Ocular Tuberculosis: A One Health multiparameter approach to diagnosis

In humans, ocular tuberculosis (OTB) can be associated with significant morbidity leading to blindness if not correctly diagnosed and treated. Diagnosing OTB is complicated by a lack of robust diagnostics, hence novel highly sensitive diagnostic tests are needed to replace those which are currently relied on. Using methodologies developed for the detection of pulmonary TB - such as direct microscopy and culture of Mycobacterium tuberculosis - have thus far proved insufficient, particularly in light of the associated risk in obtaining samples of fluid and tissue from the eye. More detailed understanding of the pathophysiology of tuberculous disease in the eye is required. In particular, understanding the mechanisms driving ocular inflammation and those underlying specific phenotypic presentations may allow for the development of evidence-based diagnostic guidelines and enable more appropriate treatment strategies.
Two recent publications highlight the importance of animal studies in providing insights that can be extrapolated to inform diagnosis and treatment of human OTB (Basu et al., 2020; Mitchell et al., 2020). Experimental animal models which allow in vivo imaging, histopathological and molecular analysis of tissue, and clinicopathological correlation would be particularly useful.
Currently, mouse, rabbit, and guinea pig models with M. tuberculosis are well-developed; mirroring human disease in their susceptibility to infection via a physiological route (inhalation) and their ability to mount an innate and acquired immune response (Basu et al., 2020). However, none of these models encompass the entire spectrum of human disease: this may reflect differences in timing, the type of exposure (acute versus chronic), latency, co-infections (etc.) that may be more accurately mimicked by natural infection models.
Naturally occurring ocular TB is observed in a number of species known to be infected with Mycobacterium bovis, including cattle, alpacas and domestic cats. This infection causes immunological and pathological changes similar to those observed in humans with M. tuberculosis, with cattle studies already providing valuable insights for human TB (Waters et al., 2011).
We propose to examine OTB in cattle, alpacas and domestic cats that are naturally infected with M. bovis, to describe the phenotypic changes in the eye and to further examine the inflammatory and infectious processes associated with OTB. This will be achieved in a multi-parametric approach using imaging to identify changes in the eye, molecular detection of bacteria within tissues, and immunological methods to examine the role of inflammation in the disease process. Through a well-established collaborative network of researchers and clinicians we have access to the tools, tissues and expertise required for this project.
We hypothesise that this study will provide significant insight leading to the development of improved diagnostic tests for OTB in humans and animals. It will also determine whether OTB has a direct cause (infection of the eye) or is an indirect consequence of infection elsewhere in the body; which will influence treatment regimes.
The data generated will be analysed and compared with available data from ongoing human clinical cases in collaboration with Mr Harry Petrushkin at Moorfields Eye Hospital. The project has potential benefits to both veterinary and human medicine the project fits well within the One Health remit.
References:
Basu S et al. Animal Models of Ocular Tuberculosis: Implications for Diagnosis and Treatment. Ocul Immunol Inflamm. 2020 4:1-7. doi: 10.1080/09273948.2020.1746358.
Mitchell JL et al. Ocular Tuberculosis: More than 'Of Mice and Men'. Ocul Immunol Inflamm. 2020 doi: 10.1080/09273948.2020.1797116.
Waters WR et al. Tuberculosis immunity: opportunities from studies with cattle. Clin Dev Immunol. 2011. DOI: 10.1155/2011/768542