Abstract
IntroductionInherited variability in host immune responses influences susceptibility and outcome of Influenza A virus (IAV) infection, but these factors remain largely unknown. Components of the innate immune response may be crucial in the first days of the infection. The collectins surfactant protein (SP)-A1, -A2, and -D and mannose-binding lectin (MBL) neutralize IAV infectivity, although only SP-A2 can establish an efficient neutralization of poorly glycosylated pandemic IAV strains.MethodsWe studied the role of polymorphic variants at the genes of MBL (MBL2), SP-A1 (SFTPA1), SP-A2 (SFTPA2), and SP-D (SFTPD) in 93 patients with H1N1 pandemic 2009 (H1N1pdm) infection.ResultsMultivariate analysis showed that two frequent SFTPA2 missense alleles (rs1965708-C and rs1059046-A) and the SFTPA2 haplotype 1A0 were associated with a need for mechanical ventilation, acute respiratory failure, and acute respiratory distress syndrome. The SFTPA2 haplotype 1A1 was a protective variant. Kaplan-Meier analysis and Cox regression also showed that diplotypes not containing the 1A1 haplotype were associated with a significantly shorter time to ICU admission in hospitalized patients. In addition, rs1965708-C (P = 0.0007), rs1059046-A (P = 0.0007), and haplotype 1A0 (P = 0.0004) were associated, in a dose-dependent fashion, with lower PaO2/FiO2 ratio, whereas haplotype 1A1 was associated with a higher PaO2/FiO2 ratio (P = 0.001).ConclusionsOur data suggest an effect of genetic variants of SFTPA2 on the severity of H1N1pdm infection and could pave the way for a potential treatment with haplotype-specific (1A1) SP-A2 for future IAV pandemics.
Highlights
Inherited variability in host immune responses influences susceptibility and outcome of Influenza A virus (IAV) infection, but these factors remain largely unknown
The surfactant protein (SP) have been shown to exert an important role against IAV infection in animal models: mice lacking SP-A or SP-D have increased susceptibility to IAV infection, and their role seem to depend on IAV strains, pandemic versus seasonal strains [9,10,11,12,13,14]
Frequencies of the genetic variants under analysis were not found to be significantly different between H1N1 pandemic 2009 (H1N1pdm)-infected patients and the general population (Table 2)
Summary
Inherited variability in host immune responses influences susceptibility and outcome of Influenza A virus (IAV) infection, but these factors remain largely unknown. Several secreted human Ctype lectins of the collectin family, the serum mannosebinding lectin (MBL), the pulmonary surfactant proteins (SP) –A1, –A2, and –D, and collectin 11 (CL-11, alias collectin kidney 1, CL-K1) may neutralize IAV infectivity in vitro [5,6,7,8] Among these collectins, the SPs have been shown to exert an important role against IAV infection in animal models: mice lacking SP-A or SP-D have increased susceptibility to IAV infection, and their role seem to depend on IAV strains, pandemic versus seasonal strains [9,10,11,12,13,14]. Variability at the collectin genes, MBL2 (Ensembl: ENSG00000165471), SFTPA1 (Ensembl: ENSG00000122852), SFTPA2 (Ensembl: ENSG00000185 303), and SFTPD (Ensembl: ENSG00000133661) have been found to be associated with susceptibility to and/or severity of several bacterial and viral infectious diseases [6,15]
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