An integrative systems biology study to understand immune aging in people living with HIV

Antiretroviral therapy (ART) reduces viral replication, restores T helper cells and improves the survival of people living with HIV (PWH), transforming a life-threatening disease into a manageable chronic infection. Nevertheless, PWH under ART shows aging-related diseases such as bone abnormalities, non-HIV-associated cancers, and cardiovascular and neurocognitive diseases. The complex immune metabolic dysregulation leading to these comorbidities is called immune aging. The main question raised by my thesis was, what are the complex mechanisms responsible for immune aging in HIV? Using advanced system biology and machine learning tools, I used multi-omics-based patient stratification to identify biologic perturbations associated with immune aging in PWH. First, we investigated PWH with Metabolic Syndrome (MetS), a relatively common agingrelated disease in HIV-1. In paper I, we identified the dysregulation of glutamate metabolism in PWH with MetS using plasma metabolomics and measure of cell transporters by flow cytrometry. Then, we investigated the mechanisms of differing PWH on long-term successful ART from HIV-negative controls (HC). In paper II, we identified the dysregulation of amino acids and, more specifically, glutaminolysis (i.e., lysis of glutamine to glutamate) in PWH compared to HC using metabolomics in two independent cohorts to avoid the potential cohort biases. We identified five neurosteroids to be lower in PWH and potentially create neurological impairments in PWH. The glutaminolysis inhibition in chronically infected HIV-1 promonocytic (U1) cells induced apoptosis and latency reversal which could clear HIV reservoirs. The first two papers universally clarified our knowledge about dysregulated metabolic traits following a prolonged ART in PWH. However, we observed heterogeneity among the clinically defined PWH. Therefore, we focused more on the multi-omics data-driven approaches to stratify the at-risk group who were either dysregulated metabolically atrisk PWH (paper III) or immunometabolic at-risk group (paper IV) and clarified the biological aging process by measuring transcriptomics age (paper V). In paper III, we found three groups of PWH based on multi-omics integration of lipidomics, metabolomics, and microbiome. The severe at-risk metabolic complications showed increased weight-related comorbidities and di- and triglycerides compared to the other clusters. At-risk and HC-like groups displayed similar metabolic profiles but were different from HC. An increase in Prevotella was linked to the overrepresentation of men having sex with men (MSM) in the at-risk group. The microbiome-associated metabolites (MAM) appeared dysregulated in all HIV groups compared to controls. We improved this clustering by adding transcriptomics and proteomics data for a refined immunometabolic at-risk-related clustering in PWH. In paper IV, immune-driven HC-like and at-risk groups were clustered based on metabolomics, transcriptomics, and proteomics. Several biomarkers from central carbon metabolism (CCM) and senescence-associated proteins were linked to the at-risk phenotype based on random forest, structural causal modeling, and co-expression networks. Senescent protein changes were associated with a deficiency in macrophage function based on single-cell data, cell profiling, flow cytometry, and proteomics from macrophage data and in vitro validation. We also developed personalized and group-level genome-scale metabolic models (GSMM) and confirmed the implication of metabolites from CCM and polyamides in at-risk phenotypes. Finally, we investigated the accelerated aging process (AAP) in PWH. In paper V, we calculated the biological age of PWH using transcriptomics data and grouped patients into aging groups; The decelerated aging process (DAP) group was linked with higher age, European origin, and a higher proportion of tenofovir disoproxil fumarate /alafenamide (TDF/TAF). AAP had a downregulation of metabolic pathways and an upregulation of inflammatory pathways. In conclusion, my thesis identifies underlying mechanisms of immune aging using system biology tools in three independent cohorts of PWH for mechanistic studies and to improve their care and achieve healthy aging

Risk of herpes zoster in patients prescribed inhaled corticosteroids: a cohort study

<p>Abstract</p> <p>Background</p> <p>Little is known concerning risk factors for herpes zoster in the general population. We hypothesised that inhaled corticosteroids (ICS) are a risk factor for herpes zoster especially among users of inhibitors of cytochrome P450 enzymes involved in their metabolism.</p> <p>Methods</p> <p>We identified a cohort of adult users of respiratory medications in the General Practice Research Database and carried out a nested case control analysis of inhaled corticosteroid use among 8900 new cases of herpes zoster and 88032 controls matching on age and calendar time.</p> <p>Results</p> <p>The adjusted odds ratio for the relationship between current use of ICS and the occurrence of herpes zoster was 1.00 (95% confidence interval (CI), 0.94-1.07). There was no increase in risk of herpes zoster even at higher ICS doses; odds ratio 1.05 (95% CI, 0.96-1.14). Among subjects with concomitant prescriptions for an ICS and an inhibitor of cytochrome P450 3A4, the point estimate for the association between herpes zoster and the use of higher doses of inhaled corticosteroids was 1.23 (95% CI, 0.81-1.88).</p> <p>Conclusions</p> <p>The use of inhaled corticosteroids, even at high doses and in conjunction with inhibitors of their metabolism, was not a significant risk factor for the occurrence of herpes zoster in adults.</p

Sostituzione valvolare contemporanea dell'aorta, della mitrale e della tricuspide. Rischio operatorio. Risultati a breve e a lungo termine

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Avenues of future research in homotransplantation of the liver with particular reference to hepatic supportive procedures, antilymphocyte serum, and tissue typing

Three general areas of research which bear on the developing field of liver transplantation are reviewed. These are: (1) the prospects of obtaining better immunosuppression with particular reference to heterologous antilymphocyte serum; (2) the possible use of antigen matching technics as an advanced indicator of donorrecipient histocompatibility; (3) a simlified system of extracorporeal transplntation designed to provide teporary hepatic support. © 1966

Rare brain biopsy findings in a first ADEM-like event of pediatric MS: histopathologic, neuroradiologic and clinical features

Pediatric MS tends to present more often with an acute onset and a polysymptomatic form of the disease, possibly with encephalopathy and large tumefactive lesions similar to those observed in some cases of acute disseminated encephalomyelitis (ADEM), which makes it more difficult to differentiate between an explosive and severe onset of MS vs. ADEM. An ADEM-like first demyelinating event can be the first attack of pediatric MS, but international consensus definitions require two or more non-ADEM demyelinating events for diagnosis of MS. In our patient KIDMUS MRI criteria for MS (Mikaeloff et al. J Pediatr 144:246–252, 2004a; Mikaeloff et al. Brain 127:1942–1947, 2004b) were negative at first attack, but Barkhof criteria for lesion dissemination in space in adults (Barkhof et al. 120:2059–2069, 1997), Callen modified MS-criteria and Callen MS-ADEM criteria for children (Callen et al. Neurology 72:961–967, 2009a; Callen et al. Neurology 72:968–973, 2009b) were positive suggesting pediatric MS. As the clinical course was devastating with non-responsiveness upon high-dose immune modulatory therapy and due to the absence of an alternative diagnosis other than demyelinating disease brain biopsy was performed. Brain biopsy studies or autopsy case reports of fulminant pediatric MS patients are extremely rare. Histopathology revealed an inflammatory demyelinating CNS process with confluent demyelination, indicating the likelihood of a relapsing disease course compatible with an acute to subacute demyelinating inflammatory disease. This pattern was corresponding to the early active multiple sclerosis subtype I of Lucchinetti et al. (Ann Neurol 47(6):707–717, 2000)

Long-term Effectiveness and Tolerability of Topiramate in Children with Epilepsy under the Age of 2 Years: 4-Year Follow-up

This is a long-term, open label, observational study aimed to broaden our clinical experiences in managing infants and toddlers with epilepsy. The long-term retention rate and side effects of topiramate (TPM) in them were evaluated and compared with carbamazepine (CBZ). A total of 146 children were involved in the study (TPM=41, CBZ=105). The retention rates at 24 , 36, and 48 months were 46.3%, 34.1%, 26.8% for TPM and 36.2%, 23.8%, 13.3% for CBZ, respectively. At 6 months after starting antiepileptic drugs (AED), the seizure freedom or clinical efficacy (seizure reduction rate more than 50 percent) were 73.2% for TPM and 62.9% for CBZ. The major side effects led to discontinuation included psychomotor slowing, poor oral intake from TPM and sleepiness and skin rash from CBZ. TPM was discontinued due to side effects in one case (2.4%) and lack of efficacy in five cases (12.2%), whereas CBZ was discontinued due to lack of efficacy (22.9%) and side effects (6.7%). As compared with CBZ, TPM showed the same long-term retention rate in children under the age of 2 yr, and no serious side effects. It is therefore concluded that TPM can be considered as a major AED for treating children with epilepsy under the age of 2 yr

Transcriptomics age acceleration in prolonged treated HIV infection

Biological aging in people with HIV (PWH) with prolonged successful antiretroviral therapy (ART) is convoluted and poorly defined. Here, we aimed to investigate the transcriptomics age estimator (TAE) in a cohort of 178 PWH on prolonged successful ART with immune reconstitution and viral suppression from the Copenhagen Comorbidity (COCOMO) cohort. We also used 143 clinical, demographical, and lifestyle factors to identify the confounders potentially responsible or associated with age acceleration. Among the PWH, 43% had an accelerated aging process (AAP), and 21% had decelerated aging process (DAP). DAP is linked with older age, European ancestry, and higher use of tenofovir disoproxil/alafenamide fumarate. A directionally class-based gene set enrichment analysis identified the upregulation of inflammatory pathways (e.g., cytokine and Retinoic acid-inducible gene I (RIG-I)-like receptor signaling pathways) and immune response like T-cell receptor signaling, antigen processing, and presentation in AAP and the downregulation of metabolic processes like oxidative phosphorylation, pyruvate metabolism

Functional SARS-CoV-2 cross-reactive CD4+ T cells established in early childhood decline with age.

Pre-existing SARS-CoV-2-reactive T cells have been identified in SARS-CoV-2-unexposed individuals, potentially modulating COVID-19 and vaccination outcomes. Here, we provide evidence that functional cross-reactive memory CD4+ T cell immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is established in early childhood, mirroring early seroconversion with seasonal human coronavirus OC43. Humoral and cellular immune responses against OC43 and SARS-CoV-2 were assessed in SARS-CoV-2-unexposed children (paired samples at age two and six) and adults (age 26 to 83). Pre-existing SARS-CoV-2-reactive CD4+ T cell responses targeting spike, nucleocapsid, and membrane were closely linked to the frequency of OC43-specific memory CD4+ T cells in childhood. The functional quality of the cross-reactive memory CD4+ T cell responses targeting SARS-CoV-2 spike, but not nucleocapsid, paralleled OC43-specific T cell responses. OC43-specific antibodies were prevalent already at age two. However, they did not increase further with age, contrasting with the antibody magnitudes against HKU1 (β-coronavirus), 229E and NL63 (α-coronaviruses), rhinovirus, Epstein-Barr virus (EBV), and influenza virus, which increased after age two. The quality of the memory CD4+ T cell responses peaked at age six and subsequently declined with age, with diminished expression of interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor (TNF), and CD38 in late adulthood. Age-dependent qualitative differences in the pre-existing SARS-CoV-2-reactive T cell responses may reflect the ability of the host to control coronavirus infections and respond to vaccination

A high-risk gut microbiota configuration associates with fatal hyperinflammatory immune and metabolic responses to SARS-CoV-2.

Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and associated clinical sequelae requires well-coordinated metabolic and immune responses that limit viral spread and promote recovery of damaged systems. However, the role of the gut microbiota in regulating these responses has not been thoroughly investigated. In order to identify mechanisms underpinning microbiota interactions with host immune and metabolic systems that influence coronavirus disease 2019 (COVID-19) outcomes, we performed a multi-omics analysis on hospitalized COVID-19 patients and compared those with the most severe outcome (i.e. death, n = 41) to those with severe non-fatal disease (n = 89), or mild/moderate disease (n = 42), that recovered. A distinct subset of 8 cytokines (e.g. TSLP) and 140 metabolites (e.g. quinolinate) in sera identified those with a fatal outcome to infection. In addition, elevated levels of multiple pathobionts and lower levels of protective or anti-inflammatory microbes were observed in the fecal microbiome of those with the poorest clinical outcomes. Weighted gene correlation network analysis (WGCNA) identified modules that associated severity-associated cytokines with tryptophan metabolism, coagulation-linked fibrinopeptides, and bile acids with multiple pathobionts, such as Enterococcus. In contrast, less severe clinical outcomes are associated with clusters of anti-inflammatory microbes such as Bifidobacterium or Ruminococcus, short chain fatty acids (SCFAs) and IL-17A. Our study uncovered distinct mechanistic modules that link host and microbiome processes with fatal outcomes to SARS-CoV-2 infection. These features may be useful to identify at risk individuals, but also highlight a role for the microbiome in modifying hyperinflammatory responses to SARS-CoV-2 and other infectious agents