Evaluating contribution of the cellular and humoral immune responses to the control of shedding of Mycobacterium avium spp. paratuberculosis in cattle.

Ad P. Koets,Don Klinkenberg,Vitaly V. Ganusov,Douwe Bakker

doi:10.1186/s13567-015-0204-1

Abstract

Mycobacterium avium spp. paratuberculosis (MAP) causes a persistent infection and chronic inflammation of the gut in ruminants leading to bacterial shedding in feces in many infected animals. Although there are often strong MAP-specific immune responses in infected animals, immunological correlates of protection against progression to disease remain poorly defined. Analysis of cross-sectional data has suggested that the cellular immune response observed early in infection is effective at containing bacterial growth and shedding, in contrast to humoral immune responses. In this study, 20 MAP-infected calves were followed for nearly 5 years during which MAP shedding, antigen-specific cellular (LPT) and humoral (ELISA) immune responses were measured. We found that MAP-specific cellular immune response developed slowly, with the peak of the immune response occurring one year post infection. MAP-specific humoral immunity expanded only in a subset of animals. Only in a subset of animals there was a statistically significant negative correlation between the amount of MAP shedding and magnitude of the MAP-specific cellular immune response. Direct fitting of simple mechanistic mathematical models to the shedding data suggested that MAP-specific immune responses contributed significantly to the kinetics of MAP shedding in most animals. However, whereas the MAP-specific cellular immune response was predicted to suppress shedding in some animals, in other animals it was predicted to increase shedding. In contrast, MAP-specific humoral response was always predicted to increase shedding. Our results illustrate the use of mathematical methods to understand relationships between mycobacteria and immunity in vivo but also highlight problems with establishing cause-effect links from observational data.Electronic supplementary materialThe online version of this article (doi:10.1186/s13567-015-0204-1) contains supplementary material, which is available to authorized users.

Highlights

Mycobacterial infections represent major health problems both in humans and in farm animals [1,2]
Only 6 correlations between Lymphocyte Proliferation Tests (LPT) and ELISA levels out of 20 animals were statistically significant (3 correlations were positive and 3 were negative, see Additional file 1) suggesting that in most animals, there was no evidence of competition or synergy between Mycobacterium avium subsp. paratuberculosis (MAP)-specific cellular and humoral immunity in contrast with the prevailing dogma on exclusiveness of these types of responses
Over the course of disease progression there is an expectation that MAP shedding should be inversely related to the magnitude of the MAP-specific cellular immune response and there should be negative correlation between cellular (Th1) and humoral (Th2) immunity [21]

Summary

Introduction

Mycobacterial infections represent major health problems both in humans and in farm animals [1,2]. Paratuberculosis (MAP) is the causative agent of Johne's disease in ruminants such as cows and sheep [3] causing chronic inflammation of the small intestine. Exposed animals enter a subclinical period of 2 to 5 years after which a proportion of the infected animals develops a severe enteropathy with chronic diarrhea and . The length of which varies greatly between cows, the animals progress into a phase of real or apparent intermittent fecal shedding but as the disease develops, shedding in feces becomes continuous [8]. There is a licensed vaccine against Johne’s disease, Mycopar®, which contains inactivated MAP with an oil adjuvant [9]. Mycopar® induces both MAP-specific cellular (CD4 T cells) and humoral (antibodies) responses but the correlates of protection against the infection or disease have not been clearly defined [6]. Understanding which arms of the immune response control bacterial replication will be instrumental for the development of more efficacious vaccines

Methods

Results

Conclusion