Michael J. Preston

Human Monoclonal Antibodies to Pseudomonas aeruginosa Alginate That Protect against Infection by Both Mucoid and Nonmucoid Strains

Two fully human mAbs specific for epitopes dependent on intact carboxylate groups on the C6 carbon of the mannuronic acid components of Pseudomonas aeruginosa alginate were found to promote phagocytic killing of both mucoid and nonmucoid strains as well as protection against both types of strains in a mouse model of acute pneumonia. The specificity of the mAbs for alginate was determined by ELISA and killing assays. Some strains of P. aeruginosa did not make detectable alginate in vitro, but in vivo protection against lethal pneumonia was obtained and shown to be due to rapid induction of expression of alginate in the murine lung. No protection against strains genetically unable to make alginate was achieved. These mAbs have potential to be passive therapeutic reagents for all strains of P. aeruginosa and the results document that alginate is a target for the proper type of protective Ab even when expressed at low levels on phenotypically nonmucoid strains.

Tissue Inhibitor of Metalloproteinase 1 Regulates Resistance to Infection

ABSTRACT Tissue inhibitor of metalloproteinase 1 (TIMP-1)-deficient mice are resistant to Pseudomonas aeruginosa corneal infections. Corneas healed completely in TIMP-1-deficient mice, and infections were cleared faster in TIMP-1-deficient mice than in wild-type littermates. Genetic suppression studies using matrix metalloproteinase (MMP)-deficient mice showed that MMP-9, MMP-3, and MMP-7 but not MMP-2 or MMP-12 are needed for resistance. Increased resistance was also seen during pulmonary infections. These results identify a novel pathway regulating infection resistance.

Human mAbs to Pseudomonas aeruginosa alginate that protect against infection by both mucoid and nonmucoid strains.

Analysis of the nucleotide and amino acid sequences indicated that clones F428 and F429 contained the same H chain V region but different L chain V region, whereas clone F431 had a distinct H chain V region but shared the L chain V region of clone F428 (GenBank accession numbers: AY626661, IGLV-J of mAbs F428 and F431; AY626662, IGLV-J of mAb F429; AY626664, IGHV-D-J of mAbs F428 and F429; and AY626663, IGHV-D-J of mAb F431).