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study

“…This is consistent with findings that patients with IEIs that specifically affect B-and T-cell development or function do not exhibit increased susceptibility to severe disease caused by influenza infection. 31,32 Our findings that patients with CVID comprised a large proportion of our cohort (>30%), and that 4 of these patients died (45% of all deaths), may infer that intact humoral immunity is important for host defense against SARS-CoV-2. However, these patients were generally older than the rest of the cohort (median age range, 45-54 years), and many had pre-existing health conditions that predispose to severe COVID-19 in the general population (lung disease in ;50%, kidney/heart/gut/liver disease in ;20%; Table II).…”

“…39,40 In the first study, 650 patients with lifethreatening COVID-19 were studied by whole-exome sequencing under the hypothesis that severe COVID-19 is allelic with severe influenza 39 or that genes biologically related to these loci would be involved. 31,32 Indeed, 3.5% of patients had known (AR IRF7 and IFNAR1 deficiency, autosomal-dominant TLR3, TICAM1, TBK1, and IRF3 deficiency) and new (autosomal-dominant UNC93B1, IRF7, IFNAR1, and IFNAR2 deficiency) genetic defects abolishing induction or amplification of type I IFNs. 39 In the second study, neutralizing autoantibodies against type I IFNs were found in 10.2% of 987 patients with life-threatening COVID-19 pneumonia, resulting in low or undetectable serum levels of IFN-a during acute disease; 94% of the patients with autoantibodies were male.…”

Heterogeneity of monocyte subsets and susceptibility to influenza virus contribute to inter-population variability of protective immunity

“…Interestingly, among the candidate genes identified, we found the well-known host viral restriction factors encoded by IFITM3, OAS3, and MX1, as well as critical TFs (IRF7, IRF9) involved in the severity of IAV-infection both in mice and humans (Allen et al, 2017;Ciancanelli et al, 2016;Zhang, 2020). Notably, IFITM3 expression was higher in nonclassical and intermediate monocytes relative to classical monocytes, and presented higher expression in ex vivo resistant versus susceptible individuals across all subsets ( Figure 6D).…”

A rare variant in ANP32B impairs influenza virus replication in human cells

“…Genetic variation in such proteins can affect susceptibility to infectious disease (; Ciancanelli, Abel, Zhang, & Casanova, 2016; Karlsson, Kwiatkowski, & Sabeti, 2014; Pittman, Glover, Wang, & Ko, 2016; Q. Zhang, 2020). Perhaps the best-known mutation conferring genetic resistance to viral infection is the Δ32 variant of the HIV-1 co-receptor C-C chemokine receptor type 5 ( CCR5 ) (Carrington, Dean, Martin, & O’Brien, 1999).…”

“…Additional mutations associated with severe influenza (reviewed in (Ciancanelli et al, 2016; Q. Zhang, 2020)) have been described in the complement factor CD55/DAF (Chatzopoulou, Gioula, Kioumis, Chatzidimitriou, & Exindari, 2019), the pulmonary surfactant protein SFTPA2 (Herrera-Ramos et al, 2014), the protease TMPRSS2 (Cheng et al, 2015), the endothelial transcriptional activator GATA2 (Sologuren et al, 2018), interferon regulators IRF7 and IRF9 (Bravo Garcia-Morato et al, 2019; Ciancanelli et al, 2015; Hernandez et al, 2018), and the endosomal dsRNA receptor TLR3 (Esposito et al, 2012; Hidaka et al, 2006; Lim et al, 2019).…”