Publication highlights

Researchers at the Crick have discovered that Mtb, the bacterium causing tuberculosis (TB), alters its outermost layer, its lipid cell envelope, when it encounters low phosphate conditions. This allows it to survive inside human immune cells, where phosphate is restricted. It can scavenge phosphate from human lipids (fats), which are present in the lungs, allowing the bacteria to grow when no other source of phosphate is present. These findings demonstrate a method that Mtb employs to overcome the human host’s attempts to restrict its growth. The replacement lipids produced
when phosphate is restricted therefore represent new drug targets for the treatment of TB. Additionally, vaccines that target TB via its lipids should take into account the particular lipids present when the cell is phosphate starved, as demonstrated here.

Researchers at the Crick have shown that early in infection with Mycobacterium tuberculosis, the bacterium that causes TB, molecules called type I IFNs trigger neutrophil swarming in the lung. This impedes interactions between protective immune cells called macrophages and T cells required for early control of infection. They found that neutrophil swarming is reversed by blockade of the type I IFN receptor, allowing interaction of these protective immune cells to control TB disease.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, infects lung macrophages and subverts immune responses. In this work, researchers at the Crick developed genetically encoded probes to visualise calcium fluxes in human macrophages. By visualising calcium, they discovered that calcium is an important signal during infection that leaks from Mtb phagosomes. This calcium flux triggers a complex membrane remodelling and the association of autophagic proteins ATG8/LC3 to these membranes. They show that this membrane remodelling is important to limit the damage that Mtb inflicts in macrophage membranes and restrict Mtb infection as part the innate immune response.

Researchers at the Francis Crick Institute, The Hospital for Sick Children (SickKids) and Johns Hopkins University have found that mitochondria depend on a newly discovered recycling mechanism in order to clear away damaged sections and continue functioning. Using high resolution microscopy, the team identified that a mitochondrion’s damaged crista can squeeze through its outer membrane. A lysosome then engulfs the crista and breaks it down. The scientists named this process VDIM (‘vesicles derived from the inner mitochondrial membrane’) formation.

Researchers at the Francis Crick Institute and UCL have identified a gene that causes heart defects in Down syndrome, by studying human Down Syndrome fetal hearts and embryonic hearts from a mouse model of Down syndrome. They identified a gene on human chromosome 21 called Dyrk1a, which causes heart defects when present in three copies in the mouse model of Down syndrome. An extra copy of Dyrk1a turned down the activity of genes required for cell division in the developing heart and the function of the mitochondria, correlating with a failure to correctly separate the chambers of the heart. A DYRK1A inhibitor partially reversed the genetic changes when tested on mice pregnant with pups that model the heart defects in Down syndrome.

Pyrazinamide is one of the standard quartet of antibiotics used to treat TB, but its mechanism of action has been unclear. In this study, the Gutierrez lab used a novel dual live-imaging approach to show that the drug works through disrupting the ability of M. tuberculosis to maintain intrabacterial pH irrespective of the environment in the cell it has infected.