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Abstract
The DosR regulon and the Enduring Hypoxic Response (EHR) define a group of M. tuberculosis genes that are specifically induced in bacilli exposed in vitro to conditions thought to mimic the environment encountered by Mycobacteria during latent infection. Although well described in humans, latent mycobacterial infection in cattle remains poorly understood. Thus, the aim of this study was to identify antigens that may potentially disclose cattle with latent M. bovis infection. To this end, we initially screened 57 pools of overlapping peptides representing 4 DosR regulon and 29 EHR antigens for their ability to stimulate an immune response in whole blood from TB-reactor cattle using IFN-γ and IL-2 as readouts. All 4 DosR regulon proteins were poorly recognized (maximum responder frequency of 10%). For the EHR antigens, both IFN-γ and IL-2 revealed similar response hierarchies, with responder frequencies ranging from 54% down to 3% depending on the given EHR antigen. Furthermore, these results demonstrated that responses in the infected cattle were largely IFN-γ biased. To support the concept for their role in latency, we evaluated if EHR antigen responses were associated with lower pathology. The EHR antigen Rv0188 was recognised predominantly in animals presenting with low pathology scores, whereas responses to ESAT-6/CFP-10 or the other EHR antigens tested were prevalent across the pathology spectrum. However, when we determined the production of additional cytokines induced by the M. bovis antigens PPD-B or ESAT-6/CFP-10, we detected significantly greater PPD-B-induced production of the pro-inflammatory cytokine IL-1β in animals recognizing Rv0188 (i.e. those with limited or no pathology). Thus, these results are consistent with the idea that responses to Rv0188 may identify a subset of animals at early stages of infection or in which disease progression may be limited.
Highlights
Tuberculosis (TB) is a mycobacterial infection that affects numerous species of mammals and poses a major global threat to both public health and the farming industry
To investigate the immunogenicity of potential stage-specific antigens, a total of 57 pools of overlapping peptides representing 4 DosR regulon and 29 Enduring Hypoxic Response (EHR) antigens (Table S1) were screened for their ability to stimulate an immune response in whole blood from TB-reactor cattle
As initial experiments revealed that the DosR regulon proteins were poorly recognized, we focused our attention on the panel of EHR antigens (Figure 1)
Summary
Tuberculosis (TB) is a mycobacterial infection that affects numerous species of mammals and poses a major global threat to both public health and the farming industry. Following exposure to Mycobacterium tuberculosis (M. tb), only a small percentage of individuals (5 to 10%) will progress to a clinically active stage of disease within the first two years, with symptoms including fever, weight loss, coughing, the presence of acid-fast bacilli in sputa or other clinical samples and abnormal chest radiographs. The majority of M. tb-infected individuals are able to control disease progression through the induction of a robust cellmediated immune response. Despite the absence of clinical disease, mycobacteria remain viable in these individuals for many years [1]. These ‘‘latent’’ mycobacterial infections have the potential to reactivate to active disease [2], probably as a consequence of events resulting in host immunosupression [2,3,4]. Based on the tuberculin skin test, it is thought that one-third of the world’s population is latently infected with M. tb, which presents an enormous reservoir from which contagious TB disease may arise
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