Type I Interferon Induced By NTHi-DNA Modulates Inflammatory Cytokine Profile To Promote Susceptibility To Non-Typeable Haemophilus Influenzae

Objective: To investigate the role of NTHi-DNA-induced IFN-I in host against NTHi infection and its regulatory mechanism.Background: Non-typeable Haemophilus influenzae(NTHi)is a Gram-negative coccus colonized in the upper respiratory tract of most healthy adults.When the body’s immunity is weakened,NTHi could spread to the lower respiratory tract and cause lung inflammation or aggravation of existing diseases,such as chronic obstructive pulmonary disease(COPD).Study on the mechanism of interaction between NTHi and host can provide new ideas and new methods for developing strategies for prevention and treatment of NTHi infection.Our previous work found that NTHi-DNA can induce the production of type I interferon(IFN-I)in macrophages and epithelial cells.IFN-I is essential for antiviral immunity,but its role in bacterial infection is complex and unclear.In a number of bacterial infection models,such as Salmonella typhi,Mycobacterium tuberculosis,and Streptococcus pneumoniae,it has been demonstrated that the role of IFN-I in host defense against bacterial infection varies from bacterial species and is associated with the regulation of inflammatory cytokines.However,in the NTHi-infected COPD and pneumonia models,the role of IFN-I in the interaction between host and pathogen has not been fully elucidated.Therefore,we propose whether NTHi-DNA-induced IFN-I changes the host susceptibility to NTHi by regulating the expression of inflammatory cytokines,thereby influencing the host’s anti-NTHi effect.Methods and Results:1.NTHi-DNA-induced IFN-I attenuated the phagocytosis and killing ability of PEMs to NTHi,and aggravated the pulmonary inflammatory response of NTHi-infected mimic COPD mice,which was detrimental to the survival of NTHi-infected mice.Compared with WT PEMs,IFNAR-/-PEMs enhanced phagocytosis and killing of NTHi.IFNAR-/-mice showed weaker pulmonary inflammatory response,lighter tissue damage,and stronger resistance to NTHi infection.2.NTHi-DNA-induced IFN-I up-regulated the expression of inflammatory cytokines IL-1β,IL-6,IL-12 and chemokine CXCL10 in NTHi-infected PEMs and infected mice,whereas the defect in IFNAR lead to a decrease in expression of these inflammatory cytokines and chemokines.3.Augmented inflammatory response mediated by NTHi-DNA-induced IFN-I was relative to p38 MAPK activation.Conclusions: This study confirmed that NTHi-DNA-induced IFN-I attenuated the phagocytosis and killing ability of PEMs to NTHi,and aggravated the inflammatory damage in the lungs of NTHi-infected simulated COPD mice,thereby promoting the host susceptibility to NTHi.This deleterious inflammatory response was associated with the upregulation of the inflammatory cytokines IL-1β,IL-6,IL-12,and chemokine CXCL10 caused by activation of p38 MAPK by IFNAR after recognition of IFN-I.We believed that the IFN-I response elicited by NTHi-DNA may be utilized by bacteria as a strategy to counteract host immune clearance,which was detrimental to the prognosis of NTHi infection in the host(especially COPD patients).This study will help to improve our understanding of the interaction between NTHi and host immune cells,and provide a new theoretical basis for COPD patients to find anti-NTHi infection and drug resistance treatment strategies.