Molecular basis of increased serum resistance among pulmonary isolates of non-typeable Haemophilus influenzae

• Published in: PLoS pathogens 2011-01, Vol.7 (1), p.e1001247-e1001247
• Main Authors: Nakamura, Shigeki, Shchepetov, Mikhail, Dalia, Ankur B, Clark, Sarah E, Murphy, Timothy F, Sethi, Sanjay, Gilsdorf, Janet R, Smith, Arnold L, Weiser, Jeffery N
• Format: Article
• Language: English
• Subjects: ABC transporters; Biosynthesis; Blood Bactericidal Activity - genetics; Blood Bactericidal Activity - immunology; Chronic obstructive pulmonary disease; Development and progression; Disease; Ear diseases; Experiments; Genes, Bacterial; Genetic aspects; Genetic Variation; Haemophilus Infections - genetics; Haemophilus Infections - immunology; Haemophilus Infections - microbiology; Haemophilus influenzae; Haemophilus influenzae - genetics; Haemophilus influenzae - immunology; Haemophilus influenzae - pathogenicity; Hemophilus influenzae; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Humans; Immunity, Innate - genetics; Immunity, Innate - immunology; Immunology/Immunity to Infections; Infectious Diseases/Bacterial Infections; Lipids; Lung - immunology; Lung - microbiology; Medical research; Microbiology; Microbiology/Immunity to Infections; Microbiology/Medical Microbiology; Microbiology/Microbial Physiology and Metabolism; Public health; Respiratory Medicine/COPD and Allied Disorders; Respiratory Medicine/Respiratory Infections; Respiratory tract diseases; Respiratory Tract Infections - genetics; Respiratory Tract Infections - immunology; Respiratory Tract Infections - microbiology; Virulence (Microbiology)
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1001247

Non-typeable Haemophilus influenzae (NTHi), a common commensal of the human pharynx, is also an opportunistic pathogen if it becomes established in the lower respiratory tract (LRT). In comparison to colonizing isolates from the upper airway, LRT isolates, especially those associated with exacerbations of chronic obstructive pulmonary disease, have increased resistance to the complement- and antibody-dependent, bactericidal effect of serum. To define the molecular basis of this resistance, mutants constructed in a serum resistant strain using the mariner transposon were screened for loss of survival in normal human serum. The loci required for serum resistance contribute to the structure of the exposed surface of the bacterial outer membrane. These included loci involved in biosynthesis of the oligosaccharide component of lipooligosaccharide (LOS), and vacJ, which functions with an ABC transporter encoded by yrb genes in retrograde trafficking of phospholipids from the outer to inner leaflet of the cell envelope. Mutations in vacJ and yrb genes reduced the stability of the outer membrane and were associated with increased cell surface hyrophobicity and phospholipid content. Loss of serum resistance in vacJ and yrb mutants correlated with increased binding of natural immunoglobulin M in serum as well as anti-oligosaccharide mAbs. Expression of vacJ and the yrb genes was positively correlated with serum resistance among clinical isolates. Our findings suggest that NTHi adapts to inflammation encountered during infection of the LRT by modulation of its outer leaflet through increased expression of vacJ and yrb genes to minimize recognition by bactericidal anti-oligosaccharide antibodies.