Adaptation of Candida albicans to environmental pH induces cell wall remodelling and enhances innate immune recognition

Candida albicans is able to proliferate in environments that vary dramatically in ambient pH, a trait required for colonising niches such as the stomach, vaginal mucosal and the GI tract. Here we show that growth in acidic environments involves cell wall remodelling which results in enhanced chitin and β-glucan exposure at the cell wall periphery. Unmasking of the underlying immuno-stimulatory β-glucan in acidic environments enhanced innate immune recognition of C. albicans by macrophages and neutrophils, and induced a stronger proinflammatory cytokine response, driven through the C-type lectin-like receptor, Dectin-1. This enhanced inflammatory response resulted in significant recruitment of neutrophils in an intraperitoneal model of infection, a hallmark of symptomatic vaginal colonisation. Enhanced chitin exposure resulted from reduced expression of the cell wall chitinase Cht2, via a Bcr1-Rim101 dependent signalling cascade, while increased β-glucan exposure was regulated via a non-canonical signalling pathway. We propose that this “unmasking” of the cell wall may induce non-protective hyper activation of the immune system during growth in acidic niches, and may attribute to symptomatic vaginal infection

How are falls and fear of falling associated with objectively measured physical activity in a cohort of community-dwelling older men?

BACKGROUND: Falls affect approximately one third of community-dwelling older adults each year and have serious health and social consequences. Fear of falling (FOF) (lack of confidence in maintaining balance during normal activities) affects many older adults, irrespective of whether they have actually experienced falls. Both falls and fear of falls may result in restrictions of physical activity, which in turn have health consequences. To date the relation between (i) falls and (ii) fear of falling with physical activity have not been investigated using objectively measured activity data which permits examination of different intensities of activity and sedentary behaviour. METHODS: Cross-sectional study of 1680 men aged 71-92 years recruited from primary care practices who were part of an on-going population-based cohort. Men reported falls history in previous 12 months, FOF, health status and demographic characteristics. Men wore a GT3x accelerometer over the hip for 7 days. RESULTS: Among the 12% of men who had recurrent falls, daily activity levels were lower than among non-fallers; 942 (95% CI 503, 1381) fewer steps/day, 12(95% CI 2, 22) minutes less in light activity, 10(95% CI 5, 15) minutes less in moderate to vigorous PA [MVPA] and 22(95% CI 9, 35) minutes more in sedentary behaviour. 16% (n = 254) of men reported FOF, of whom 52% (n = 133) had fallen in the past year. Physical activity deficits were even greater in the men who reported that they were fearful of falling than in men who had fallen. Men who were fearful of falling took 1766(95% CI 1391, 2142) fewer steps/day than men who were not fearful, and spent 27(95% CI 18, 36) minutes less in light PA, 18(95% CI 13, 22) minutes less in MVPA, and 45(95% CI 34, 56) minutes more in sedentary behaviour. The significant differences in activity levels between (i) fallers and non-fallers and (ii) men who were fearful of falling or not fearful, were mediated by similar variables; lower exercise self-efficacy, fewer excursions from home and more mobility difficulties. CONCLUSIONS: Falls and in particular fear of falling are important barriers to older people gaining health benefits of walking and MVPA. Future studies should assess the longitudinal associations between falls and physical activity

HECTD2, a candidate susceptibility gene for Alzheimer's disease on 10q

Background: Late onset Alzheimer's disease (LOAD) is a neurodegenerative disorder characterised by the deposition of amyloid plaques and neurofibrillary tangles in the brain and is the major cause of dementia. Multiple genetic loci, including 10q, have been implicated in LOAD but to date, with the exception of APOE, the underlying genes have not been identified. HECTD2 maps to 10q and has been implicated in susceptibility to human prion diseases which are also neurodegenerative conditions associated with accumulation of misfolded host proteins. In this study we test whether the HECTD2 susceptibility allele seen in prion disease is also implicated in LOAD.Methods: DNA from 320 individuals with Alzheimer's disease and 601 controls were genotyped for a HECTD2 intronic tagging SNP, rs12249854 (A/T). Groups were further analysed following stratification by APOE genotype.Results: The rs12249854 minor allele (A) frequency was higher (5.8%) in the Alzheimer's disease group as compared to the controls (3.9%), however, this was not statistically significant (P = 0.0668). No significant difference was seen in minor allele frequency in the presence or absence of the APOE epsilon 4 allele.Conclusion: The common haplotypes of HECTD2, tagged by rs12249854, are not associated with susceptibility to LOAD

A randomised controlled trial comparing the effectiveness of Tai Chi alongside usual care with usual care alone on the postural balance of community-dwelling people with dementia: Protocol for The TACIT Trial (TAi ChI for people with dementia).

Background: Falls are a public health issue for the older adult population and more so for people with dementia (PWD). Compared with their cognitively intact peers, PWD are at higher risk of falls and injurious falls. This randomised controlled trial aims to test the clinical and cost effectiveness of Tai Chi to improve postural balance among community-dwelling PWD and to assess the feasibility of conducting a larger definitive trial to reduce the incidence of falls among PWD. Methods: A 3-centre parallel group randomised controlled trial with embedded process evaluation. One hundred and fifty community-dwelling dyads of a person with dementia and their informal carer will be recruited and assessed at baseline and at six-month follow-up. Dyads will be randomised in a 1:1 ratio to either usual care or usual care plus a Tai Chi intervention for 20 weeks. The Tai Chi intervention will consist of weekly classes (45 minutes’ Tai Chi plus up to 45 minutes for informal discussion, with up to 10 dyads per class) and home-based exercises (20 minutes per day to be facilitated by the carer). Home practice of Tai Chi will be supported by the use of behaviour change techniques with the Tai Chi instructor at a home visit in week 3-4 of the intervention (action planning, coping planning, self-monitoring, and alarm clock reminder) and at the end of each class (feedback on home practice). The primary outcome is dynamic balance measured using the Timed Up and Go test, coinciding with the end of the 20-week intervention phase for participants in the Tai Chi arm. Secondary outcomes for PWD include functional balance, static balance, fear of falling, global cognitive functioning, visual-spatial cognitive functioning, quality of life, and falls. Secondary outcomes for carers include dynamic balance, static balance, quality of life, costs, and carer burden. Discussion: This trial is the first in the UK to test the effectiveness of Tai Chi to improve balance among PWD. The trial will inform a future study that will be the first in the world to use Tai Chi in a trial to prevent falls among PWD. Trial registration: NCT02864056

Regulation of cell wall remodeling during adaptation to environmental pH.

<p><b>a)</b> In environments above pH5.5, the Rim101 pathway is activated resulting in C-terminal processing of Rim101 and enhance expression of <i>CHT2</i>. The She3 complex then transports <i>CHT2</i> mRNA to the cell wall, where it is translated and attached via its GPI anchor. At pH4 Rim101 is not activated, resulting in reduced expression of Cht2. <b>b) (i)</b> When present in the cell wall (i.e. above pH5.5), Cht2 hydrolyses the growing chitin polymer into shorter fragments which may hydrogen bond and form short chitin microfibrils that are embedded deep within the cell wall. <b>(ii)</b> When there is reduced amounts of Cht2 in the cell wall (i.e. environments below pH4), the growing chitin polymer is cleaved less efficiently, resulting in the incorporation of longer chitin polymers that are more exposed on the outer surface of the cell wall.</p

Unmasking of β-glucan in response to environmental pH is specific to <i>C</i>. <i>albicans</i> and <i>C tropicalis</i>.

<p><b>a)</b> Exponentially growing cells in YPD, YPD buffered to pH4 and YPD buffered to pH8 were incubated with recombinant β1,3-glucanase. The decrease in OD₆₀₀ represents cell lysis as the β1,3-glucanase digests the cell wall and is expressed as a % of the starting OD₆₀₀. Data represent the mean ± SEM from four independent experiments. <b>b)</b> Initial rate of cell lysis was calculated from the first 100 min after the addition of β-glucanase. Data represent the mean ± SEM from four independent repeats (* p < 0.05, ** p < 0.01).</p

<i>C</i>. <i>albicans</i> cells adapted to acidic environments recruit more innate immune cells <i>in vivo</i>.

<p><b>a)</b> Total number of CD45+, CD11b+ and Ly-6B.2+ (7/4 clone) cells (including monocytes and neutrophils) recruited to the peritoneal cavity following 4 h exposure to <i>C</i>. <i>albicans</i> incubated in pH6 or pH4 YPD (p = 0.007). <b>b)</b> Total number of neutrophils (further identified using F4/80) recruited to the peritoneal cavity (p = 0.010) <b>c)</b> Percentage of neutrophils in the total population of recruited innate immune cells (p = 0.540).</p

Exposure of β-glucan and chitin do not co-localise.

<p>Wild type <i>Candida albicans</i> cells (NGY152) were grown to mid-log phase in YPD buffered at pH2, pH4 and pH6, washed, fixed with 4% PFA and stained with CFW, TRITC-labeled WGA, and Fc-Dectin-1 (FITC). White arrowheads indicate patches of β-glucan exposure. Scale bar represents 10 μm.</p