New study finds that special immune cells called neutrophils have their genetic material modified by low blood oxygen levels. These changes reduce the ability of neutrophils to remove disease-causing microbes in the body, leading to recurrent infections. Remarkably, these genetic changes and defective infection outcomes are partially prevented by BCG vaccination. Immune cells called neutrophils are one of the first lines of defence in your blood, protecting you from disease-causing microbes. The activity of these neutrophils is important – if their activity is too weak, microbes won’t be destroyed efficiently; if their activity is too strong, this could lead to damage of your own tissues and chronic inflammation. When the body is deprived of an adequate oxygen supply (hypoxia) (e.g., during acute respiratory distress syndrome or in a tumour microenvironment), it has been shown that these neutrophils don’t work as well, and individuals can experience recurrent infections in the long term. However, it is not known why. Understanding the blood components that trigger persistent changes in neutrophils is crucial, given their essential role in fighting infections and their harmful potential when their responses are not tightly controlled. Dr Manuel Alejandro Sanchez Garcia IRR postdoctoral researcher and paper’s first author Low blood oxygen modifies the genetic material and behaviour of neutrophilsNeutrophils have a relatively short lifespan and were traditionally thought to be incapable of retaining memory from past events. It’s recently been shown that the cells in the bone marrow that create neutrophils can acquire memory of past changes in their environment by modifying their genetic material. These genetic changes can be passed on to newly-formed neutrophils, modifying their behaviour for future events. However, it is not known whether this happens in response to hypoxia.In a new study, IRR postdoc Dr Manuel Alejandro Sanchez Garcia (Walmsley lab) and colleagues investigated neutrophils from patients following acute respiratory distress syndrome and volunteers that recently experienced altitude-induced hypoxia. They found that the neutrophils in their blood were altered by modifications in their genetic material.Dr Garcia and colleagues also found that the genetic changes seen in these neutrophils were also seen in a population of their predecessor cells in the bone marrow. These predecessor cells experienced a process called “histone clipping” in response to low oxygen levels, which modified their genetic material. This is interesting as it provides an explanation to the persistent neutrophil defective response observed following hypoxia. BCG vaccination reduces genetic changes and improves infection outcomesIRR researchers also found that giving hypoxic mice a BCG vaccination (usually given to protect against tuberculosis (TB)), partially prevented the hypoxia-induced genetic changes and defective infection outcomes. This work shows that our immune response is altered by low oxygen levels, and that these alterations are retained months after the hypoxic exposure. This provides evidence of long-term reprogramming of the immune response. This is important as it shows we can educate our immediate immune repose to infections based on prior exposures. BCG vaccines partially reverse the dysfunctional immune response providing new therapeutic avenues to explore, for example, in acute respiratory distress where there is 40% mortality Professor Sarah Walmsley Chair of Respiratory Medicine The researchers are now keen to further explore the effect of low oxygen levels on histone clipping in the cells which create neutrophils. They are also keen to study the involvement of other cellular components, such as hypoxia-inducible factor (HIF), to better understand the effect of low oxygen levels on the body. This work was funded by Wellcome and UKRI NIHR UK Coronavirus Immunology Consortium. Read the full paper in Nature ImmunologyWalmsley research group Walmsley lab group photo, celebrating the manuscript’s official acceptance Tags CIR Publication date 10 Oct, 2025
