Title: Does aerobic glycolysis exaggerate age related neutrophil dysfunction in community acquired pneumonia and sepsis: time for a new therapeutic strategy?
Funder: Dunhill Medical Trust

Abstract: Community acquired pneumonia (CAP) is the leading cause of infectious disease deaths worldwide(Cilloniz et al., 2013) and disproportionately affects older adults who are more likely to develop sepsis (CAP+S)(Welte and Kohnlein, 2009). Survivors of CAP+S have increased re-admissions, long term mortality and morbidity(Schnoor et al., 2009, Koster-Brouwer et al., 2016, Martin et al., 2006). We need more effective treatments to reduce this burden of ill health. There is an age-associated decline in neutrophil function, contributing to the increased incidence and severity of infections. The age related decline in neutrophil function is exaggerated in lung infection: with a progressive decline in neutrophil responses during infection with the degree of dysfunction corresponding to the severity of the insult, this dysfunction is seen across the spectrum of key effector functions(Sapey et al., 2017a). Such a profound dysregulation of multiple key responses suggests impairment of a global mechanism of cellular function rather than just effects on individual signalling pathways Neutrophils are highly glycolytic cells(Borregaard and Herlin, 1982) leading to significant lactate production, especially when activated (Khatib-Massalha et al., 2017) and when sepsis is present(Haji-Michael et al., 1999). Recent studies involving the effects of tumour-derived lactate suggest that lactate itself has an immunomodulatory effect in its local environment and is an active signalling molecule for immune cells via specific receptors (GPR81). (Hoque et al., 2014, Fischer et al., 2007, Brand et al., 2016, Haas et al., 2015, Colegio et al., 2014). I hypothesise that an episode of CAP+S in patients over 65 exaggerates age related neutrophil dysfunction due to dysregulated aerobic glycolysis that is driven by environmental exposure to lactate during sepsis but can be restored by modulating lactate biology. To test this, I will recruit a cohort of older patients with CAP+S and sequentially assess changes in neutrophil phenotype and cellular metabolic profile in relation to age, lactatemia, aetiology (bacterial/viral/co-infection), co-morbidity, and outcomes, compared to young adult CAP+S patients and age and morbidity matched controls. I will assess neutrophil effector functions and bioenergetics to examine the metabolic consequences of sepsis. I will determine how how the CAP+S environment alters neutrophils metabolic profile, interrogating the glycolytic pathway and assessing if the dysfunction is due to the septic environment, or lactate specifically. I will determine whether neutrophil dysfunction can be prevented or restored by lactate biology modification. Crucially whether function can be restored after the sepsis event.

Lay abstract: Pneumonia is a severe lung infection and a leading cause of death, especially in older people. Older people who survive pneumonia also experience increased rates of readmission to hospital, poorer quality of life and reduced independence. These poor outcomes are not caused by ineffective antibiotics, as the bacteria that cause most pneumonias remain susceptible to antibiotic treatment. New strategies are urgently needed to improve outcomes for older patients. The immune system (including white blood cells) doesn’t function normally in older people, and this impairment is worse during a severe infection. Neutrophils are the most numerous white blood cell and are key to fighting bacterial infections such as pneumonia. Neutrophils circulate in the blood stream but then move (or “migrate”) to areas of infection in the body’s tissues, ingesting bacteria (termed “phagocytosis”) and releasing toxic products both around the ingested bacteria and in the infected tissue (degranulation). We know that all these functions are altered in older people, especially during infection. Other research groups have tried to improve functions by targeting a single pathway, but this hasn’t been wholly successful. Such a profound blunting of all neutrophil functions is likely due to an impairment of a fundamental process within the cell, such as metabolism. Metabolism describes the process where a cell takes up glucose (a sugar) and converts this to energy which it can use to migrate, phagocytose and degranulate. My early experiments suggest that neutrophils from older adults during sepsis are less able to take up glucose and generate energy. This may cause the blunted responses we see in older adults with severe infections and could form a new means to treat infection. To investigate this, I will recruit older and younger adults who are admitted to hospital with pneumonia to my study. I will take blood samples from them on enrolment, four days later and then six weeks later to assess their neutrophil function at the start of pneumonia and as they recover. I will assess neutrophil metabolism and identify why metabolism is altered. I will test if using new treatments which target metabolism can improve the neutrophil’s ability to migrate towards and kill bacteria in a test tube. This will give me evidence and data to progress to early human studies with the eventual aim of developing a therapy that can improve neutrophil function in older adults, and thus improve survival while decreasing the complications associated with pneumonia.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM