Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, USA
Infect Immun. 2021 May 17;89(6). doi: 10.1128/IAI.00676-20.
Nontypeable (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 and an isogenic 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 mutant versus the wild type in the murine lung. Complement depletion with cobra venom factor increased survival of the mutant in the nasopharynx but not in the lungs, suggesting differing roles of sialylation at these sites. Prior infection increased IgM against 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.
不可分型流感嗜血杆菌（NTHi）是人类鼻咽部和上呼吸道的常见寄居者，可引起机会性呼吸道感染，且常反复发作和慢性化。NTHi 利用宿主中的唾液酸逃避抗菌防御并在黏膜组织中持续存在；然而，NTHi 在感染过程中摄取的唾液酸的作用尚未完全阐明。我们之前的研究表明，唾液酸化可保护正常人体血清中杀菌性 IgM 针对的 NTHi 脂寡糖（LOS）上的特定表位。在此，我们使用野生型和不能对 LOS 进行唾液酸化的同种基因缺失突变体 ，在小鼠呼吸道中评估了 LOS 唾液酸化介导的免疫逃避的重要性。唾液酸化保护了人源和鼠源 IgM 识别的常见 NTHi 聚糖结构，并保护了 NTHi 免受针对这些结构的 IgM 介导的补体杀伤。唾液酸化 LOS 对 IgM 结合的保护作用与 突变体在小鼠肺部的存活率低于野生型相关。 cobra venom factor 耗尽补体可增加 突变体在鼻咽部的存活率，但不能增加肺部的存活率，表明唾液酸化在这些部位的作用不同。先前的感染增加了针对 但不针对唾液酸保护表位的 IgM，与感染过程中唾液酸介导的免疫逃避一致。这些结果为 NTHi 逃避针对宿主物种保守的免疫防御的策略提供了机制见解，突出了针对 NTHi LOS 抗原的小鼠模型在开发抗感染策略方面的潜力。
