We are grateful for the comments of Marrietta et al, [1] and welcome the opportunity to provide further details on the coagulopathy observed in our patients with COVID‐19 infection [2]. The weight‐adjusted low molecular weight heparin (LMWH) thromboprophylaxis used in the study is that routinely used for hospital in‐patients in our institution, consistent with national recommendations [3,4] With respect to the cohort of patients with COVID‐19 enrolled in our study, it is important to highlight that 74% of patients received enoxaparin 40mg (4000 IU) subcutaneously once daily.

Background Persistent fatigue, breathlessness and reduced exercise tolerance have been reported following acute COVID‐19 infection. Although immuno‐thrombosis has been implicated in acute COVID‐19 pathogenesis, the biological mechanisms underpinning Long COVID remain unknown. We hypothesized that pulmonary microvascular immuno‐thrombosis may be important in this context. Methods 150 COVID‐19 patients were reviewed at St James’s Hospital Dublin between May and September 2020 at a median of 80.5 (range 44 – 155) days after initial diagnosis. These included patients hospitalized during initial illness (n=69) and others managed entirely as outpatients (n=81). Clinical examination, chest x‐ray and 6‐minute walk tests were performed. In addition, a range of coagulation and inflammatory markers were assessed. Results Increased D‐dimer levels (>500ng/ml) were observed in 25.3% patients up to four months post‐SARS‐CoV‐2 infection. On univariate analysis, elevated convalescent D‐dimers were more common in COVID‐19 patients who had required hospital admission and in patients aged more than 50 years (p 90% of convalescent patients. Conclusions Elucidating the biological mechanisms responsible for sustained D‐dimer increases may be of relevance in Long COVID pathogenesis and has implications for clinical management of these patients.

Autophagy controls IL-1β secretion by regulating inflammasome activation and by targeting pro–IL-1β for degradation. In this article, we show that inhibition of autophagy, either with the PI3K inhibitors 3-methyladenine, wortmannin, and LY294002 or with small interfering RNA against autophagy proteins augmented the secretion of IL-23 by human and mouse macrophages and dendritic cells in response to specific TLR agonists. This process occurred at the transcriptional level and was dependent on reactive oxygen species and IL-1R signaling; it was abrogated with an IL-1R antagonist or with IL-1–neutralizing Abs, whereas treatment with either rIL-1α or IL-1β induced IL-23 secretion. Dendritic cells treated with LPS and 3-methyladenine secreted enhanced levels of both IL-1β and IL-23, and supernatants from these cells stimulated the innate secretion of IL-17, IFN-γ, and IL-22 by γδ T cells. These data demonstrate that autophagy has a potentially pivotal role to play in the induction and regulation of inflammatory responses by innate immune cells, largely driven by IL-1 and its consequential effects on IL-23 secretion.

Mycobacteria are a genus of bacteria that range from the non-pathogenic Mycobacterium smegmatis to Mycobacterium tuberculosis, the causative agent of tuberculosis in humans. Mycobacteria primarily infect host tissues through inhalation or ingestion. They are phagocytosed by host macrophages and dendritic cells. Here, conserved pathogen-associated molecular patterns (PAMPs) on the surface of mycobacteria are recognized by phagocytic pattern recognition receptors (PRRs). Several families of PRRs have been shown to non-opsonically recognize mycobacterial PAMPs, including membrane-bound C-type lectin receptors, membrane-bound and cytosolic Toll-like receptors and cytosolic NOD-like receptors. Recently, a possible role for intracellular cytosolic PRRs in the recognition of mycobacterial pathogens has been proposed. Here, we discuss currentideas on receptor-mediated recognition of mycobacterial pathogens by macrophages and dendritic cells.

Individuals of lower socio-economic position (SEP) carry a heavier burden of disease and morbidity and live shorter lives on average compared with their more advantaged counterparts. This has sparked research interest in the processes and mechanisms via which social adversity gets biologically embedded. The present study directly compares the empirical worth of two candidate mechanisms: Allostatic Load (AL) and the Epigenetic Clock(s) for advancing our understanding of embodiment using a sub-sample of 490 individuals from the Irish Longitudinal Study (TILDA) who were explicitly selected for this purpose based on their inter-generational life course social class trajectory. A battery of 14 biomarkers representing the activity of 4 different physiological systems: Immunological, Cardiovascular, Metabolic, and Renal was used to construct the AL score. Biomarkers were dichotomised into high and low risk groups according to sex-specific quartiles of risk and summed to create a count ranging from 0-14. Three measures of epigenetic age acceleration were computed according to three sets of age-associated Cytosine-phosphate-Guanine (CpG) sites described by Horvath, Hannum and Levine. AL was strongly socially patterned across a number of measures of SEP, while the epigenetic clocks were not. AL partially mediated the association between measures of SEP and an objective measure of physiological functioning: performance on the Timed Up and Go (TUG test). We conclude that AL may represent the more promising candidate for understanding the pervasive link between SEP and health.

Summary: A growing body of evidence points to autophagy as an essential component in the immune response to tuberculosis. Autophagy is a direct mechanism of killing intracellular Mycobacterium tuberculosis and also acts as a modulator of proinflammatory cytokine secretion. In addition, autophagy plays a key role in antigen processing and presentation. Autophagy is modulated by cytokines; it is stimulated by T helper type 1 (Th1) cytokines such as tumour necrosis factor (TNF)-α and interferon (IFN)-γ, and is inhibited by the Th2 cytokines interleukin (IL)-4 and IL-13 and the anti-inflammatory cytokine IL-10. Vitamin D, via cathelicidin, can also induce autophagy, as can Toll-like receptor (TLR)-mediated signals. Autophagy-promoting agents, administered either locally to the lungs or systemically, could have a clinical application as adjunctive treatment of drug-resistant and drug-sensitive tuberculosis. Moreover, vaccines which effectively induce autophagy could be more successful in preventing acquisition or reactivation of latent tuberculosis.