The immune system in the face of a widespread infection

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MT is the agent of tuberculosis, a complex bacillus that has co-evolved with man for at least 70,000 years. Tuberculosis has caused an estimated one billion deaths over the last 200 years. It is estimated that over 9 million people are infected each year, 13% of whom are co-infected with HIV. The ^20th century was marked by a decline in the incidence of infection, thanks to improvements in living conditions, diagnosis, treatment from 1950 onwards and, to a lesser extent, vaccination. The development of multi-resistant forms of TB to antimycobacterial agents (around 500,000 cases per year worldwide) is a cause for concern. The natural history of tuberculosis is marked by the fact that only 10% of infected subjects develop tuberculosis disease, while 90% remain latently infected. The primary lesion is a granuloma formed by MT-infected macrophages surrounded by recruited immune cells: dendritic cells, T and B lymphocytes. The granuloma may open up and disseminate the necrotic material present at its center, causing the disease to spread; alternatively, the granuloma may lead to sterilization of the lesion or long-term containment of the MTs it contains. Infected macrophages secrete factors that recruit (chemokines) and activate T (and B) lymphocytes. The production of interferon γ by TH1 lymphocytes confers on infected macrophages the ability to kill MT through several mechanisms, including the production of NO (nitric oxide). Hereditary immune system anomalies teach us that the production of oxygen radicals released by macrophages and the IL-12 interferon γ axis are essential for the control of mycobacterial infections, their defects being responsible for disseminated infections by mycobacteria even those lacking MT virulence factors.

A major issue in the management of patients infected with MT is the prediction of the progression of the infection. A study has established that the expression profile of type 1 interferon response genes can to some extent predict disease progression, providing a basis for targeted therapeutic intervention. MT has selected numerous evolutionary mutations resulting in a capacity to resist immune responses, from inhibition of phagosome-liposome fusion, to inhibition of antigen presentation to T lymphocytes, inhibition of autophagy, induction of paradoxical suppressive effects of neutrophils and other myeloid cells, and infection-facilitating effects of type 1 interferon. Most of these virulence (resistance) factors have been molecularly characterized.

Vaccination with BCG, live attenuated MT, was introduced over 90 years ago. This vaccine provides partial protection against tuberculosis in infants and children, but not against pulmonary tuberculosis. In particular, it does not induce a CD8 T cell response. Numerous attempts are being made to modify BCG by genetic recombination, with the aim of enabling dendritic cells to cross-present antigens to CD8 T lymphocytes. Clinical trials are currently underway, but it is still too early to assess efficacy. Further modifications, based on a better understanding of MT virulence factors and immune responses, may be required to obtain a fully effective vaccine.