Multiple pathways can lead to TB disease, from opposing immunological extremes.

Generally, these can be viewed as immune deficiencies or immune excess, but the majority of patients who develop TB are relatively young with a competent immune response, illustrating the complexity of this spectrum. Though not quantitative, font size relates to contribution to global incidence. Left arrow: Ghon focus at lung base; Right arrow: cavity at lung apex.

Selection pressure of prolonged co-evolution favours individuals permissive to asymptomatic Mtb colonisation but resistant to active disease.

Over millennia, Mtb circulation in society will remove genetic traits that cause high susceptibility to active TB infection. Perhaps less intuitively, if Mtb generates trained immunity that protects against other fatal diseases, individuals with low susceptibility to initial Mtb infection will also be selected against due to increased mortality from other infections. The resulting population would then reflect modern humans; highly susceptible to initial Mtb colonisation but with low susceptibility to TB disease.

Schematic of the interactions needed for Mtb to escape the host immune response.

As control of Mtb requires a co-ordinated host response, there are multiple sequences of immune events that can ultimately result in progression to active TB disease. A major immune disturbance, such as TNF-α or PD-1 inhibition, gives a relatively direct pathway to active TB. However, most individuals develop TB due to a series of less apparent immune events and no clear global immune disturbance that can be identified by current immune profiling approaches.