Host-directed therapy in diabetes and tuberculosis comorbidity, towards global TB elimination

Host-directed therapy could potentially revolutionise tuberculosis control, as adjunct to traditional antibiotics for the treatment of tuberculosis disease, and as a strategy to prevent disease progression following Mycobacterium tuberculosis infection. The growing type 2 diabetes pandemic is hampering tuberculosis control worldwide, as people with diabetes have an increased risk of developing tuberculosis disease as well as worse treatment outcomes. Pulmonary tuberculosis is characterised by an inflammatory response which can cause alveolar tissue destruction and cavitation, and this inflammation is exacerbated in people with tuberculosis-diabetes comorbidity. Thus, the reduction of the inflammatory response is a key goal of host-directed therapy to dampen immunopathology, but it is vital that the inflammatory response is not suppressed too much or the immune system will not be able to react to Mycobacterium tuberculosis and mycobacterial replication will intensify. Furthermore, the type I interferon response and host cell metabolism are further dysregulated in tuberculosis-diabetes comorbidity, likely contributing to poor treatment outcomes. Achieving the right balance in terms of modulating the inflammatory and immune responses, both quantitatively and temporally, is more complex in tuberculosis-diabetes comorbidity and this population should be included specifically in clinical trials of new regimen. In this regard, mathematical modelling has a key role in elucidating which biological pathways should be targeted in different people. Host-directed therapy for people with tuberculosis-diabetes comorbidity will reduce immunopathology and post-tuberculosis lung disease, as well as boost microbiological cure and treatment outcomes, and thus help in the fight towards global tuberculosis elimination.