Oral Administration of Lactococcus lactis Producing Interferon Type II, Enhances the Immune Response Against Bacterial Pathogens in Rainbow Trout Alvaro Santibañez 1,2 , Diego Paine 1,2 , Mick Parra 1,2 , Carlos Muñoz 1,2 , Natalia Valdes 1,2 , Claudia Zapata 1,2 , Rodrigo Vargas 1 , Alex Gonzalez 3 and Mario Tello 1,2,4 * 1 Departamento de Biologı ´a, Laboratorio de Metageno ´ mica Bacteriana, Facultad de Quı ´mica y Biologı ´a, Universidad de Santiago de Chile, Santiago, Chile, 2 Consorcio Tecnolo ´ gico de Sanidad Acuı ´cola, Ictio Biotechnologies S.A., Santiago, Chile, 3 Laboratorio de Microbiologı ´a Ambiental y Extremo ´ filos, Departamento de Ciencias Biolo ´ gicas, Universidad de los Lagos, Osorno, Chile, 4 IctioBiotic SpA, Santiago, Chile Lactic acid bacteria are a powerful vehicle for releasing of cytokines and immunostimulant peptides at the gastrointestinal level after oral administration. However, its therapeutic application against pathogens that affect rainbow trout and Atlantic salmon has been little explored. Type II interferon in Atlantic salmon activates the antiviral response, protecting against viral infection, but its role against bacterial infection has not been tested in vivo. In this work, through the design of a recombinant lactic acid bacterium capable of producing Interferon gamma from Atlantic salmon, we explore its role against bacterial infection and the ability to stimulate systemic immune response after oral administration of the recombinant probiotic. Recombinant interferon was active in vitro, mainly stimulating IL-6 expression in SHK-1 cells. In vivo, oral administration of the recombinant probiotic produced an increase in IL-6, IFNg and IL-12 in the spleen and kidney, in addition to stimulating the activity of lysozyme in serum. The challenge trials indicated that the administration of the IFNg-producing probiotic doubled the survival in fish infected with F. psychrophilum. In conclusion, our results showed that the oral administration of lactic acid bacteria producing IFNg managed to stimulate the immune response at a systemic level, conferring protection against pathogens, showing a biotechnological potential for its application in aquaculture. Keywords: Lactococcus lactis, interferon type II, Flavobacterium psychrophilum, salmonids, oral administration INTRODUCTION Interferons are a group of cytokines originally discovered by its antiviral properties (1). In mammals, these cytokines can be classified in three families according their homology, receptors, structure and function (2). Interferon types I and III are multi-gene families (17 type I and four type III) strongly induced by viruses, playing a major role controlling viral infection (3–5). Interferon Frontiers in Immunology | www.frontiersin.org June 2021 | Volume 12 | Article 696803 1 Edited by: Peter Bossier, Ghent University, Belgium Reviewed by: Kerry Lynne Bartie, University of Stirling, United Kingdom Patricia Diaz-Rosales, Centro de Investigacio ´ n en Sanidad Animal (CISA), Spain *Correspondence: Mario Tello mario.tello@usach.cl Specialty section: This article was submitted to Comparative Immunology, a section of the journal Frontiers in Immunology Received: 17 April 2021 Accepted: 08 June 2021 Published: 25 June 2021 Citation: Santibañez A, Paine D, Parra M, Muñoz C, Valdes N, Zapata C, Vargas R, Gonzalez A and Tello M (2021) Oral Administration of Lactococcus lactis Producing Interferon Type II, Enhances the Immune Response Against Bacterial Pathogens in Rainbow Trout. Front. Immunol. 12:696803. doi: 10.3389/fimmu.2021.696803 ORIGINAL RESEARCH published: 25 June 2021 doi: 10.3389/fimmu.2021.696803