Characterization of the NLRP1 inflammasome response in bovine species

Authors: VRENTAS, CATHERINE - US Department Of Agriculture (USDA); Boggiatto, Paola; Olsen, Steven; LEPPLA, STEPHEN - National Institutes Of Health (NIH); MOAYERI, MAHTAB - National Institutes Of Health (NIH)

Submitted to: Innate Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/26/2019
Publication Date: 5/1/2020
Citation: Vrentas, C.E., Boggiatto, P.M., Olsen, S.C., Leppla, S.H., Moayeri, M. 2020. Characterization of the NLRP1 inflammasome response in bovine species. Innate Immunity. 26(4):301-311. https://doi.org/10.1177/1753425919886649.
DOI: https://doi.org/10.1177/1753425919886649

Interpretive Summary: While our understanding of the immune systems of rodent models like mice and rats is detailed, much less is known about the immune responses of livestock to important pathogens. In this manuscript, we examine the "NLRP1 inflammasome" response of a type of immune cells called macrophages. Inflammasomes are systems by which humans and animals can sense the invasion of foreign material, like bacteria. The NLRP1 inflammasome in particular can detect certain bacterial toxins, such as lethal toxin, and may be important in the response of cattle to intracellular bacteria, which include Shigella and Brucella, causative agents of shigellosis and brucellosis. Here, we provide the first characterization of the NLRP1 inflammasome in cattle, using the bacterial toxin called LT, which is a know activator of the NLRP1 inflammasome in rodents, as a means of probing the response of bovine NLRP1. Additionally, we assess the NLRP1 inflammasome in cells from American bison. We demonstrate that consistent with the evolutionary similarity of the bovine NLRP1 protein sequence to the human NLRP1 sequence, the response of cattle macrophages to activators of NLRP1 is similar to the human macrophage response, but distinct from the response of sensitive mouse macrophages. We provide a detailed characterization of the forms of NLRP1 that are produced in cattle cells, and relate our findings to the nature of the bovine immune system as compared to other species (rodents and humans). Overall, this manuscript adds to our understanding of the immune response mechanisms of cattle and bison to bacteria and their toxins.

Technical Abstract: Inflammasomes act as sensors of infection or damage to initiate immune responses. While extensively studied in rodents, understanding of livestock inflammasomes is limited. The NLRP1 inflammasome in rodents is a sensor for Toxoplasma gondii, the Bacillus anthracis lethal toxin (LT), and potentially other zoonotic pathogens. LT activates NLRP1 by N-terminal proteolysis, inducing pyroptosis of macrophages and a proinflammatory cytokine response. In contrast, NLRP1 in macrophages from humans and certain rodent strains is resistant to LT cleavage and pyroptosis. Evolution of NLRP1 sequences towards pyroptosis is of interest in understanding the innate immune response to pathogens in different hosts. Therefore, we characterized NLRP1 in cattle (Bos taurus) and American bison (Bison bison). Bovine NLRP1 is not cleaved by LT, and macrophages from cattle and bison do not undergo pyroptosis. Resistance to LT in both bovine and human NLRP1 correlated with their evolutionary sequence similarity. Consistent with LT-resistant rodents, bovine macrophages undergo slow death in the presence of LPS and LT. Additionally, we found a predicted Nlrp1 splicing isoform in cattle macrophages that lacks the N-terminal domain. Overall, our findings support the model that NLRP1 activation by LT requires N-terminal cleavage, and provide novel information about diversity of immune responses across species.