Bovine Gamma Delta T Cells Contribute to Exacerbated IL-17 Production in Response to Co-Infection with Bovine RSV and Mannheimia haemolytica

Abstract

Human respiratory syncytial virus (HRSV) is a leading cause of severe lower respiratory tract infection in children under five years of age. IL-17 and Th17 responses are increased in children infected with HRSV and have been implicated in both protective and pathogenic roles during infection. Bovine RSV (BRSV) is genetically closely related to HRSV and is a leading cause of severe respiratory infections in young cattle. While BRSV infection in the calf parallels many aspects of human infection with HRSV, IL-17 and Th17 responses have not been studied in the bovine. Here we demonstrate that calves infected with BRSV express significant levels of IL-17, IL-21 and IL-22; and both CD4 T cells and γδ T cells contribute to this response. In addition to causing significant morbidity from uncomplicated infections, BRSV infection also contributes to the development of bovine respiratory disease complex (BRDC), a leading cause of morbidity in both beef and dairy cattle. BRDC is caused by a primary viral infection, followed by secondary bacterial pneumonia by pathogens such as Mannheimia haemolytica. Here, we demonstrate that in vivo infection with M. haemolytica results in increased expression of IL-17, IL-21 and IL-22. We have also developed an in vitro model of BRDC and show that co-infection of PBMC with BRSV followed by M. haemolytica leads to significantly exacerbated IL-17 production, which is primarily mediated by IL-17-producing γδ T cells. Together, our results demonstrate that calves, like humans, mount a robust IL-17 response during RSV infection; and suggest a previously unrecognized role for IL-17 and γδ T cells in the pathogenesis of BRDC.

Specific immune response in neonate Holstein heifer calves fed fresh or frozen colostrum

“…The full complement of gamma--delta cells represents all of the described activities for these cells, including their APC and cytokine producing roles. As calves from both treatment groups demonstrated early IL-17 production followed by the capacity to produce IFN--gamma, the data from this project is relatively consistent with the earlier reports by McGill et al (2014McGill et al ( , 2016. Still, the function of the high number of gamma-delta cells in neonate calves needs to be better defined in future studies.…”

Regulatory T cells and T helper 17 cells in viral infection

“…Studies have shown that an elevated level of IL‐17 was found in the peripheral blood of RSV‐infected infants and calves, suggesting that the differentiation of Th17 cells may be induced during RSV infection . Later, it was further confirmed that the increase in Th17 cell number was not present in healthy infants but only in infants with RSV infection .…”

Bovine respiratory syncytial virus infection enhances Pasteurella multocida adherence on respiratory epithelial cells

“…These cytokines play important roles in BRDC-related pneumonia. Cytokines and other mediators released by bovine cells and virus-infected cells contribute to the pathogenesis of BRDC by inducing leukocyte recruitment, attachment, and activation (N'jai et al, 2013;McGill et al, 2016). BHV-1 infection of bovine bronchial epithelial cells (Rivera-Rivas et al, 2009) and mononuclear cells (Leite et al, 2004) triggers cytokine expression; these cytokines then recruit and activate neutrophils and exacerbate the detrimental effects of MH.…”