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Abstract M. ovipneumoniae is a respiratory pathogen that can cause mild to moderate pneumonia and reduced productivity in domestic lambs. However, studies on both natural and experimental M. ovipneumoniae infection have reported highly variable clinical signs and pathology. Here, we assessed the impact of administering M. ovipneumoniae to the upper respiratory tract (URT) or to the lower respiratory tract (LRT) of two-month-old specific pathogen-free lambs. Lambs were inoculated with PBS (control) or with ceftiofur-treated nasal wash fluid obtained from sheep with natural M. ovipneumoniae infection, monitored for eight weeks, and subsequently euthanized. All lambs in the URT and LRT groups developed a stable infection with M. ovipneumoniae. M. ovipneumoniae infection led to lower weight gains and mild respiratory disease, with significantly greater effects following LRT inoculation compared to URT inoculation. At necropsy, lambs inoculated via the LRT showed consolidation of the cranial lung lobes. In addition, histological signs of alveolar, bronchiolar, and interstitial inflammation were significantly more severe in the LRT compared to the URT group. M. ovipneumoniae loads in the trachea and bronchi also were significantly higher after LRT than URT inoculation. Interestingly, 9/10 inoculated lambs also tested positive for M. haemolytica in nasal swab but not in bronchial swab samples. In summary, our study suggests that bypassing protective mechanisms of the URT by delivering respiratory pathogens to the LRT leads to more severe respiratory disease and lung damage than delivery to the URT.

Polymicrobial pneumonias occur frequently in cattle, swine, and sheep, resulting in major economic losses. Individual pathogens comprising these complex infections may be mild on their own but can instead exhibit synergism or increase host susceptibility. Two examples of such pathogens, Mycoplasma ovipneumoniae (M. ovipneumoniae) and influenza D viruses (IDVs), naturally infect domestic sheep. In sheep, the role of M. ovipneumoniae in chronic nonprogressive pneumonia is well-established, but the pathogenesis of IDV infection has not previously been studied. We utilized a specific-pathogen-free sheep flock to study the clinical response to IDV infection in naïve vs. M. ovipneumoniae-exposed lambs. Lambs were inoculated intranasally with M. ovipneumoniae or mock infection, followed after four weeks by infection with IDV. Pathogen shedding was tracked, and immunological responses were evaluated by measuring acute phase response and IDV-neutralizing antibody titers. While lamb health statuses remained subclinical, M. ovipneumoniae-exposed lambs had significantly elevated body temperatures during IDV infection compared to M. ovipneumoniae-naïve, IDV-infected lambs. Moreover, we found a positive correlation between prior M. ovipneumoniae burden, early-infection IDV shedding, and IDV-neutralizing antibody response. Our findings suggest that IDV infection may not induce clinical symptoms in domestic sheep, but previous M. ovipneumoniae exposure may promote mild IDV-associated inflammation.