Oral vaccination stimulates neutrophil functionality and exerts protection in a Mycobacterium avium subsp. paratuberculosis infection model

Iraia Ladero-Auñon,Diego Barriales,Rakel Arrazuria,Elena Molina,Miguel Fuertes,Juan Anguita,Lucy Luo,Jeroen De Buck,Maddi Oyanguren,Natalia Elguezabal,Iker A Sevilla

doi:10.1038/s41541-021-00367-8

Abstract

Mycobacterium avium subsp. paratuberculosis (Map) causes paratuberculosis (PTB), a granulomatous enteritis in ruminants that exerts high economic impact on the dairy industry worldwide. Current vaccines have shown to be cost-effective against Map and in some cases confer beneficial non-specific effects against other pathogens suggesting the existence of trained immunity. Although Map infection is mainly transmitted by the fecal-oral route, oral vaccination has not been deeply studied. Therefore, the aim of this study was to compare the oral route with a set of mycobacterial and non-mycobacterial vaccines with a subcutaneously administered commercially available vaccine. Training effects on polymorphonuclear neutrophils (PMNs) and homologous and heterologous in vivo protection against Map were investigated in the rabbit infection model. Oral vaccination with inactivated or live vaccines was able to activate mucosal immunity as seen by elevation of serum IgA and the expression of IL4 in peripheral blood mononuclear cells (PBMCs). In addition, peripheral PMN phagocytosis against Map was enhanced by vaccination and extracellular trap release against Map and non-related pathogens was modified by both, vaccination and Map-challenge, indicating trained immunity. Finally, PBMCs from vaccinated animals stimulated in vitro with Map antigens showed a rapid innate activation cytokine profile. In conclusion, our data show that oral vaccination against PTB can stimulate neutrophil activity and both innate and adaptive immune responses that correlate with protection.

Highlights

Johne’s disease or paratuberculosis (PTB) is an infectious granulomatous enteritis that primarily affects domestic[1] and wild[2] ruminants, it has been detected in other non-ruminant species including rabbits[3,4] and birds, among others[5].Mycobacterium avium subspecies paratuberculosis (Map), the etiological agent of the disease, is an intracellular bacterium that is transmitted through the fecal-oral route
A commercial inactivated Mycobacterium avium subsp. paratuberculosis (Map) vaccine has shown heterologous protection against other mycobacterial infections[11] and reduction in overall mortality in dairy cattle[12], effects that could emerge from innate trained mechanisms or from cross-reactive T-cell mediated adaptive immunity. This vaccine has shown priming of monocytederived macrophages as seen by increased Map killing activity compared to non-vaccinated animals[13]. All these findings suggest that trained immunity, such as that observed with the BCG vaccine in human newborns against Mycobacterium tuberculosis (Mtb), Candida albicans, and Staphylococcus aureus, can be behind this effect[14]
One of the main mechanisms that contribute to bacterial clearance by polymorphonuclear neutrophils (PMNs) is phagocytosis so we assessed if oral vaccination would affect PMN phagocytic capacity

Summary

Introduction

Mycobacterium avium subspecies paratuberculosis (Map), the etiological agent of the disease, is an intracellular bacterium that is transmitted through the fecal-oral route It ensures its survival and dissemination by infecting macrophages and exerting evasion mechanisms that permit its replication inside this immune cell. A commercial inactivated Map vaccine has shown heterologous protection against other mycobacterial infections[11] and reduction in overall mortality in dairy cattle[12], effects that could emerge from innate trained mechanisms or from cross-reactive T-cell mediated adaptive immunity. This vaccine has shown priming of monocytederived macrophages as seen by increased Map killing activity compared to non-vaccinated animals[13]. All these findings suggest that trained immunity, such as that observed with the BCG vaccine in human newborns against Mycobacterium tuberculosis (Mtb), Candida albicans, and Staphylococcus aureus, can be behind this effect[14]

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