We measured the changes in heart rate (HR) variability estimated from the standard deviation of the R-R intervals to evaluate cardiac parasympathetic tone noninvasively before and during activation of muscle metaboreflex induced by postexercise muscle ischemia. Eight healthy male subjects performed sustained handgrip at 50% maximal voluntary contraction followed by forearm occlusion. Mean arterial pressure, cardiac stroke volume, and ratio of cardiac preejection period to left ventricular ejection time (PEP/LVET) were also measured. During the 2-min occlusion after 60 s of handgrip with voluntary respiration, HR variability and mean arterial pressure were significantly increased from baseline (54.4 +/- 6.1 to 80.1 +/- 12.8 ms and 81 +/- 1 to 99 +/- 3 mmHg, respectively) and PEP/LVET was decreased from resting level of 0.404 +/- 0.022 to 0.363 +/- 0.036. During occlusion and recovery, HR did not change from baseline level in any experiment. There was no influence of occlusion itself or of cessation of exercise per se on any parameters. Although overall enhanced HR variability was seen, probably due to lower breathing frequency and larger tidal volume, similar results were also obtained from an experiment with controlled respiration, showing that the increase in HR variability was not due to the changes in tidal volume or breathing frequency during occlusion. In conclusion, the HR variability is increased during activation of the muscle metaboreflex induced by postexercise muscle ischemia in humans. This finding shows that the parasympathetic cardiac tone is enhanced during activation of the muscle metaboreflex in humans and balances enhanced cardiac sympathetic activity to result in an unchanged HR.(ABSTRACT TRUNCATED AT 250 WORDS)
Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
Consecutive mRNA vaccinations against SARS-CoV-2 reinforced both innate and adaptive immune responses. However, it remains unclear whether the enhanced innate immune responses are mediated by epigenetic regulation and, if so, whether these effects persist. Using mass cytometry, RNA-seq, and ATAC-seq, we show that BNT162b2 mRNA vaccination upregulated antiviral and IFN-stimulated gene expression in monocytes with greater effects after the second vaccination than those after the first vaccination. Transcription factor-binding motif analysis also revealed enriched IFN regulatory factors and PU.1 motifs in accessible chromatin regions. Importantly, although consecutive BNT162b2 mRNA vaccinations boosted innate immune responses and caused epigenetic changes in isolated monocytes, we showed that these effects occur only transiently and disappear 4 weeks after the second vaccination. Furthermore, single-cell RNA sequencing analysis revealed that a similar gene signature was impaired in the monocytes of unvaccinated COVID-19 patients with acute respiratory distress syndrome. These results reinforce the importance of the innate immune response in the determination of COVID-19 severity but indicate that, unlike adaptive immunity, innate immunity is not unexpectedly sustained even after consecutive vaccination. This study, which focuses on innate immmune memory, may provide novel insights into the vaccine development against infectious diseases.
Sex-biased humoral immune responses to COVID-19 patients have been observed, but the cellular basis for this is not understood. Using single-cell proteomics by mass cytometry, we find disrupted regulation of humoral immunity in COVID-19 patients, with a sex-biased loss of circulating follicular regulatory T cells (cTfr) at a significantly greater rate in male patients. In addition, a male sex-associated cellular network of T-peripheral helper, plasma blasts, proliferating and extrafollicular/atypical CD11c + memory B cells was strongly positively correlated with neutralizing antibody concentrations and negatively correlated with cTfr frequency. These results suggest that sex-specific differences to the balance of cTfr and a network of extrafollicular antibody production-associated cell types may be a key factor in the altered humoral immune responses between male and female COVID-19 patients.
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