I.V. BCG better for TB
Researchers at the University of Pittsburgh have discovered that intravenous (I.V.) delivery of the Bacille Calmette-Guérin (BCG) vaccine sharply improved its ability to provoke a protective T-cell response in the lungs. BCG is the only approved vaccine against Mycobacterium tuberculosis, but the vaccine is most effective against disseminated disease in children, while most active TB cases and most fatalities are due to lung disease in adolescents and adults. The researchers reasoned that I.V. delivery might increase the vaccine’s ability to elicit a T-cell response in the lungs. They vaccinated macaque monkeys either via I.V., intradermal or aerosol delivery, and challenged the animals with virulent TB. The majority of monkeys in the I.V. delivery group showed no detectable levels of infection, and only one out of 10 animals showed what the authors deemed significant inflammation. “The finding that intravenous BCG prevents or substantially limits [TB] infection in highly susceptible rhesus macaques has important implications for vaccine delivery and clinical development, and provides a model for defining immune correlates and mechanisms of vaccine-elicited protection against tuberculosis,” the authors wrote. They reported their findings in the Jan. 1, 2020, issue of Nature.
Bacteria prevent host cell apoptosis
Scientists at the University of Cologne have identified a mechanism by which Shigella bacteria prevent apoptosis by their host cells, thus preserving their own ability to replicate and sustain infections. Bacterial infections set off apoptosis as part of organismal host defense. In their experiments, the investigators showed that Shigella bacteria, which cause gastrointestinal infections, displayed lipopolysaccharides (LPS) on their surface that inhibited caspases, the enzymes that set off apoptosis. “Next to the recently discovered pro-inflammatory role of cytosolic LPS, our data reveal a distinct mode of LPS action that, through the disruption of the early coordinated non-lytic cell death response, ultimately supports the inflammatory breakdown of infected cells at later time points,” the authors wrote. Their work appeared in the Dec. 23, 2019, online issue of Nature Microbiology.
PD-1 blockade affects myeloid more than T cells
There are now half a dozen approved therapies that unleash antitumor immunity via blocking the interaction between PD-1 and its ligand, PD-L1. Collectively, those therapies are assumed to act primarily by affecting T cells. But by knocking out PD-1 expression selectively on either myeloid cells or T cells, researchers at Beth Israel Deaconess Medical Center have demonstrated that PD-1/PD-L1 blockers may owe more of their effects to increasing the activity of myeloid cells. The authors found that “compared with T cell-specific PD-1 ablation, myeloid cell-specific PD-1 ablation more effectively decreased tumor growth.” More detailed investigation of the mechanism suggested that myeloid cells lacking PD-1 expression underwent metabolic changes, including increased cholesterol synthesis, which is necessary for the differentiation of tumor-fighting cells and promotes antigen-presenting function. “Our findings indicate that metabolic reprogramming of emergency myelopoiesis and differentiation of effector myeloid cells might be a key mechanism of antitumor immunity mediated by PD-1 blockade,” the authors wrote. Their work appeared in the Jan. 3, 2020, issue of Science Immunology.
New regeneration factor for muscle cells
Muscle cells grow and regenerate with ease in response to exercise, but harnessing that ability for regenerative therapies in muscle wasting disorders has so far proved elusive. Several lines of previous research have supported the idea that expressing the transcription factor PAX7 is important for the regenerative potential of satellite cells, which make new muscle fibers. Now, investigators at the Charite clinic have shown that satellite cells lacking PAX7 nevertheless could regenerate if they expressed another protein, CLEC14. They showed that cells from a patient lacking both copies of PAX7 could regenerate when transplanted into mice. “Transplanted PAX7neg cells repopulate the satellite cell niche where they re-express PAX7, or, strikingly, CLEC14A,” the authors wrote. “Transplanted human cells do not depend on PAX7 for muscle regeneration.” The team reported its findings in the Dec. 18, 2019, online issue of Nature Communications.
Carbon dioxide and the brain
Researchers from the University of Luebeck have demonstrated that cerebrovascular reactivity to carbon dioxide influenced the emotional state of mice. Carbon dioxide influences blood vessels in the brain, a phenomenon known as cerebrovascular reactivity. Reduced cerebrovascular reactivity predicts increased risk for stroke and hypertension, but whether it directly affects brain function has been unclear. In their studies, the authors showed that the effect of reduced cerebrovascular reactivity differed by brain region. In the brainstem, impaired reactivity depressed respiration, which in turn reduced the clearance of carbon dioxide. In the amygdala, an emotional center of the brain, carbon dioxide dilated blood vessels and increased anxiety. The authors concluded that “our data suggest the central nervous system (CNS) endothelium as a target to treat respiratory and affective disorders associated with vascular diseases.” They reported their findings in the Jan. 2, 2020, online issue of the Proceedings of the National Academy of Sciences.