Natural antibodies mediate resistance to Acinetobacter baumanniirespiratory infections.

Abstract Acinetobacter baumanniiis a growing public health threat due to increasing incidence of carbapenem-resistant strains in U.S. hospitals. With widespread antibiotic resistance, there is an urgent need for alternative therapies to treat these infections, which are often acquired in hospital intensive care units. Antibody-based immunotherapies offer one potential treatment avenue, however, adaptive immune responses to A. baumanniihave not been well characterized. Pilot experiments, using a mouse pneumonia model to explore the role of adaptive immunity in clearing A. baumannii, uncovered an unexpected and severe defect in resistance to A. baumanniiinfection in Rag2−/-mice during the first 48 hours after infection. Subsequent experiments showed that intranasally infected Rag2−/−or B cell-deficient μMT mice are impaired compared to wild type mice in clearing bacteria from lung, liver, and spleen at 24 hours post infection. Prophylactic administration of normal mouse serum or purified immunoglobulins from naive mice demonstrates a protective effect of natural antibodies (NAbs) by rescuing Rag2−/−mice from severe infection. Analysis of C3 complement protein binding demonstrated that NAbs increased C3 protein deposition on A. baumanniicells, indicating the activation of the classical complement pathway as a potential mechanism of action. Overall, our study demonstrates a previously unknown role for natural antibodies in the innate resistance to Acinetobacterpneumonia, a finding that may lead to the development of effective therapies against human infections caused by this antibiotic-resistant pathogen.