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Surfactant protein A (SP-A) is involved in lung innate host defense and surfactant-related functions. The human SFTPA1 and SFTPA2 genes encode SP-A1 and SP-2 proteins, and each gene has been identified with numerous genetic variants. SP-A1 and SP-A2 differentially enhance bacterial phagocytosis. Sex differences have been observed in pulmonary disease and in survival of wild type and SP-A knockout (KO) mice. The impact of human SP-A variants on survival after infection is unknown. In this study, we determined whether SP-A variants differentially affect survival of male and female mice infected with  Klebsiella pneumoniae . Transgenic (TG) mice, where each carries a different human (h) SP-A1 (6A 2 , 6A 4 ), SP-A2 (1A 0 , 1A 3 ) variant or both variants SP-A1/SP-A2 (6A 2 /1A 0 , co-ex), and SP-A- KO, were utilized. The hTG and KO mice were infected intratracheally with  K. pneumoniae  bacteria, and groups of KO mice were treated with SP-A1 or SP-A2 either prior to and/or at the time of infection and survival for both experimental groups was monitored over 14 days. The binding of purified SP-A1 and SP-A2 proteins to phagocytic and non-phagocytic cells and expression of cell surface proteins in alveolar macrophages (AM) from SP-A1 and SP-A2 mice was examined. We observed gene-, variant-, and sex-specific (except for co-ex) differences with females showing better survival: (a) Gene-specific differences: co-ex = SP-A2 > SP-A1 > KO (both sexes); (b) Variant-specific survival co-ex (6A 2 /1A 0 ) = 1A 0  > 1A 3  = 6A 2  > 6A 4  (both sexes); (c) KO mice treated with SPs (SP-A1 or SP-A2) proteins exhibit significantly ( p  < 0.05) better survival; (d) SP-A1 and SP-A2 differentially bind to phagocytic, but not to non-phagocytic cells, and AM from SP-A1 and SP-A2 hTG mice exhibit differential expression of cell surface proteins. Our results indicate that sex and SP-A genetics differentially affect survival after infection and that exogenous SP-A1/SP-A2 treatment significantly improves survival. We postulate that the differential SP-A1/SP-A2 binding to the phagocytic cells and the differential expression of cell surface proteins that bind SP-A by AM from SP-A1 and SP-A2 mice play a role in this process. These findings provide insight into the importance of sex and innate immunity genetics in survival following infection.

frontiers in immunology

Survival of Surfactant Protein-A1 and SP-A2 Transgenic Mice After Klebsiella pneumoniae Infection, Exhibits Sex-, Gene-, and Variant Specific Differences; Treatment With Surfactant Protein Improves Survival