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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.
Raegan M. Skelton; Kelly M. Shepardson; Alexis Hatton; Patrick T. Wilson; Chithra Sreenivasan; Jieshi Yu; Dan Wang; Victor C. Huber; Agnieszka Rynda-Apple. Contribution of Host Immune Responses Against Influenza D Virus Infection Toward Secondary Bacterial Infection in a Mouse Model. Viruses 2019, 11, 994 .
AMA StyleRaegan M. Skelton, Kelly M. Shepardson, Alexis Hatton, Patrick T. Wilson, Chithra Sreenivasan, Jieshi Yu, Dan Wang, Victor C. Huber, Agnieszka Rynda-Apple. Contribution of Host Immune Responses Against Influenza D Virus Infection Toward Secondary Bacterial Infection in a Mouse Model. Viruses. 2019; 11 (11):994.
Chicago/Turabian StyleRaegan M. Skelton; Kelly M. Shepardson; Alexis Hatton; Patrick T. Wilson; Chithra Sreenivasan; Jieshi Yu; Dan Wang; Victor C. Huber; Agnieszka Rynda-Apple. 2019. "Contribution of Host Immune Responses Against Influenza D Virus Infection Toward Secondary Bacterial Infection in a Mouse Model." Viruses 11, no. 11: 994.
Influenza virus infections particularly when followed by bacterial superinfections (BSI) result in significant morbidities and mortalities especially during influenza pandemics. Type I interferons (IFNs) regulate both anti-influenza immunity and host susceptibility to subsequent BSIs. These type I IFNs consisting of, among others, 14 IFN-α's and a single IFN-β, are recognized by and signal through the heterodimeric type I IFN receptor (IFNAR) comprised of IFNAR1 and IFNAR2. However, the individual receptor subunits can bind IFN-β or IFN-α's independently of each other and induce distinct signaling. The role of type I IFN signaling in regulating host susceptibility to both viral infections and BSI has been only examined with respect to IFNAR1 deficiency. Here, we demonstrate that despite some redundancies, IFNAR1 and IFNAR2 have distinct roles in regulating both anti-influenza A virus (IAV) immunity and in shaping host susceptibility to subsequent BSI caused by S. aureus. We found IFNAR2 to be critical for anti-viral immunity. In contrast to Ifnar1−/− mice, IAV-infected Ifnar2−/− mice displayed both increased and accelerated morbidity and mortality compared to WT mice. Furthermore, unlike IFNAR1, IFNAR2 was sufficient to generate protection from lethal IAV infection when stimulated with IFN-β. With regards to BSI, unlike what we found previously in Ifnar1−/− mice, Ifnar2−/− mice were not susceptible to BSI induced on day 3 post-IAV, even though absence of IFNAR2 resulted in increased viral burden and an increased inflammatory environment. The Ifnar2−/− mice similar to what we previously found in Ifnar1−/− mice were less susceptible than WT mice to BSI induced on day 7 post-IAV, indicating that signaling through a complete receptor increases BSI susceptibility late during clinical IAV infection. Thus, our results support a role for IFNAR2 in induction of anti-IAV immune responses that are involved in altering host susceptibility to BSI and are essential for decreasing the morbidity and mortality associated with IAV infection. These results begin to elucidate some of the mechanisms involved in how the individual IFNAR subunits shape the anti-viral immune response. Moreover, our results highlight the importance of examining the contributions of entire receptors, as individual subunits can induce distinct outcomes as shown here.
Kelly M. Shepardson; Kyle Larson; Laura L. Johns; Kayla Stanek; Hanbyul Cho; Julia Wellham; Haley Henderson; Agnieszka Rynda-Apple. IFNAR2 Is Required for Anti-influenza Immunity and Alters Susceptibility to Post-influenza Bacterial Superinfections. Frontiers in Immunology 2018, 9, 2589 .
AMA StyleKelly M. Shepardson, Kyle Larson, Laura L. Johns, Kayla Stanek, Hanbyul Cho, Julia Wellham, Haley Henderson, Agnieszka Rynda-Apple. IFNAR2 Is Required for Anti-influenza Immunity and Alters Susceptibility to Post-influenza Bacterial Superinfections. Frontiers in Immunology. 2018; 9 ():2589.
Chicago/Turabian StyleKelly M. Shepardson; Kyle Larson; Laura L. Johns; Kayla Stanek; Hanbyul Cho; Julia Wellham; Haley Henderson; Agnieszka Rynda-Apple. 2018. "IFNAR2 Is Required for Anti-influenza Immunity and Alters Susceptibility to Post-influenza Bacterial Superinfections." Frontiers in Immunology 9, no. : 2589.
Although viruses and viral capsids induce rapid immune responses, little is known about viral pathogen-associated molecular patterns (PAMPs) that are exhibited on their surface. Here, we demonstrate that the repeating protein subunit pattern common to most virus capsids is a molecular pattern that induces a Toll-like-receptor-2 (TLR2)-dependent antiviral immune response. This early antiviral immune response regulates the clearance of subsequent bacterial superinfections, which are a primary cause of morbidities associated with influenza virus infections. Utilizing this altered susceptibility to subsequent bacterial challenge as an outcome, we determined that multiple unrelated, empty, and replication-deficient capsids initiated early TLR2-dependent immune responses, similar to intact influenza virus or murine pneumovirus. These TLR2-mediated responses driven by the capsid were not dependent upon the capsid’s shape, size, origin, or amino acid sequence. However, they were dependent upon the multisubunit arrangement of the capsid proteins, because unlike intact capsids, individual capsid subunits did not enhance bacterial clearance. Further, we demonstrated that even a linear microfilament protein built from repeating protein subunits (F-actin), but not its monomer (G-actin), induced similar kinetics of subsequent bacterial clearance as did virus capsid. However, although capsids and F-actin induced similar bacterial clearance, in macrophages they required distinct TLR2 heterodimers for this response (TLR2/6 or TLR2/1, respectively) and different phagocyte populations were involved in the execution of these responses in vivo . Our results demonstrate that TLR2 responds to invading viral particles that are composed of repeating protein subunits, indicating that this common architecture of virus capsids is a previously unrecognized molecular pattern. IMPORTANCE Rapid and precise pathogen identification is critical for the initiation of pathogen-specific immune responses and pathogen clearance. Bacteria and fungi express common molecular patterns on their exteriors that are recognized by cell surface-expressed host pattern recognition receptors (PRRs) prior to infection. In contrast, viral molecular patterns are primarily nucleic acids, which are recognized after virus internalization. We found that an initial antiviral immune response is induced by the repeating subunit pattern of virus exteriors (capsids), and thus, induction of this response is independent of viral infection. This early response to viral capsids required the cell surface-expressed PRR TLR2 and allowed for improved clearance of subsequent bacterial infection that commonly complicates respiratory viral infections. Since the repeating protein subunit pattern is conserved across viral capsids, this suggests that it is not easy for a virus to change without altering fitness. Targeting this vulnerability could lead to development of a universal antiviral vaccine.
Kelly M. Shepardson; Benjamin Schwarz; Kyle Larson; Rachelle V. Morton; John Avera; Kimberly McCoy; Alayna Caffrey; Ann Harmsen; Trevor Douglas; Agnieszka Rynda-Apple. Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent. mBio 2017, 8, e01356-17 .
AMA StyleKelly M. Shepardson, Benjamin Schwarz, Kyle Larson, Rachelle V. Morton, John Avera, Kimberly McCoy, Alayna Caffrey, Ann Harmsen, Trevor Douglas, Agnieszka Rynda-Apple. Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent. mBio. 2017; 8 (6):e01356-17.
Chicago/Turabian StyleKelly M. Shepardson; Benjamin Schwarz; Kyle Larson; Rachelle V. Morton; John Avera; Kimberly McCoy; Alayna Caffrey; Ann Harmsen; Trevor Douglas; Agnieszka Rynda-Apple. 2017. "Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent." mBio 8, no. 6: e01356-17.
Bacterial superinfections are a primary cause of death during influenza pandemics and epidemics. Type I interferon (IFN) signaling contributes to increased susceptibility of mice to bacterial superinfection around day 7 post-influenza A virus (IAV) infection. Here we demonstrate that the reduced susceptibility to methicillin-resistant Staphylococcus aureus (MRSA) at day 3 post-IAV infection, which we previously reported was due to interleukin-13 (IL-13)/IFN-γ responses, is also dependent on type I IFN signaling and its subsequent requirement for protective IL-13 production. We found, through utilization of blocking antibodies, that reduced susceptibility to MRSA at day 3 post-IAV infection was IFN-β dependent, whereas the increased susceptibility at day 7 was IFN-α dependent. IFN-β signaling early in IAV infection was required for MRSA clearance, whereas IFN-α signaling late in infection was not, though it did mediate increased susceptibility to MRSA at that time. Type I IFN receptor (IFNAR) signaling in CD11c + and Ly6G + cells was required for the observed reduced susceptibility at day 3 post-IAV infection. Depletion of Ly6G + cells in mice in which IFNAR signaling was either blocked or deleted indicated that Ly6G + cells were responsible for the IFNAR signaling-dependent susceptibility to MRSA superinfection at day 7 post-IAV infection. Thus, during IAV infection, the temporal differences in type I IFN signaling increased bactericidal activity of both CD11c + and Ly6G + cells at day 3 and reduced effector function of Ly6G + cells at day 7. The temporal differential outcomes induced by IFN-β (day 3) and IFN-α (day 7) signaling through the same IFNAR resulted in differential susceptibility to MRSA at 3 and 7 days post-IAV infection. IMPORTANCE Approximately 114,000 hospitalizations and 40,000 annual deaths in the United States are associated with influenza A virus (IAV) infections. Frequently, these deaths are due to community-acquired Gram-positive bacterial species, many of which show increasing resistance to antibiotic therapy. Severe complications, including parapneumonic empyema and necrotizing pneumonia, can arise, depending on virulence factors expressed by either the virus or bacteria. Unfortunately, we are unable to control the expression of these virulence factors, making host responses a logical target for therapeutic interventions. Moreover, interactions between virus, host, and bacteria that exacerbate IAV-related morbidities and mortalities are largely unknown. Here, we show that type I interferon (IFN) expression can modulate susceptibility to methicillin-resistant Staphylococcus aureus (MRSA) infection, with IFN-β reducing host susceptibility to MRSA infection while IFN-α increases susceptibility. Our data indicate that treatments designed to augment IFN-β and/or inhibit IFN-α production around day 7 post-IAV infection could reduce susceptibility to deadly superinfections.
Kelly M. Shepardson; Kyle Larson; Rachelle V. Morton; Justin R. Prigge; Edward E. Schmidt; Victor C. Huber; Agnieszka Rynda-Apple. Differential Type I Interferon Signaling Is a Master Regulator of Susceptibility to Postinfluenza Bacterial Superinfection. mBio 2016, 7, e00506-16 .
AMA StyleKelly M. Shepardson, Kyle Larson, Rachelle V. Morton, Justin R. Prigge, Edward E. Schmidt, Victor C. Huber, Agnieszka Rynda-Apple. Differential Type I Interferon Signaling Is a Master Regulator of Susceptibility to Postinfluenza Bacterial Superinfection. mBio. 2016; 7 (3):e00506-16.
Chicago/Turabian StyleKelly M. Shepardson; Kyle Larson; Rachelle V. Morton; Justin R. Prigge; Edward E. Schmidt; Victor C. Huber; Agnieszka Rynda-Apple. 2016. "Differential Type I Interferon Signaling Is a Master Regulator of Susceptibility to Postinfluenza Bacterial Superinfection." mBio 7, no. 3: e00506-16.
Superinfection in mice at day 7 postinfluenza infection exacerbates bacterial pneumonia at least in part via downstream effects of increased IFN-γ signaling. Here we show that up to 3 days postinfluenza infection, mice have reduced susceptibility to superinfection with methicillin-resistant Staphylococcus aureus (MRSA), but that superinfection during that time exacerbated influenza disease. This was due to IL-13 signaling that was advantageous for resolving MRSA infection via inhibition of IFN-γ, but was detrimental to the clearance of influenza virus. However, if superinfection did not occur until the near resolution of influenza infection (day 7), IL-13 signaling was inhibited, at least in part by upregulation of IL-13 decoy receptor (IL-13Rα2), which in turn caused increases in IFN-γ signaling and exacerbation of bacterial infection. Understanding these cytokine sequelae is critical to development of immunotherapies for influenza-MRSA coinfection since perturbations of these sequelae at the wrong time could increase susceptibility to MRSA and/or influenza.
Agnieszka Rynda-Apple; Ann Harmsen; Anfin S. Erickson; Kyle Larson; Rachelle V. Morton; Laura E. Richert; Allen G. Harmsen. Regulation of IFN-γ by IL-13 dictates susceptibility to secondary postinfluenza MRSA pneumonia. European Journal of Immunology 2014, 44, 3263 -3272.
AMA StyleAgnieszka Rynda-Apple, Ann Harmsen, Anfin S. Erickson, Kyle Larson, Rachelle V. Morton, Laura E. Richert, Allen G. Harmsen. Regulation of IFN-γ by IL-13 dictates susceptibility to secondary postinfluenza MRSA pneumonia. European Journal of Immunology. 2014; 44 (11):3263-3272.
Chicago/Turabian StyleAgnieszka Rynda-Apple; Ann Harmsen; Anfin S. Erickson; Kyle Larson; Rachelle V. Morton; Laura E. Richert; Allen G. Harmsen. 2014. "Regulation of IFN-γ by IL-13 dictates susceptibility to secondary postinfluenza MRSA pneumonia." European Journal of Immunology 44, no. 11: 3263-3272.
The importance of the priming of the lung environment by past infections is being increasingly recognized. Exposure to any given antigen can either improve or worsen the outcome of subsequent lung infections, depending on the immunological history of the host. Thus, an ability to impart transient alterations in the lung environment in anticipation of future insult could provide an important novel therapy for emerging infectious diseases. In this study, we show that nasal administration of virus-like particles (VLPs) before, or immediately after, lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA) of mice i) ensures complete recovery from lung infection and near absolute clearance of bacteria within 12 hours of challenge, ii) reduces host response-induced lung tissue damage, iii) promotes recruitment and efficient bacterial clearance by neutrophils and CD11c+ cells, and iv) protects macrophages from MRSA-induced necrosis. VLP-mediated protection against MRSA relied on innate immunity. Complete recovery occurred in VLP-dosed mice with severe combined immunodeficiency, but not in wild-type mice depleted of either Ly6G+ or CD11c+ cells. Early IL-13 production associated with VLP-induced CD11c+ cells was essential for VLP-induced protection. These results indicate that VLP-induced alteration of the lung environment protects the host from lethal MRSA pneumonia by enhancing phagocyte recruitment and killing and by reducing inflammation-induced tissue damage via IL-13–dependent mechanisms.
Agnieszka Rynda-Apple; Erin Dobrinen; Mark McAlpine; Amanda Read; Ann Harmsen; Laura E. Richert; Matthew Calverley; Kyler Pallister; Jovanka Voyich; James A. Wiley; Ben Johnson; Mark Young; Trevor Douglas; Allen G. Harmsen. Virus-Like Particle-Induced Protection Against MRSA Pneumonia Is Dependent on IL-13 and Enhancement of Phagocyte Function. The American Journal of Pathology 2012, 181, 196 -210.
AMA StyleAgnieszka Rynda-Apple, Erin Dobrinen, Mark McAlpine, Amanda Read, Ann Harmsen, Laura E. Richert, Matthew Calverley, Kyler Pallister, Jovanka Voyich, James A. Wiley, Ben Johnson, Mark Young, Trevor Douglas, Allen G. Harmsen. Virus-Like Particle-Induced Protection Against MRSA Pneumonia Is Dependent on IL-13 and Enhancement of Phagocyte Function. The American Journal of Pathology. 2012; 181 (1):196-210.
Chicago/Turabian StyleAgnieszka Rynda-Apple; Erin Dobrinen; Mark McAlpine; Amanda Read; Ann Harmsen; Laura E. Richert; Matthew Calverley; Kyler Pallister; Jovanka Voyich; James A. Wiley; Ben Johnson; Mark Young; Trevor Douglas; Allen G. Harmsen. 2012. "Virus-Like Particle-Induced Protection Against MRSA Pneumonia Is Dependent on IL-13 and Enhancement of Phagocyte Function." The American Journal of Pathology 181, no. 1: 196-210.