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Background: Bovine Viral Diarrhoea Virus (BVDV) infection remains endemic in many countries worldwide. Ireland, in common with several other European counties, commenced an BVDV eradication programme in the last decade, Managing eradication programmes requires careful monitoring of diseases prevalence and understanding factors associated with disease exposure to ensure eradication programmes remain evidence based and tailored to the evolving epidemiological situation. Methods: In this study, we explore the seroprevalence of BVDV exposure over a four-year period (2017 to 2020) in Ireland from a cohort of animals (n = 6,449) under 30 months of age sampled at slaughter, who were born subsequent to the commencement of a compulsory national eradication programme. Temporal trends and risk factor analysis were undertaken using multilevel logit regression models. Results: There was a declining temporal trend in seroprevalence over the sample years of the study, and risk varied at both county- and herd-levels. The unadjusted marginal animal-level seroprevalence reduced from 9.1% in 2017 (95%; CI: 7.2—10.9) to 3.9% in 2020 (95%; CI: 3.2—4.6). The final model suggested that seropositivity in study cattle was strongly related with the presence of a PI animal in the herd during the year of the animal's birth, and to a lesser extent the status of the herd from which the animal was slaughtered. The risk of seroconversion increased significantly with increasing size of the herd of slaughter, in females relative to males, and in dairy relative to suckler herds. Conclusions: This study has shown that the BVDV serostatus of cattle at slaughter is correlated to the BVD infection history of the herd into which the animal was born and the herd from which it was slaughtered. Herd location, increased herd size and dairy production were associated with increased probability of serconversion. These findings will be used to inform the targeting of surveillance strategies once BVDV freedom has been achieved. [ABSTRACT FROM AUTHOR]

Humans exposed to hypoxia are susceptible to physiological and psychological impairment. Music has ergogenic effects through enhancing psychological factors such as mood, emotion, and cognition. This study aimed to investigate music as a tool for mitigating the performance decrements observed in hypoxia. Thirteen males (mean ± SD; 24 ± 4 years) completed one familiarization session and four experimental trials; (1) normoxia (sea level, 0.209 FiO2) and no music; (2) normoxia (0.209 FiO2) with music; (3) normobaric hypoxia (∼3800 m, 0.13 FiO2) and no music; and (4) normobaric hypoxia (0.13 FiO2) with music. Experimental trials were completed at 21°C with 50% relative humidity. Music was self-selected prior to the familiarization session. Each experimental trial included a 15-min time trial on an arm bike, followed by a 60-s isometric maximal voluntary contraction (MVC) of the biceps brachii. Supramaximal nerve stimulation quantified central and peripheral fatigue with voluntary activation (VA%) calculated using the doublet interpolation method. Average power output (W) was reduced with a main effect of hypoxia (p = 0.02) and significantly increased with a main effect of music (p = 0.001). When combined the interaction was additive (p = 0.87). Average MVC force (N) was reduced in hypoxia (p = 0.03) but VA% of the biceps brachii was increased with music (p = 0.02). Music reduced subjective scores of mental effort, breathing discomfort, and arm discomfort in hypoxia (p < 0.001). Music increased maximal physical exertion through enhancing neural drive and diminishing detrimental mental processes, enhancing performance in normoxia (6.3%) and hypoxia (6.4%). [ABSTRACT FROM AUTHOR]

This study investigated the individual and combined effects of mental fatigue (MF) and hypoxia (HYP) on physical and cognitive performance. Fifteen males (24 ± 3 years) completed one familiarization session and six experimental trials, including: 1) normoxia (0.209 FiO2) and no MF; 2) normoxia (0.209 FiO2) with MF; 3) mild normobaric HYP (0.13 FiO2) and no MF; 4) mild normobaric HYP (0.13 FiO2) with MF; 5) severe normobaric HYP (0.10 FiO2) and no MF; 6) severe normobaric HYP (0.10 FiO2) with MF. Each condition included a 15-min self-paced time trial, followed by a 60-s isometric maximal voluntary contraction of the biceps brachii. MF was induced using a 16-min individualized cognitive test prior to exercise performance. Following each time trial, participants performed the Tower of Hanoi cognitive test. A main effect of HYP was observed on average power output, oxygen consumption and muscle oxygenation (P ≤ 0.004), with no effect of MF (P ≥ 0.599). Voluntary activation of the biceps brachii was also reduced in HYP (68.42 ± 5.64%, P = 0.039). No effect of MF or HYP was observed on cognitive performance (P ≥ 0.138). HYP impacted physical performance, whilst MF had no effect on self-paced physical or cognitive performance. [ABSTRACT FROM AUTHOR]

Polymorphonuclear neutrophils (PMN) are critical for first line innate immune defence against Staphylococcus aureus. Mature circulating PMN maintain a short half-life ending in constitutive apoptotic cell death. This makes them unlikely candidates as a bacterial intracellular niche. However, there is significant evidence to suggest that S. aureus can survive intracellularly within PMN and this contributes to persistence and dissemination during infection. The precise mechanism by which S. aureus parasitizes these cells remains to be established. Herein we propose a novel mechanism by which S. aureus subverts both autophagy and apoptosis in PMN in order to maintain an intracellular survival niche during infection. Intracellular survival of S. aureus within primary human PMN was associated with an accumulation of the autophagic flux markers LC3-II and p62, while inhibition of the autophagy pathway led to a significant reduction in intracellular survival of bacteria. This intracellular survival of S. aureus was coupled with a delay in neutrophil apoptosis as well as increased expression of several anti-apoptotic factors. Importantly, blocking autophagy in infected PMN partially restored levels of apoptosis to that of uninfected PMN, suggesting a connection between the autophagic and apoptotic pathways during intracellular survival. These results provide a novel mechanism for S. aureus intracellular survival and suggest that S. aureus may be subverting crosstalk between the autophagic and apoptosis pathways in order to maintain an intracellular niche within human PMN. [ABSTRACT FROM AUTHOR]

Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans. [ABSTRACT FROM AUTHOR]

Despite showing promise in preclinical models, anti–Staphylococcus aureus vaccines have failed in clinical trials. To date, approaches have focused on neutralizing/opsonizing antibodies; however, vaccines exclusively inducing cellular immunity have not been studied to formally test whether a cellular-only response can protect against infection. We demonstrate that nasal vaccination with targeted nanoparticles loaded with Staphylococcus aureus antigen protects against acute systemic S. aureus infection in the absence of any antigen-specific antibodies. These findings can help inform future developments in staphylococcal vaccine development and studies into the requirements for protective immunity against S. aureus. [ABSTRACT FROM PUBLISHER]

Staphylococcus aureus asymptomatically colonises the anterior nares, but the host and bacterial factors that facilitate colonisation remain incompletely understood. The S. aureus surface protein ClfB has been shown to mediate adherence to squamous epithelial cells in vitro and to promote nasal colonisation in both mice and humans. Here, we demonstrate that the squamous epithelial cell envelope protein loricrin represents the major target ligand for ClfB during S. aureus nasal colonisation. In vitro adherence assays indicated that bacteria expressing ClfB bound loricrin most likely by the “dock, lock and latch” mechanism. Using surface plasmon resonance we showed that ClfB bound cytokeratin 10 (K10), a structural protein of squamous epithelial cells, and loricrin with similar affinities that were in the low µM range. Loricrin is composed of three separate regions comprising GS-rich omega loops. Each loop was expressed separately and found to bind ClfB, However region 2 bound with highest affinity. To investigate if the specific interaction between ClfB and loricrin was sufficient to facilitate S. aureus nasal colonisation, we compared the ability of ClfB+ S. aureus to colonise the nares of wild-type and loricrin-deficient (Lor−/−) mice. In the absence of loricrin, S. aureus nasal colonisation was significantly impaired. Furthermore a ClfB− mutant colonised wild-type mice less efficiently than the parental ClfB+ strain whereas a similar lower level of colonisation was observed with both the parental strain and the ClfB− mutant in the Lor−/− mice. The ability of ClfB to support nasal colonisation by binding loricrin in vivo was confirmed by the ability of Lactococcus lactis expressing ClfB to be retained in the nares of WT mice but not in the Lor−/− mice. By combining in vitro biochemical analysis with animal model studies we have identified the squamous epithelial cell envelope protein loricrin as the target ligand for ClfB during nasal colonisation by S. aureus. [ABSTRACT FROM AUTHOR]