Surfactant protein A genetic variants associate with severe respiratory insufficiency in pandemic influenza A virus infection

Herrera-Ramos, Estefanía; López-Rodríguez, Marta; Ruiz-Hernández, J.J.; Horcajada, Juan Pablo; Borderías, Luis; Lerma, Elisabeth; Blanquer, José; Pérez-González, María Carmen; García‐Laorden, M. Isabel; Florido, Yanira; Mas-Bosch, Virginia; Montero, Milagro; Ferrer, José M.; Sorlí, Luisa; Vilaplana, Carlos; Rajas, Olga; Briones, M. Luisa; Aspa, Javier; López‐Granados, Eduardo; Solé‐Violán, Jordi; Castro, Felipè Rodríguez de; Rodríguez-Gallego, Carlos

doi:10.1186/cc13934

Cited by 55 publications

(48 citation statements)

References 30 publications

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“…We also discovered that genetic variation in SP-A2 at position 223, which is associated with multiple lung diseases (7, 24), leads to dramatic differences in binding to MMF. We generated humanized knock-in transgenic mice that lack mouse SP-A, but express hSP-A2 with either Gln or Lys at position 223.…”

Section: Introductionmentioning

confidence: 91%

Genetic Variation in SP-A2 Leads to Differential Binding to Mycoplasma pneumoniae Membranes and Regulation of Host Responses

Ledford

Voelker

Addison

et al. 2015

The Journal of Immunology

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Mycoplasma pneumoniae (Mp) is an extracellular pathogen that colonizes mucosal surfaces of the respiratory tract and is associated with asthma exacerbations. Previous reports demonstrate that surfactant protein-A (SP-A) binds live Mp and mycoplasma membranes (MMF) with high affinity. Humans express a repertoire of single amino acid genetic variants of SP-A that may be associated with lung disease, and our findings demonstrate that allelic differences in SP-A2 (Gln223Lys) affect the binding to MMF. We show that SP-A−/− mice are more susceptible to MMF exposure and have significant increases in mucin production and neutrophil recruitment. Novel humanized-SP-A2 transgenic mice harboring the hSP-A2 223K allele exhibit reduced neutrophil influx and mucin production in the lungs, when challenged with MMF, compared to SP-A−/− mice. Conversely, mice expressing hSP-A2 223Q have increased neutrophil influx and mucin production that is similar to SP-A−/− mice. Using tracheal epithelial cell cultures, we show that enhanced mucin production to MMF occurs in the absence of SP-A, and is not dependent upon neutrophil recruitment. Increased phosphorylation of the epidermal growth factor receptor (EGFR) was evident in the lungs of MMF-challenged mice when SP-A was absent. Pharmacologic inhibition of EGFR prior to MMF challenge dramatically reduced mucin production in SP-A−/− mice. These findings suggest a protective role for SP-A in limiting MMF-stimulated mucin production that occurs through interference with EGFR mediated signaling. The SP-A interaction with the EGFR signaling pathway appears to occur in an allele specific manner that may have important implications for SP-A polymorphisms in human diseases.

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Section: Introductionmentioning

confidence: 91%

Genetic Variation in SP-A2 Leads to Differential Binding to Mycoplasma pneumoniae Membranes and Regulation of Host Responses

Ledford

Voelker

Addison

et al. 2015

The Journal of Immunology

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“…One notable finding from these studies is that SNPs in genes encoding lung surfactant proteins (SFTPs), including SFTPA and SFTPB, have been associated with severe influenza virus infections (53, 155), as well as other respiratory infections as discussed below. SFTPs are secreted into the lung alveolar space, and may have direct antiviral or immunomodulatory activities (47), although additional studies are needed to fully validate the importance of SFTP variations in human influenza virus infections.…”

Section: Influenza Virusmentioning

confidence: 99%

Human Genetic Determinants of Viral Diseases

et al. 2017

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Much progress has been made in the identification of specific human gene variants that contribute to enhanced susceptibility or resistance to viral diseases. Herein we review multiple discoveries made with genome-wide or candidate gene approaches that have revealed significant insights into virus–host interactions. Genetic factors that have been identified include genes encoding virus receptors, receptor-modifying enzymes, and a wide variety of innate and adaptive immunity-related proteins. We discuss a range of pathogenic viruses, including influenza virus, respiratory syncytial virus, human immunodeficiency virus, human T cell leukemia virus, human papilloma virus, hepatitis B and C viruses, herpes simplex virus, norovirus, rotavirus, parvovirus, and Epstein-Barr virus. Understanding the genetic underpinnings that affect infectious disease outcomes should allow tailored treatment and prevention approaches in the future.

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“…However, another study failed to reach significance in a similar cohort of European ancestry [112]. More interestingly, regulatory SNPs affecting expression of surfactant proteins, SFPTA (rs1965708 and rs1059046) in a Spanish cohort and in SFPTB (rs1130866) in a Chinese cohort [113,114], were associated with severe pH1N1 2009 influenza. Independent studies of Japanese and Chinese children who developed severe and/or fatal influenza-associated encephalopathy found significant association with exonic variants in CPT2 that result in thermolabile proteins that are hypomorphic during fever [115,116].…”

Section: Introductionmentioning

confidence: 99%

Host genetics of severe influenza: from mouse Mx1 to human IRF7

Ciancanelli

Abel

Zhang

et al. 2016

Current Opinion in Immunology

109

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Influenza viruses cause mild to moderate respiratory illness in most people, and only rarely devastating or fatal infections. The virulence factors encoded by viral genes can explain seasonal or geographic differences at the population level but are unlikely to account for inter-individual clinical variability. Inherited or acquired immunodeficiencies may thus underlie severe cases of influenza. The critical role of host genes was first demonstrated by forward genetics in inbred mice, with the identification of interferon (IFN)-α/β-inducible Mx as a canonical influenza susceptibility gene. Reverse genetics has subsequently characterized the in vivo role of other mouse genes involved in IFN-α/β and –λ immunity. A series of in vitro studies with mouse and human cells have also refined the cell-intrinsic mechanisms of protection against influenza viruses. Population-based human genetic studies have not yet uncovered variants with a significant impact. Interestingly, human primary immunodeficiencies affecting T and B cells were also not found to predispose to severe influenza. Recently however, human IRF7 was shown to be essential for IFN-α/β- and IFN-λ-dependent protective immunity against primary influenza in vivo, as inferred patient with life-threatening influenza revealed to be IRF7-deficient by whole exome sequencing. Next generation sequencing of human exomes and genomes will facilitate the analysis of the human genetic determinism of severe influenza.

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Surfactant protein A genetic variants associate with severe respiratory insufficiency in pandemic influenza A virus infection

Cited by 55 publications

References 30 publications

Genetic Variation in SP-A2 Leads to Differential Binding to Mycoplasma pneumoniae Membranes and Regulation of Host Responses

Genetic Variation in SP-A2 Leads to Differential Binding to Mycoplasma pneumoniae Membranes and Regulation of Host Responses

Human Genetic Determinants of Viral Diseases

Host genetics of severe influenza: from mouse Mx1 to human IRF7

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