Abstract
Among infectious diseases, tuberculosis is the leading cause of death worldwide, and represents a serious threat, especially in developing countries. The protective effects of Bacillus Calmette-Guerin (BCG), the current vaccine against tuberculosis, have been related not only to specific induction of T-cell immunity, but also with the long-term epigenetic and metabolic reprogramming of the cells from the innate immune system through a process termed trained immunity. Here we show that MTBVAC, a live attenuated strain of Mycobacterium tuberculosis, safe and immunogenic against tuberculosis antigens in adults and newborns, is also able to generate trained immunity through the induction of glycolysis and glutaminolysis and the accumulation of histone methylation marks at the promoters of proinflammatory genes, facilitating an enhanced response after secondary challenge with non-related bacterial stimuli. Importantly, these findings in human primary myeloid cells are complemented by a strong MTBVAC-induced heterologous protection against a lethal challenge with Streptococcus pneumoniae in an experimental murine model of pneumonia.
Highlights
For thousands of years Mycobacterium tuberculosis (Mtb) has caused considerable infectious burden for our species [1,2]
In a setting of acute stimulation of human monocytes, we found that MTBVAC had a dose-dependent effect on the stimulation of the pro-inflammatory cytokines IL-1β, IL-6 and TNFα by human monocytes (Fig 1A)
Since MTBVAC is a live attenuated strain of Mtb, we assessed if the presence or absence of the antibiotic gentamicin in the culture medium, which may affect the viability of the mycobacteria, had any influence in the induction of cytokine production
Summary
For thousands of years Mycobacterium tuberculosis (Mtb) has caused considerable infectious burden for our species [1,2]. According to the last report from the WHO, 23% of the global population presents latent TB infection (LTBI), meaning that they are infected by the pathogen but they have not yet become ill and cannot transmit the infection [3,4]. There are around 10 million new cases every year, of which almost half a million are multidrug-resistant TB, characterized by resistance to isoniazid and rifampicin, the two main pharmacological treatments against the disease. In this scenario, it is fundamental to investigate and develop new therapeutic approaches against TB. BCG is administered worldwide as a single dose of intradermal inoculation, providing protection against disseminated forms of TB such as milliary TB in infants, but offering variable degrees of protection against pulmonary and LTBI in adults of both sexes and all ages ranging from 0% to 80% depending on the setting [6]
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