Host directed therapies (HDTs) and immune response signatures: insights into a role for interleukin-32

The clinical manifestations of recurrent episodes of TB reflect the complex interaction between Mycobacterium tuberculosis (M.tb) and the host immune response (1). There are an estimated 2 billion people in the world who have latent M.tb infection (LTBI) with no symptoms and signs of ill health. Co-evolution between M.tb and humans over centuries has established a delicate, balanced liaison between the host and pathogen (2). The clinical outcome of the encounter with M.tb in immune-competent individuals is apparently a success story: more than 90% of individuals exposed to M.tb (3) do not develop clinical TB. Therefore, TB provides a highly relevant paradigm of how optimally-activated and balanced host response networks tailor the outcome of an infection, which leads either to latent LTBI or to a life-threatening disease (4). Despite some advances in defining clinically relevant markers of immune protection against M.tb (5), the identification of host factors which enable protection to clinical TB remain elusive. Increasing evidence shows that biomarkers present in individuals with latent LTBI may represent components that orchestrate complex host anti-M.tb immune response networks and ultimately determine protection from expression of clinical TB disease. Contrary to this, M.tb infection can lead to intense immune and inflammatory responses which result in severe pulmonary pathology, eventually resulting in death. The paradigm that limiting overt inflammation in infectious diseases may result in benefit to the patient has been shown in settings of several infectious diseases, for example, the use of cytotoxic drugs such as etoposide and cyclosporine A, or limiting excessive inflammation and removing regulatory T cells (Tregs) in severe avian influenza A (H5N1) infection by (6), and use corticosteroids for the treatment of community—acquired pneumonia (7). The strength of inflammation is not only determined by the pathogen type [e.g., infection with the M.tb Beijing lineage that results in stronger pro-inflammatory responses (8)], but also by the host genetic background e.g., determined by SNPs associated with arachidonic acid metabolism, and pro-inflammatory cytokine receptors (8).