Effect of Stress on Viral–Bacterial Synergy in Bovine Respiratory Disease: Novel Mechanisms to Regulate Inflammation

The severity of bovine respiratory infections has been linked to a variety offactors, including environmental and nutritional changes, transportation, and socialreorganization of weaned calves. Fatal respiratory infections, however, usually occurwhen a primary viral infection compromises host defences and enhances the severityof a secondary bacterial infection. This viral–bacterial synergy can occur by a numberof different mechanisms and disease challenge models have been developed to analysehost responses during these respiratory infections. A primary bovine herpesvirus-1(BHV-1) respiratory infection followed by a secondary challenge with Mannheimia haemolyticaresults in fatal bovine respiratory disease (BRD) and host responses to these two pathogens have been studied extensively. We used this disease model todemonstrate that stress significantly altered the viral–bacterial synergy resulting infatal BRD. Functional genomic analysis revealed that BHV-1 infection enhanced toll-likereceptors (TLR) expression and increased pro-inflammatory responses whichcontribute to the severity of a Mannheimia haemolytica infection. TLRs play a criticalrole in detecting bacterial infections and inducing pro-inflammatory responses. It isdifficult to understand, however, how stress-induced corticosteroids could enhancethis form of viral–bacterial synergy. Nuclear translocation of the glucocorticoidreceptor activates cell signalling pathways which inhibit both TLR signallingand pro-inflammatory responses. The apparent conundrum between stress-inducedcorticosteroids and enhanced BRD susceptibility is discussed in terms of present data and previous investigations of stress and respiratory disease.