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.

Three million people globally suffer from infections caused by Aspergillus fumigatus (Af). Over 300,000 of these cases are due to invasive pulmonary aspergillosis (IPA) in patients with suppressed immune systems. The recent increase of aspergillosis in influenza-infected patients suggests that influenza infection creates transiently suppressed immune environments permissive to fungal infection. Consistent with this, we found that influenza infected WT mice had increased Af lung fungal burden and cellular damage compared to Af-only infected mice. We recently discovered that type I interferon (IFN) signaling, via IFNAR2 of the IFNAR1/2 receptor, regulates susceptibility to and damage from influenza. A main factor contributing to IPA pathology and outcome is the level of damage the host incurs. Importantly, we found that IFNAR2 deficiency (Ifnar2−/− mice) resulted in increased cellular damage and morbidity at 24 hrs post-Af compared to WT and Ifnar1−/− mice. Interestingly, Ifnar2−/− mice cleared spores more efficiently than both WT and Ifnar1−/− mice but were unable to control invasive disease and maintain pulmonary architecture, evidenced by hyphal growth and fibrosis-like tissue at 48 hrs post-Af. Although cellular recruitment was unaltered, the levels of inflammatory cytokines in Ifnar2−/− mice was two-fold higher than WT and Ifnar1−/− mice, and Ifnar2−/− neutrophils produced more external ROS in response to Af suggesting altered effector cell function may be involved in the IFNAR2 regulated damage response. Together, our results begin to establish a role for IFNAR2 in regulation of the host damage response to Af and suggest that aberrant type I IFN signaling creates a permissive environment allowing for Af infection to occur.

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