RESUMO
UNLABELLED: Inhibitory CD33-related Siglec receptors regulate immune cell activation upon engaging ubiquitous sialic acids (Sias) on host cell surface glycans. Through molecular mimicry, Sia-expressing pathogen group B Streptococcus binds inhibitory human Siglec-9 (hSiglec-9) to blunt neutrophil activation and promote bacterial survival. We unexpectedly discovered that hSiglec-9 also specifically binds high molecular weight hyaluronan (HMW-HA), another ubiquitous host glycan, through a region of its terminal Ig-like V-set domain distinct from the Sia-binding site. HMW-HA recognition by hSiglec-9 limited neutrophil extracellular trap (NET) formation, oxidative burst, and apoptosis, defining HMW-HA as a regulator of neutrophil activation. However, the pathogen group A Streptococcus (GAS) expresses a HMW-HA capsule that engages hSiglec-9, blocking NET formation and oxidative burst, thereby promoting bacterial survival. Thus, a single inhibitory lectin receptor detects two distinct glycan "self-associated molecular patterns" to maintain neutrophil homeostasis, and two leading human bacterial pathogens have independently evolved molecular mimicry to exploit this immunoregulatory mechanism. KEY MESSAGE: HMW-HA is the first example of a non-sialic acid containing glycan to be recognized by CD33-related Siglecs. HMW-HA engagement of hSiglec-9 attenuates neutrophil activation. Group A Streptococcus exploits hSiglec-9 recognition via its polysaccharide HMW-HA capsule to subvert neutrophil killing.
Assuntos
Antígenos CD/metabolismo , Interações Hospedeiro-Patógeno , Ácido Hialurônico/metabolismo , Ativação de Neutrófilo/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Animais , Antígenos CD/química , Antígenos CD/genética , Apoptose/genética , Apoptose/imunologia , Bactérias/imunologia , Bactérias/metabolismo , Quimiotaxia de Leucócito/imunologia , Armadilhas Extracelulares/genética , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ácido Hialurônico/química , Imunidade Inata , Fragmentos Fc das Imunoglobulinas/metabolismo , Peso Molecular , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes de Fusão , Explosão Respiratória/imunologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/química , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/genética , Streptococcus/fisiologiaRESUMO
We describe the case of a 14-year-old boy who developed airway obstruction due to acute upper respiratory tract infection. Following emergency tracheostomy, he developed pulmonary oedema and required ventilation. The postoperative course was complicated by the development of adult respiratory distress syndrome, characterised by marked respiratory distress, diffuse pulmonary infiltrates on chest radiography, reduced pulmonary compliance and marked increase in alveolar-arterial oxygen difference. He also developed persistent high-grade pyrexia, renal failure and cardiac instability. A social history of substance abuse (crack cocaine, amphetamines, alcohol and cigarettes) was obtained three weeks post-admission and is thought to have made a significant contribution to the severity of his disease.