Abstract
Mycobacterial diseases of cattle are responsible for considerable production losses worldwide. In addition to their importance in animals, these infections offer a nuanced approach to understanding persistent mycobacterial infection in native host species. Mycobacterium avium ssp. paratuberculosis (MAP) is an enteric pathogen that establishes a persistent, asymptomatic infection in the small intestine. Difficulty in reproducing infection in surrogate animal models and limited understanding of mucosal immune responses that control enteric infection in the natural host have been major barriers to MAP vaccine development. We previously developed a reproducible challenge model to establish a consistent MAP infection using surgically isolated intestinal segments prepared in neonatal calves. In the current study, we evaluated whether intestinal segments could be used to screen parenteral vaccines that alter mucosal immune responses to MAP infection. Using Silirum® – a commercial MAP bacterin – we demonstrate that intestinal segments provide a platform for assessing vaccine efficacy within a relatively rapid period of 28 days post-infection. Significant differences between vaccinates and non-vaccinates could be detected using quantitative metrics including bacterial burden in intestinal tissue, MAP shedding into the intestinal lumen, and vaccine-induced mucosal immune responses. Comparing vaccine-induced responses in mucosal leukocytes isolated from the site of enteric infection versus blood leukocytes revealed substantial inconsistences between these immune compartments. Moreover, parenteral vaccination with Silirum did not induce equal levels of protection throughout the small intestine. Significant control of MAP infection was observed in the continuous but not the discrete Peyer’s patches. Analysis of these regional mucosal immune responses revealed novel correlates of immune protection associated with reduced infection that included an increased frequency of CD335+ innate lymphoid cells, and increased expression of IL21 and IL27. Thus, intestinal segments provide a novel model to accelerate vaccine screening and discovery by testing vaccines directly in the natural host and provides a unique opportunity to interrogate mucosal immune responses to mycobacterial infections.
Highlights
The majority of pathogenic mycobacteria are mucosal pathogens that establish a chronic state of infection
The continuous PP (CPP) is the predominant site of persistent Mycobacterium avium ssp. paratuberculosis (MAP) infection in cattle [29, 33, 45, 46]
The failure of caprine discrete Peyer’s patches (DPP) to control MAP infection differs from our observations that MAP-infection was controlled in bovine DPP at 12 months post-infection with no development of lesions [29]
Summary
The majority of pathogenic mycobacteria are mucosal pathogens that establish a chronic state of infection. With no effective vaccine to control or prevent infection, Johne’s disease remains endemic in cattle, sheep and goats [1] and contributes to significant global production losses [2,3,4]. The development of an effective MAP vaccine remains an elusive goal despite decades of research [9] primarily due to the lack of understanding the mucosal immune responses that control enteric MAP infections within the natural host (i.e., cattle, goat, and sheep). Such analyses may provide new insights into mucosal mycobacterial diseases in humans and other animal host species [10]
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