Petris, Alina-Maria; (2019) Non-typeable Haemophilus influenzae and rhinovirus co-infection of the respiratory epithelium. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Non-typeable Haemophilus influenzae (NTHi) and rhinovirus 16 (RV16) are strongly associated with symptomatic disease in healthy individuals and with disease exacerbations in patients with chronic lung conditions such as chronic obstructive pulmonary disease (COPD). Co-infection with RV16 and NTHi is thought to cause more severe exacerbations, although the mechanism behind this remains unknown. The hypothesis of this project was that RV16 and NTHi co-infection of the respiratory epithelium results in increased bacterial growth, greater epithelial damage and inflammation compared to single NTHi infection. To investigate this, healthy and COPD primary respiratory epithelial cells cultured at air-liquid interface for 6 days (pre-ciliation) or 28 days (ciliated) were infected with RV16 and 24 hours later challenged with NTHi. // In healthy and COPD ciliated epithelial cultures, NTHi bound to motile cilia within minutes, then formed filamentous morphotypes and biofilm-like aggregates which reduced ciliary beat amplitude by 24 hours post infection. NTHi epithelial invasion occurred preferentially in non-ciliated epithelial cells suggesting that ciliation may protect against NTHi invasion. This might be of importance in COPD cultures, where the number of ciliated cells was reduced, reflecting what is seen in vivo. // Co-infection of ciliated cultures with RV16 and NTHi resulted in a reduced ciliary beat frequency, epithelial barrier dysfunction and a more complex inflammatory response from healthy and COPD ciliated cultures, compared to NTHi single infection. RV16 co-infection also promoted mucin gene expression and enhanced NTHi growth by altering epithelial cell apical fluid secretion. In contrast, pre-ciliation cultures showed markedly reduced responses to single RV16 or NTHi infection and their co-infection compared to ciliated cultures. However, pre-ciliation cultures were susceptible to NTHi invasion and promoted NTHi growth during co-infection with RV16, suggesting they may act like a niche for bacterial colonisation. // In conclusion, this study has shown that NTHi infection is able to affect ciliary function, form biofilm and invade the epithelium without epithelial barrier damage or induction of a complex inflammatory response, suggestive of a colonizer behaviour. In contrast, co-infection with RV16 and NTHi led to NTHi growth, a goblet cell-specific transcriptional profile, impaired ciliary function and epithelial barrier and increased inflammation which could result in increased bacterial dissemination and COPD exacerbation.

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