Sialic Acid Protects Nontypeable Haemophilus influenzae from Natural IgM and Promotes Survival in Murine Respiratory Tract.

Abstract

Nontypeable Haemophilus influenzae (NTHi), a common inhabitant of the human nasopharynx and upper airways, causes opportunistic respiratory tract infections that are frequently recurring and chronic. NTHi utilizes sialic acid from the host to evade antibacterial defenses and persist in mucosal tissues; however, the role of sialic acid scavenged by NTHi during infection is not fully understood. We previously showed that sialylation protects specific epitopes on NTHi lipooligosaccharide (LOS) targeted by bactericidal IgM in normal human serum. Here, we evaluated the importance of immune evasion mediated by LOS sialylation in the mouse respiratory tract using wild-type H. influenzae and an isogenic siaB mutant incapable of sialylating the LOS. Sialylation protected common NTHi glycan structures recognized by human and murine IgM and protected NTHi from complement-mediated killing directed by IgM against these structures. Protection from IgM binding by sialylated LOS correlated with decreased survival of the siaB mutant versus the wild type in the murine lung. Complement depletion with cobra venom factor increased survival of the siaB mutant in the nasopharynx but not in the lungs, suggesting differing roles of sialylation at these sites. Prior infection increased IgM against H. influenzae but not against sialic acid-protected epitopes, consistent with sialic acid-mediated immune evasion during infection. These results provide mechanistic insight into an NTHi evasive strategy against an immune defense conserved across host species, highlighting the potential of the mouse model for development of anti-infective strategies targeting LOS antigens of NTHi.