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In pathogens that produce lipooligosaccharide (LOS), sugar residues within the surface-exposed LOS outer core mediate interactions with components of the host immune system, promoting bacterial infection. Many LOS structures are controlled by phase variation mediated by random slipped-strand base mispairing, which can reversibly switch gene expression on or off. Phase variation diversifies the LOS, however its adaptive role is not well-understood. Nontypeable  Haemophilus influenzae  (NTHi) is an important pathogen that causes a range of illnesses in the upper and lower respiratory tract. In NTHi a phase variable galactosyltransferase encoded by  lic2A  initiates galactose chain extension of the LOS outer core. The donor substrate for Lic2A, UDP-galactose, is generated from UDP-glucose by UDP-galactose epimerase encoded by  galE . Our previous fitness profiling of  H. influenzae  mutants in a murine lung model showed that the  galE  mutant had a severe survival defect, while the  lic2A  mutant's defect was modest, leading us to postulate that unidentified factors act as suppressors of potential defects in a  lic2A  mutant. Herein we conducted a genome-wide genetic interaction screen to identify genes epistatic on  lic2A  for survival in the murine lung. An unexpected finding was that  galE  mutants exhibited restored virulence properties in a  lic2A  mutant background. We identified an alternative antibody epitope generated by Lic2A in the  galE  mutant that increased sensitivity to classical complement mediated killing in human serum. Deletion of  lic2A  or restoration of UDP-galactose synthesis alleviated the  galE  mutant's virulence defects. These studies indicate that when deprived of its galactosyl substrate, Lic2A acquires an alternative activity leading to increased recognition of NTHi by IgM and decreased survival in the lung model. Biofilm formation was increased by deletion of  galE  and by increased availability of UDP-GlcNAc precursors that can compete with UDP-galactose production. NTHi's ability to reversibly inactivate  lic2A  by phase-variation may influence survival in niches of infection in which UDP-Galactose levels are limiting.

frontiers in cellular and infection microbiology

Suppression of Alternative Lipooligosaccharide Glycosyltransferase Activity by UDP-Galactose Epimerase Enhances Murine Lung Infection and Evasion of Serum IgM