Senecavirus A (SVA), an emerging picornavirus of swine, causes vesicular disease (VD) that is clinically indistinguishable from foot-and-mouth disease (FMD) in pigs. Many aspects of SVA interactions with the host and the host immune responses to infection, however, remain unknown. In the present study, humoral and cellular immune responses to SVA were evaluated following infection in pigs. We show that SVA infection elicited an early and robust virus-neutralizing (VN) antibody response, which coincided and was strongly correlated with VP2- and VP3-specific IgM responses. Notably, the neutralizing antibody (NA) responses paralleled the reduction of viremia and resolution of the disease. Analysis of the major porcine T-cell subsets revealed that during the acute/clinical phase of SVA infection (14 days postinfection [p.i.]), T-cell responses were characterized by an increased frequency of αβ T cells, especially CD4 T cells, which were first detected by day 7 p.i. and increased in frequency until day 14 p.i. Additionally, the frequency of CD8 and double-positive CD4 CD8 T cells (effector/memory T cells) expressing interferon gamma (IFN-γ) or proliferating in response to SVA antigen stimulation increased after day 10 p.i. Results presented here show that SVA elicits B- and T-cell activation early upon infection, with IgM antibody levels being correlated with early neutralizing activity against the virus and peak B- and T-cell responses paralleling clinical resolution of the disease. The work provides important insights into the immunological events that follow SVA infection in the natural host. Senecavirus A (SVA) has recently emerged in swine, causing outbreaks of vesicular disease (VD) in major swine-producing countries around the world, including the United States, Brazil, China, Thailand, and Colombia. Notably, SVA-induced disease is clinically indistinguishable from other high-consequence VDs of swine, such as FMD, swine vesicular disease, vesicular stomatitis, and vesicular exanthema of swine. Despite the clinical relevance of SVA-induced VD, many aspects of the virus infection biology remain unknown. Here, we assessed host immune responses to SVA infection. The results show that SVA infection elicits early B- and T-cell responses, with the levels of VN antibody and CD4 T-cell responses paralleling the reduction of viremia and resolution of the disease. SVA-specific CD8 T cells are detected later during infection. A better understanding of SVA interactions with the host immune system may allow the design and implementation of improved control strategies for this important pathogen of swine.
Cultured IFN-γ ELISPOT assays are primarily a measure of central memory T cell (Tcm) responses with humans; however, this important subset of lymphocytes is poorly characterized in cattle. Vaccine-elicited cultured IFN-γ ELISPOT responses correlate with protection against bovine tuberculosis in cattle. However, whether this assay measures cattle Tcm responses or not is uncertain. The objective of the present study was to characterize the relative contribution of Tcm (CCR7+, CD62Lhi, CD45RO+), T effector memory (Tem, defined as: CCR7-, CD62Llow/int, CD45RO+), and T effector cells (CCR7-, CD62L-/low, CD45RO-), in the immune response to Mycobacterium bovis. Peripheral blood mononuclear cells (PBMC) from infected cattle were stimulated with a cocktail of M. bovis purified protein derivative, rTb10.4 and rAg85A for 13 days with periodic addition of fresh media and rIL-2. On day 13, cultured PBMC were re-stimulated with medium alone, rESAT-6:CFP10 or PPDb with fresh autologous adherent cells for antigen presentation. Cultured cells (13 days) or fresh PBMCs (ex vivo response) from the same calves were analyzed for IFN-γ production, proliferation, and CD4, CD45RO, CD62L, CD44, and CCR7 expression via flow cytometry after overnight stimulation. In response to mycobacterial antigens, ~75% of CD4+ IFN-γ+ cells in long-term cultures expressed a Tcm phenotype while less than 10% of the ex vivo response consisted of Tcm cells. Upon re-exposure to antigen, long-term cultured cells were highly proliferative, a distinctive characteristic of Tcm, and the predominant phenotype within the long-term cultures switched from Tcm to Tem. These findings suggest that proliferative responses of Tcm cells to some extent occurs simultaneously with reversion to effector phenotypes (mostly Tem). The present study characterizes Tcm cells of cattle and their participation in the response to M. bovis infection.
Bovine tuberculosis of cattle results primarily from infection with Mycobacterium bovis, a member of the Mycobacterium tuberculosis complex. Despite intensive control efforts, bovine tuberculosis persists as a costly disease, with adverse impacts on animal health and welfare, the trade of animals and animal products, and the livelihoods of producers. In addition, the persistence of this disease necessitates the maintenance of costly regional and federal networks for control/eradication campaigns. The mainstays of bovine tuberculosis control are (i) abattoir surveillance with epidemiological investigations after detection of M. bovisinfected animals, to identify bovine tuberculosis-affected herds (1); (ii) application of antemortem testing for routine surveillance, movement of animals, and identification and removal of infected animals from tuberculosis-affected herds (2); and (iii) management of the disease in wildlife reservoirs, such as whitetailed deer in Michigan (3), brushtail possums (Trichosurus vulpecula) in New Zealand, Eurasian wild boar (Sus scrofa) and red deer (Cervus elaphus) in Spain (4), and Eurasian badgers (Meles meles) in the United Kingdom/Ireland (5). Tuberculin-based cellular immune assays, including measurements of in vitro interferon gamma release and measurements of delayed-type hypersensitivity (DTH) reactions via skin test procedures, are the principal diagnostic tests used for the control of bovine tuberculosis in cattle in most countries (6, 7). In the United States, the caudal fold test (CFT) (intradermal injection of M. bovis purified protein derivative [PPD] in the caudal skin fold) is used as a primary test and the comparative cervical test (CCT) (intradermal injection of Mycobacterium avium and M. bovis PPDs at separate sites in the neck) and the Bovigam assay (Prionics Ag, Schlieren, Switzerland) (an interferon gamma release assay) are used as secondary or confirmatory tests (8).Several serological tests designed to detect antibodies (Abs) to immunodominant M. bovis antigens (e.g., MPB83, MPB70, ESAT-6, and CFP10) have emerged for potential application in cattle (9-13). A commercial enzyme-linked immunosorbent assay (ELISA) for MPB83 and MPB70 (M. bovis Ab test; IDEXX Laboratories, Westbrook, ME) (9) has been approved by the Office International des Epizooties and the U.S. Department of Agriculture (USDA) for use in cattle in bovine tuberculosis control programs, although applications of this test are primarily limited to ancillary purposes such as confirmation of infections and potentially detection of M. bovis-infected cattle anergic in the skin test. A
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