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Surfactant protein (SP)-A is a member of the collectin family of proteins. In vitro, SP-A binds influenza A virus (IAV), neutralizes infectivity, and enhances uptake by macrophages. SP-D also binds and neutralizes certain strains of IAV. To determine if SP-A has a role in protecting the intact animal against IAV infection, we inoculated gene-targeted SP-A-deficient mice ( - / - ) and littermate controls ( + / + ) with either saline or increasing doses of an IAV strain that binds SP-A but not SP-D. IAV was more virulent in SP-A - / - compared with + / + mice, with a significantly lower mean lethal dose (LD50) and significantly greater weight loss during infection. SP-A - / - mice also had increased airway epithelial injury and more alveolar cellular infiltrates than + / + mice. On Day 2, SP-A - / - mice had more neutrophils and higher MIP-2 levels in the lung than + / + mice. We conclude the altered host response and increased susceptibility to X-79 δ 167 infection in SP-A - / - mice reflects a protective role for SP-A in regulating the host response to IAV. Because the recovery of virus from lung homogenates on Days 2 and 6 after inoculation was comparable in - / - and + / + mice, we speculate SP-A reduces IAV virulence independently of direct viral neutralization.