Influenza D viruses (IDV) are known to co-circulate with viral and bacterial pathogens in cattle and other ruminants. Currently, there is limited knowledge regarding host responses to IDV infection and whether IDV infection affects host susceptibility to secondary bacterial infections. To begin to address this gap in knowledge, the current study utilized a combination of in vivo and in vitro approaches to evaluate host cellular responses against primary IDV infection and secondary bacterial infection with Staphylococcus aureus (S. aureus). Primary IDV infection in mice did not result in clinical signs of disease and it did not enhance the susceptibility to secondary S. aureus infection. Rather, IDV infection appeared to protect mice from the usual clinical features of secondary bacterial infection, as demonstrated by improved weight loss, survival, and recovery when compared to S. aureus infection alone. We found a notable increase in IFN-β expression following IDV infection while utilizing human alveolar epithelial A549 cells to analyze early anti-viral responses to IDV infection. These results demonstrate for the first time that IDV infection does not increase the susceptibility to secondary bacterial infection with S. aureus, with evidence that anti-viral immune responses during IDV infection might protect the host against these potentially deadly outcomes.
Early innate viral recognition by the host is critical for the rapid response and subsequent clearance of an infection. Innate immune cells patrol sites of infection to detect and respond to invading microorganisms including viruses. Surface Toll-like receptors (TLRs) are a group of pattern recognition receptors (PRRs) that can be activated by viruses even before the host cell becomes infected. However, the early activation of surface TLRs by viruses can lead to viral clearance by the host or promote pathogenesis. Thus, a plethora of research has attempted to identify specific viral ligands that bind to surface TLRs and mediate progression of viral infection. Herein, we will discuss the past two decades of research that have identified specific viral proteins recognized by cell surface-associated TLRs, how these viral proteins and host surface TLR interactions affect the host inflammatory response and outcome of infection, and address why controversy remains regarding host surface TLR recognition of viral proteins.
Immune modulation via exposure to a primary stimulus can modify innate immune cell responses to a subsequent unrelated infection. Previously, we found that conserved mammalian proteins which display a pattern of repeating protein subunits (RPSP) enhance clearance of a secondary respiratory bacterial infection in a TLR2/1-dependent manner. RPSPs like filamentous actin or ferritin are expressed intracellularly in a steady-state, thus their detection by extracellular pattern recognition receptors should elicit danger-like signals. Unlike classical DAMPs, which prompt an inflammatory response, TLR2/1-based recognition of RPSPs did not result in proinflammatory cytokine production or neutrophil lung infiltration. Yet, upon challenge with Staphylococcus aureus, RPSP inoculated mice exhibited a more robust inflammatory response and better bacterial clearance than control mice. This TLR2/1-based RPSP recognition was not limited to mammalian proteins. Enhanced S. aureus clearance was achieved with a synthetic peptide (Q11; QQKFQFQFEQQ) that organizes into RPSP fibers and is non-immunogenic. Further, we found that RPSP enhanced S. aureus clearance was dependent on non-classical Type I IFN signaling whereby IFNβ production was required, but absence of the IFNAR1 subunit of the Type I IFN receptor did not abrogate S. aureus clearance. In vivo depletion and bacterial clearance assays showed that macrophages were essential for this subsequent improved response, which persisted after resting cells for days post RPSP stimulation. Our results indicate that RPSP stimulation of macrophages enhances these cell’s abilities to respond to a secondary infection in an IFNβ dependent manner and has features suggestive of trained immunity.
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