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.

If a tightly packed layer of epithelial cells gets overcrowded, excess cells are extruded, causing them to die. To find out how the body decides which cells are extruded, researchers at the Crick and King's College London set up live imaging of overcrowded epithelial cells under a microscope. They found that overcrowding triggers sodium channels on epithelial to open, bringing in salts and depolarising the cells. The strong ones can pump the sodium back out, repolarising themselves, but weak ones without energy can't, using a 'last gasp' of energy to activate a current that results in water rushing out of the cells, causing them to shrink and extrude.

This research explores the use of a biomarker of hepatitis B infection, 'core related antigen', to help identify people at highest risk of complications, who may benefit from treatment. Researchers at the Crick have investigated the role of this marker in UK and South African populations, exploring differences in its performance between settings. This is of importance given new World Health Organization guidelines which recommend offering treatment to many more people living with HBV.

Hepatitis Delta Virus (HDV) is a serious infection that worsens liver disease in people who already are living with Hepatitis B. It is highly endemic in the World Health Organisation (WHO) African region, where unique forms of the virus exist and the need for treatment is especially urgent. Novel drugs to cure this disease are being trialed. The researchers looked at all HDV clinical trials registered globally. Out of 47 trials, most were based in WHO Europe (about 7 out of 10), with some in the Americas and Western Pacific regions. Shockingly, none of the trials took place in the WHO African region. They believe clinical trials in WHO Africa are essential to make sure that new drugs work for people across different populations and virus types, and to ensure fair access when these treatments become available.

The Salmonella protein SteE forcibly reprogrammes the eukaryotic kinase GSK3 so it acts on a new set of substrates that benefit Salmonella virulence. Kinase reprogramming depends on several short linear motifs in SteE that trick GSK3 into recognising SteE as a 'normal' cellular signalling partner. Researchers at the Crick have shown how each motif contributes to manipulating GSK3, and revealed the existence of SteE-like proteins in other bacterial pathogens. This work will aid the rational design of synthetic reprogramming proteins.

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.

Hepatitis B core related antigen (HBcrAg) is a biomarker of replication in hepatitis B virus (HBV) infection. There are very few data representing the use of HBcrAg in African populations, and measuring it using a Point of Care Test has only been done in one other African setting. This study helps determine a use case and explores the extent to which a positive HBcrAg correlates with existing biomarkers for people living with HBV in Kenya.

The germinal centres (GCs) of the body act as factories where antibody-secreting B cells are fine-tuned to reach their highest antigen affinity. GC-B cells cycle between two GC zones, undergoing antigen-driven selection and initiating cell division in the light zone (LZ), before migrating to the dark zone (DZ), where they vigorously proliferate. Initiation of cell division in the LZ was a puzzle, as the low-oxygen conditions in the LZ normally induce cell cycle arrest. Researchers at the Crick showed that a microRNA called miR-155 metabolically reprogrammes LZ GC-B cells by regulating genes that enhance energy production and prevent cell death. This process is essential for effective immune function in the face of infection.

Chronic hepatitis B (CHB) affects 254 million people globally, contributing significantly to cirrhosis and liver cancer. Work led by Philippa Matthews through the UK NIHR 'Health Informatics Collaborative' for viral hepatitis looked at the dynamics of hepatitis B virus (HBV) viral load and its relationship with liver disease in patients with CHB who were on long-term nucleos/tide analogue (NA) treatment. Virologic responses to NA therapy showed significant variability, and in 20% of individuals on treatment, HBV was not suppressed, or declined slowly on treatment over more than a year. In some cases, this was associated with a twofold increased risk of liver disease progression. These insights are relevant to supporting the management of CHB patients, helping the development of personalised treatment approaches.