Bacteraemic pneumonia is a common cause of sepsis in critically ill patients 
today and is characterized by dysregulation of inflammation. The genetic factors 
predisposing to bacteraemic pneumonia are not yet fully understood. Innate 
immunity is pivotal for host defence against invading bacteria, and nuclear 
factor-kappa B (NF-kappaB) is central to bacteria-induced inflammation and 
immune responses. The deubiquitinating enzyme CYLD has been identified as a key 
negative regulator for NF-kappaB. In the present study, we investigated the role 
of CYLD in innate immune response in Escherichia coli pneumonia. Upon E. coli 
inoculation, Cyld(-/-) mice were hypersusceptible to E. coli pneumonia with 
higher mortality. Innate immune response to E. coli was enhanced in Cyld(-/-) 
cells and mice. Cyld(-/-) cells exhibited enhanced NF-kappaB activation upon E. 
coli inoculation, and the enhanced NF-kappaB activation by E. coli was abolished 
by perturbing IkappaB kinase (IKK) signalling. Furthermore, IKK inhibitor 
rescued Cyld(-/-) mice from lethal infection during E. coli pneumonia along with 
reduced inflammation. Taken together, these data showed that CYLD acts as a 
crucial negative regulator for E. coli pneumonia by negatively regulating 
NF-kappaB. These findings provide novel insight into the regulation of 
bacteraemic pneumonia and related diseases and may help develop novel 
therapeutic strategies for these diseases.