RESUMO
Respiratory viral infection increases host susceptibility to secondary bacterial infections, yet the precise dynamics within airway epithelia remain elusive. Here, we elucidate the pivotal role of CD47 in the airway epithelium during bacterial super-infection. We demonstrated that upon influenza virus infection, CD47 expression was upregulated and localized on the apical surface of ciliated cells within primary human nasal or bronchial epithelial cells. This induced CD47 exposure provided attachment sites for Staphylococcus aureus, thereby compromising the epithelial barrier integrity. Through bacterial adhesion assays and in vitro pull-down assays, we identified fibronectin-binding proteins (FnBP) of S. aureus as a key component that binds to CD47. Furthermore, we found that ciliated cell-specific CD47 deficiency or neutralizing antibody-mediated CD47 inactivation enhanced in vivo survival rates. These findings suggest that interfering with the interaction between airway epithelial CD47 and pathogenic bacterial FnBP holds promise for alleviating the adverse effects of super-infection.
Assuntos
Antígeno CD47 , Células Epiteliais , Infecções Estafilocócicas , Staphylococcus aureus , Superinfecção , Antígeno CD47/metabolismo , Antígeno CD47/genética , Humanos , Animais , Superinfecção/microbiologia , Camundongos , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Células Epiteliais/virologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologia , Influenza Humana/metabolismo , Influenza Humana/imunologia , Influenza Humana/virologia , Aderência Bacteriana , Mucosa Respiratória/metabolismo , Mucosa Respiratória/microbiologia , Mucosa Respiratória/virologia , Camundongos Endogâmicos C57BL , Brônquios/metabolismo , Brônquios/citologia , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , Camundongos Knockout , Vírus da Influenza A Subtipo H1N1RESUMO
Although early life colonization of commensal microbes contributes to long-lasting immune imprinting in host tissues, little is known regarding the pathophysiological consequences of postnatal microbial tuning of cutaneous immunity. Here, we show that postnatal exposure to specific skin commensal Staphylococcus lentus (S. lentus) promotes the extent of atopic dermatitis (AD)-like inflammation in adults through priming of group 2 innate lymphoid cells (ILC2s). Early postnatal skin is dynamically populated by discrete subset of primed ILC2s driven by microbiota-dependent induction of thymic stromal lymphopoietin (TSLP) in keratinocytes. Specifically, the indole-3-aldehyde-producing tryptophan metabolic pathway, shared across Staphylococcus species, is involved in TSLP-mediated ILC2 priming. Furthermore, we demonstrate a critical contribution of the early postnatal S. lentus-TSLP-ILC2 priming axis in facilitating AD-like inflammation that is not replicated by later microbial exposure. Thus, our findings highlight the fundamental role of time-dependent neonatal microbial-skin crosstalk in shaping the threshold of innate type 2 immunity co-opted in adulthood.