Fatal Disease Outcome Research Articles

Gene expression analysis identifies hub genes and pathways distinguishing fatal from survivor outcomes of Ebola virus disease.

The Ebola virus poses a severe public health threat, yet understanding factors influencing disease outcomes remains incomplete. Our study aimed to identify critical pathways and hub genes associated with fatal and survivor Ebola disease outcomes. We analyzed differentially expressed hub genes (DEGs) between groups with fatal and survival outcomes, as well as a healthy control group. We conducted additional analysis to determine the functions and pathways associated with these DEGs. We found 13,198 DEGs in the fatal and 12,039 DEGs in the survival group compared to healthy controls, and 1873 DEGs in the acute fatal and survivor groups comparison. Upregulated DEGs in the comparison between the acute fatal and survivor groups were linked to ECM receptor interaction, complement and coagulation cascades, and PI3K-Akt signaling. Upregulated hub genes identified from the acute fatal and survivor comparison (FGB, C1QA, SERPINF2, PLAT, C9, SERPINE1, F3, VWF) were enriched in complement and coagulation cascades; the downregulated hub genes (IL1B, 1L17RE, XCL1, CXCL6, CCL4, CD8A, CD8B, CD3D) were associated with immune cell processes. Hub genes CCL2 and F2 were unique to fatal outcomes, while CXCL1, HIST1H4F, and IL1A were upregulated hub genes unique to survival outcomes compared to healthy controls. Our results demonstrate for the first time the association of EVD outcomes to specific hub genes and their associated pathways and biological processes. The identified hub genes and pathways could help better elucidate Ebola disease pathogenesis and contribute to the development of targeted interventions and personalized treatment for distinct EVD outcomes.

Television Viewing from Young Adulthood to Middle Age and Premature Cardiovascular Disease Events: A Prospective Cohort Study

BackgroundPrevious literature has explored the relationship between television viewing and cardiovascular disease (CVD) in adults; however, there remains a paucity of longitudinal data describing how young adult television viewing relates to premature CVD events.ObjectiveTo ascertain the relationship between level and annualized changes in television viewing from young adulthood to middle age and the incidence of premature CVD events before age 60.DesignThe Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective community-based cohort with over 30 years of follow-up (1985–present).ParticipantsBlack and White men and women who were 18–30 years old at baseline (1985–1986).Main MeasuresIndependent variables: Individualized television viewing trajectories were developed using linear mixed models. Dependent variables: Fatal and nonfatal coronary heart disease (CHD), heart failure, and stroke outcomes were analyzed separately and as a combined CVD event outcome.Key ResultsAmong 4318 included participants, every 1-h increase in daily hours of television viewing at age 23 was associated with higher odds of incident CHD (adjusted odds ratio [AOR] 1.26, 95% confidence interval [CI] 1.06–1.49) and incident CVD events (AOR 1.16, 95% CI 1.03–1.32). Each additional hour of daily television viewing annually was associated with higher annual odds of CHD incidence (AOR 1.55, 95% CI 1.06–2.25), stroke incidence (AOR 1.58, 95% CI 1.02–2.46), and CVD incidence (AOR 1.32, 95% CI 1.03–1.69). Race and sex modified the association between television viewing level at age 23 and CHD, heart failure, and stroke, with White men most consistently having significant associations.ConclusionsIn this prospective cohort study, greater television viewing in young adulthood and annual increases in television viewing across midlife were associated with incident premature CVD events, particularly CHD. Young adulthood as well as behaviors across midlife may be important periods to promote healthy television viewing behavior patterns.

The effectiveness of the Mediterranean Diet for primary and secondary prevention of cardiovascular disease: An umbrella review.

This study aimed to review meta-analyses of randomised controlled trials that evaluated the effectiveness of the Mediterranean Diet for the primary and secondary prevention of cardiovascular disease. Five databases (Medline, Embase, Cochrane, CINAHL and ProQuest) were searched from inception to November 2022. Inclusion criteria were: (i) systematic review of randomised controlled studies with metanalysis; (ii) adults ≥18 years from the general population with (secondary prevention) and without (primary prevention) established cardiovascular disease; (iii) Mediterranean Diet compared with another dietary intervention or usual care. Review selection and quality assessment using AMSTAR-2 were completed in duplicate. GRADE was extracted from each review, and results were synthesised narratively. Eighteen meta-analyses of 238 randomised controlled trials were included, with an 8% overlap of primary studies. Compared to usual care, the Mediterranean Diet was associated with reduced cardiovascular disease mortality (n = 4 reviews, GRADE low certainty; risk ratio range: 0.35 [95% confidence interval: 0.15-0.82] to 0.90 [95% confidence interval: 0.72-1.11]). Non-fatal myocardial infarctions were reduced (n = 4 reviews, risk ratio range: 0.47 [95% confidence interval: 0.28-0.79] to 0.60 [95% confidence interval: 0.44-0.82]) when compared with another active intervention. The methodological quality of most reviews (n = 16/18; 84%) was low or critically low and strength of evidence was generally weak. This review showed that the Mediterranean Diet can reduce fatal cardiovascular disease outcome risk by 10%-67% and non-fatal cardiovascular disease outcome risk by 21%-70%. This preventive effect was more significant in studies that included populations with established cardiovascular disease. Better quality reviews are needed.

Case Study on Breast Cancer Detection using K-Nearest Neighbour Algorithm

Abstract: Breast cancer is one of the common occurring cancer in women across the globe, affecting about significant percentage of women at some point in their life. Even with the development of new technologies in the field of medicine and research, the accurate diagnosis of this fatal disease outcome is one of the most important tasks needed to be done till date. Our objective is to develop a sophisticated and automated diagnostic system that yields accurate and reproducible results for predicting whether a breast cancer tumour is benign (non-cancerous) or malignant (cancerous). We have implemented KNearest Neighbour Algorithm using various normalization techniques and distance functions at different values of K. A comparative study using various distance metrics, i.e., Euclidean distance, Pythagorean distance has been done. The accuracy of each variation is tested and the maximum accurate prediction is considered for the result. Highest accuracy of 121/143 = 84.6% is achieved, with KNN implementation using Euclidean distance metric at k=5.

The Effects of Hospitalisation on the Serum Metabolome in COVID-19 Patients.

COVID-19, a systemic multi-organ disease resulting from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is known to result in a wide array of disease outcomes, ranging from asymptomatic to fatal. Despite persistent progress, there is a continued need for more accurate determinants of disease outcomes, including post-acute symptoms after COVID-19. In this study, we characterised the serum metabolomic changes due to hospitalisation and COVID-19 disease progression by mapping the serum metabolomic trajectories of 71 newly hospitalised moderate and severe patients in their first week after hospitalisation. These 71 patients were spread out over three hospitals in Switzerland, enabling us to meta-analyse the metabolomic trajectories and filter consistently changing metabolites. Additionally, we investigated differential metabolite-metabolite trajectories between fatal, severe, and moderate disease outcomes to find prognostic markers of disease severity. We found drastic changes in serum metabolite concentrations for 448 out of the 901 metabolites. These results included markers of hospitalisation, such as environmental exposures, dietary changes, and altered drug administration, but also possible markers of physiological functioning, including carboxyethyl-GABA and fibrinopeptides, which might be prognostic for worsening lung injury. Possible markers of disease progression included altered urea cycle metabolites and metabolites of the tricarboxylic acid (TCA) cycle, indicating a SARS-CoV-2-induced reprogramming of the host metabolism. Glycerophosphorylcholine was identified as a potential marker of disease severity. Taken together, this study describes the metabolome-wide changes due to hospitalisation and COVID-19 disease progression. Moreover, we propose a wide range of novel potential biomarkers for monitoring COVID-19 disease course, both dependent and independent of the severity.

Immunogenicity of poxvirus-based vaccines against Nipah virus

Nipah virus (NiV), an emerging zoonotic pathogen in Southeast Asia, is transmitted from Pteropus species of fruit bats to a wide range of species, including humans, pigs, horses, dogs, and cats. NiV has killed millions of animals and caused highly fatal human outbreaks since no vaccine is commercially available. This study characterized the immunogenicity and safety of poxvirus-based Nipah vaccines that can be used in humans and species responsible for NiV transmission. Mice were vaccinated with modified vaccinia Ankara (MVA) and raccoon pox (RCN) viral vectors expressing the NiV fusion (F) and glycoprotein (G) proteins subcutaneously (SC) and intranasally (IN). Importantly, both vaccines did not induce significant weight loss or clinical signs of disease while generating high circulating neutralizing antibodies and lung-specific IgG and IgA responses. The MVA vaccine saw high phenotypic expression of effector and tissue resident memory CD8ɑ+ T cells in lungs and splenocytes along with the expression of central memory CD8ɑ+ T cells in lungs. The RCN vaccine generated effector memory (SC) and tissue resident (IN) CD8ɑ+ T cells in splenocytes and tissue resident (IN) CD8ɑ+ T cells in lung cells. These findings support MVA-FG and RCN-FG viral vectors as promising vaccine candidates to protect humans, domestic animals, and wildlife from fatal disease outcomes and to reduce the global threat of NiV.

Serum procalcitonin level is independently associated with mechanical ventilation and case-fatality in hospitalized COVID-19-positive US veterans–A potential marker for disease severity

The Coronavirus-19 disease (COVID-19) has claimed over 6.8 million lives since first being reported in late 2019. The virus that causes COVID-19 disease is highly contagious and spreads rapidly. To date, there are no approved prognostic tools that could predict why some patients develop severe or fatal disease outcomes. Early COVID-19 studies found an association between procalcitonin (PCT) and hospitalization or duration of mechanical ventilation and death but were limited by the cohort sizes. Therefore, this study was designed to confirm the associations of PCT with COVID-19 disease severity outcomes in a large cohort. For this retrospective data analysis study, 27,154 COVID-19-positive US veterans with post-infection PCT laboratory test data and their disease severity outcomes were accessed using the VA electronic healthcare data. Cox regression models were used to test the association between serum PCT levels and disease outcomes while controlling for demographics and relevant confounding variables. The models demonstrated increasing disease severity (ventilation and death) with increasing PCT levels. For PCT serum levels above 0.20 ng/ml, the unadjusted risk increased nearly 2.3-fold for mechanical ventilation (hazard ratio, HR, 2.26, 95%CI: 2.11-2.42) and in-hospital death (HR, 2.28, 95%CI: 2.16-2.41). Even when adjusted for demographics, diabetes, pneumonia, antibiotic use, white blood cell count, and serum C-reactive protein levels, the risks remained relatively high for mechanical ventilation (HR, 1.80, 95%CI: 1.67-1.94) and death (HR, 1.76, 95%CI: 1.66-1.87). These data suggest that higher PCT levels have independent associations with ventilation and in-hospital death in veterans with COVID-19 disease, validating previous findings. The data suggested that serum PCT level may be a promising prognostic tool for COVID-19 severity assessment and should be further evaluated in a prospective clinical trial.

Vitamin D, Albumin, and D-Dimer as Significant Prognostic Markers in Early Hospitalization in Patients with COVID-19.

A total of 288 patients treated for COVID-19 infection participated in the research. The patients were treated in the period from May 2020 to January 2021. All patients were divided based on the need for oxygen therapy (Sat > 94%) into patients with mild or severe clinical pictures. The biochemical and radiographic parameters of the patients were analyzed. Appropriate statistical methods were used in the statistical analysis. In patients with COVID-19 with confirmed severe clinical pictures, lower values of serum albumin (p < 0.0005) and vitamin D (p = 0.004) were recorded, as opposed to elevated values of D-dimer (p < 0.0005). Accordingly, the patients with fatal disease outcomes had lower levels of albumin (p < 0.0005) and vitamin D (p = 0.002), while their D-dimer (p < 0.0005) levels were elevated. An increase in the radiographic score, as a parameter for assessing the severity of the clinical picture, was accompanied by a decrease in serum albumin (p < 0.0005) and a simultaneous increase in D-dimer (p < 0.0005), without a change in the vitamin D concentration (p = 0.261). We also demonstrated the interrelations of the serum levels of vitamin D, albumin, and D-dimer in patients with COVID-19 as well as their significance as predictors of the outcome of the disease. The significance of the predictive parameters in our study indicates the existence of an important combined role of vitamin D, albumin, and D-dimer in the early diagnosis of the most severe patients suffering from COVID-19. Reduced values of vitamin D and albumin, in combination with elevated values of D-dimer, can be timely indicators of the development of a severe clinical picture and death due to COVID-19.

Proteomic analysis of metronidazole resistance in the human facultative pathogen Bacteroides fragilis.

The anaerobic gut bacteria and opportunistic pathogen Bacteroides fragilis can cause life-threatening infections when leaving its niche and reaching body sites outside of the gut. The antimicrobial metronidazole is a mainstay in the treatment of anaerobic infections and also highly effective against Bacteroides spp. Although resistance rates have remained low in general, metronidazole resistance does occur in B. fragilis and can favor fatal disease outcomes. Most metronidazole-resistant Bacteroides isolates harbor nim genes, commonly believed to encode for nitroreductases which deactivate metronidazole. Recent research, however, suggests that the mode of resistance mediated by Nim proteins might be more complex than anticipated because they affect the cellular metabolism, e.g., by increasing the activity of pyruvate:ferredoxin oxidoreductase (PFOR). Moreover, although nim genes confer only low-level metronidazole resistance to Bacteroides, high-level resistance can be much easier induced in the laboratory in the presence of a nim gene than without. Due to these observations, we hypothesized that nim genes might induce changes in the B. fragilis proteome and performed comparative mass-spectrometric analyses with B. fragilis 638R, either with or without the nimA gene. Further, we compared protein expression profiles in both strains after induction of high-level metronidazole resistance. Interestingly, only few proteins were repeatedly found to be differentially expressed in strain 638R with the nimA gene, one of them being the flavodiiron protein FprA, an enzyme involved in oxygen scavenging. After induction of metronidazole resistance, a far higher number of proteins were found to be differentially expressed in 638R without nimA than in 638R with nimA. In the former, factors for the import of hemin were strongly downregulated, indicating impaired iron import, whereas in the latter, the observed changes were not only less numerous but also less specific. Both resistant strains, however, displayed a reduced capability of scavenging oxygen. Susceptibility to metronidazole could be widely restored in resistant 638R without nimA by supplementing growth media with ferrous iron sulfate, but not so in resistant 638R with the nimA gene. Finally, based on the results of this study, we present a novel hypothetic model of metronidazole resistance and NimA function.

Immunoglobulin G production in COVID-19 - associations with age, outcome, viral persistence, inflammation and pro-thrombotic markers

Age represents the major risk factor for fatal disease outcome in coronavirus disease (COVID-19) due to age-related changes in immune responses. On the one hand lymphocyte counts continuously decline with advancing age, on the other hand somatic hyper-mutations of B-lymphocytes and levels of class-switched antibodies diminish, resulting in lower neutralizing antibody titers. To date the impact of age on immunoglobulin G (IgG) production in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is unknown. Therefore, we investigated the impact of age on the onset of IgG production and its association with outcome, viral persistence, inflammatory and thrombotic markers in consecutive, hospitalized COVID-19 patients admitted to the Clinic Favoriten (Vienna, Austria) between April and October 2020 that fulfilled predefined inclusion criteria. Three different IgGs against SARS-CoV-2 (spike protein S1, nucleocapsid (NC), and the spike protein receptor binding domain (RBD)) were monitored in plasma of 97 patients upon admission and three times within the first week followed by weekly assessment during their entire hospital stay. We analyzed the association of clinical parameters including C-reactive protein (CRP), D-dimer levels and platelet count as well as viral persistence with the onset and concentration of different anti-SARS-CoV-2 specific IgGs. Our data demonstrate that in older individuals anti-SARS-CoV-2 IgG production increases earlier after symptom onset and that deceased patients have the highest amount of antibodies against SARS-CoV-2 whereas intensive care unit (ICU) survivors have the lowest titers. In addition, anti-SARS-CoV-2 IgG concentrations are not associated with curtailed viral infectivity, inflammatory or thrombotic markers, suggesting that not only serological memory but also other adaptive immune responses are involved in successful viral killing and protection against a severe COVID-19 infection.

Machine Learning Successfully Detects Patients with COVID-19 Prior to PCR Results and Predicts Their Survival Based on Standard Laboratory Parameters in an Observational Study.

In the current COVID-19 pandemic, clinicians require a manageable set of decisive parameters that can be used to (i) rapidly identify SARS-CoV-2 positive patients, (ii) identify patients with a high risk of a fatal outcome on hospital admission, and (iii) recognize longitudinal warning signs of a possible fatal outcome. This comparative study was performed in 515 patients in the Maria Skłodowska-Curie Specialty Voivodeship Hospital in Zgierz, Poland. The study groups comprised 314 patients with COVID-like symptoms who tested negative and 201 patients who tested positive for SARS-CoV-2 infection; of the latter, 72 patients with COVID-19 died and 129 were released from hospital. Data on which we trained several machine learning (ML) models included clinical findings on admission and during hospitalization, symptoms, epidemiological risk, and reported comorbidities and medications. We identified a set of eight on-admission parameters: white blood cells, antibody-synthesizing lymphocytes, ratios of basophils/lymphocytes, platelets/neutrophils, and monocytes/lymphocytes, procalcitonin, creatinine, and C-reactive protein. The medical decision tree built using these parameters differentiated between SARS-CoV-2 positive and negative patients with up to 90-100% accuracy. Patients with COVID-19 who on hospital admission were older, had higher procalcitonin, C-reactive protein, and troponinI levels together with lower hemoglobin and platelets/neutrophils ratio were found to be at highest risk of death from COVID-19. Furthermore, we identified longitudinal patterns in C-reactive protein, white blood cells, and Ddimer that predicted the disease outcome. Our study provides sets of easily obtainable parameters that allow one to assess the status of a patient with SARS-CoV-2 infection, and the risk of a fatal disease outcome on hospital admission and during the course of the disease.

An Overview of the Infectious Cycle of Bunyaviruses.

Bunyaviruses represent the largest group of RNA viruses and are the causative agent of a variety of febrile and hemorrhagic illnesses. Originally characterized as a single serotype in Africa, the number of described bunyaviruses now exceeds over 500, with its presence detected around the world. These predominantly tri-segmented, single-stranded RNA viruses are transmitted primarily through arthropod and rodent vectors and can infect a wide variety of animals and plants. Although encoding for a small number of proteins, these viruses can inflict potentially fatal disease outcomes and have even developed strategies to suppress the innate antiviral immune mechanisms of the infected host. This short review will attempt to provide an overall description of the order Bunyavirales, describing the mechanisms behind their infection, replication, and their evasion of the host immune response. Furthermore, the historical context of these viruses will be presented, starting from their original discovery almost 80 years ago to the most recent research pertaining to viral replication and host immune response.

Physical activity from young adulthood to middle age and premature cardiovascular disease events: a 30-year population-based cohort study

BackgroundAlthough physical activity is generally protective of cardiovascular disease (CVD), less is known about how young adult physical activity relates to premature CVD events. The objective of this study was to determine the association between level and change in physical activity from young adulthood to middle age and incidence of premature CVD events before age 60.MethodsWe analyzed data collected across four urban sites from nine visits over 30 years of follow-up (1985–2016) from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective community-based cohort study of 5115 Black and White women and men aged 18–30 years at baseline (1985–1986). Linear mixed models were used to develop individualized moderate-to-vigorous intensity self-reported physical activity trajectories per participant. Fatal and nonfatal coronary heart disease (CHD), heart failure, and stroke outcomes were analyzed separately and as a combined CVD event outcome.ResultsOverall, physical activity declined in young adults as they progressed through middle age. Lower physical activity scores (per 100 exercise units) in 18 year-olds were associated with higher odds of premature CHD (AOR 1.14, 95% CI 1.02–1.28), heart failure (AOR 1.21, 95% CI 1.05–1.38), stroke (AOR 1.20, 95% CI 1.04–1.39), and any CVD (AOR 1.15, 95% CI 1.06–1.24) events. Each additional annual 1-unit reduction in the physical activity score was associated with a higher annual odds of incident heart failure (1.07, 95% CI 1.02–1.13), stroke (1.06, 95% CI 1.00–1.13), and CVD (1.04, 95% CI 1.01–1.07) events. Meeting the minimum (AOR 0.74, 95% CI 0.0.57–0.96) and twice the minimum (AOR 0.55, 95% CI 0.34–0.91) Department of Health and Human Services physical activity guidelines through follow up was protective of premature CVD events.ConclusionsGiven recent trends in declining physical activity with age and associated premature CVD events, the transition from young adult to midlife is an important time period to promote physical activity.

SARS-CoV-2 infection and lytic reactivation of herpesviruses: A potential threat in thepostpandemic era?

The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which is the causative pathogen for the coronavirus disease 2019 (COVID‐19) pandemic, has greatly stressed our healthcare system. In addition to severe respiratory and systematic symptoms, several comorbidities increase the risk of fatal disease outcomes, including chronic viral infections. Increasing cases of lytic reactivation of human herpesviruses in COVID‐19 patients and vaccinated people have been reported recently. SARS‐CoV2 coinfection, COVID‐19 treatments, and vaccination may aggravate those herpesvirus‐associated diseases by reactivating the viruses in latently infected host cells. In this review, we summarize recent clinical findings and limited mechanistic studies regarding the relationship between SARS‐CoV‐2 and different human herpesviruses that suggest an ongoing potential threat to human health in the postpandemic era.

Role of Th17 Cytokines in the Liver's Immune Response during Fatal Yellow Fever: Triggering Cell Damage Mechanisms.

Yellow fever (YF) is an infectious and acute viral haemorrhagic disease that triggers a cascade of host immune responses. We investigated the Th17 cytokine profile in the liver tissue of patients with fatal YF. Liver tissue samples were collected from 26 deceased patients, including 21 YF-positive and 5 flavivirus-negative patients, with preserved hepatic parenchyma architecture, who died of other causes. Histopathological and immunohistochemical analysis were performed on the liver samples to evaluate the Th17 profiles (ROR-γ, STAT3, IL-6, TGF-β, IL-17A, and IL-23). Substantial differences were found in the expression levels of these markers between the patients with fatal YF and controls. A predominant expression of Th17 cytokine markers was observed in the midzonal region of the YF cases, the most affected area in the liver acinus, compared with the controls. Histopathological changes in the hepatic parenchyma revealed cellular damage characterised mainly by the presence of inflammatory cell infiltrates, Councilman bodies (apoptotic cells), micro/macrovesicular steatosis, and lytic and coagulative necrosis. Hence, Th17 cytokines play a pivotal role in the immunopathogenesis of YF and contribute markedly to triggering cell damage in patients with fatal disease outcomes.

Plasma cytokine levels characterize disease pathogenesis and treatment response in tuberculosis patients

BackgroundMycobacterium (M.) tuberculosis-caused immunopathology is characterized by aberrant expression of plasma cytokines in human tuberculosis. Disease severity and long-term anti-mycobacterial treatment are potentially influenced by immunopathology and normalization of plasma cytokine levels during therapy may indicate treatment efficacy and recovery.Study design and methodsIn this study, we analyzed the concentrations of selected plasma cytokines (i.e., IL-6, IP-10, IL-10, IL-22, IFNγ, GM-CSF, IL-8) and M. tuberculosis sputum burden in patients with tuberculosis (n = 76). Cytokine levels were compared to healthy contacts (n = 40) and changes under treatment were monitored (i.e., 6 and 16 weeks after treatment start). According to differences in M. tuberculosis sputum burden and conversion, tuberculosis patients were classified as paucibacillary as well as ‘rapid’ or ‘slow’ treatment responders. A subgroup of tuberculosis patients had fatal disease courses.ResultsSix of seven cytokines were significantly higher in tuberculosis patients as compared to contacts and four of these (i.e., IL-6, IP-10, IL-10, and IL-22) were detectable in the majority of tuberculosis patients. IL-6 showed the strongest discriminating capacity for tuberculosis disease and in combination with IL-10 concentrations efficiently classified paucibacillary tuberculosis cases as well as those with fatal disease outcome. In addition, IL-6 and IP-10 levels decreased significantly after 6 weeks of treatment and analyses of subgroups with differential treatment response showed delayed decline of IL-6 levels in slow treatment responders.ConclusionsCombinations of different plasma cytokine (namely, IL-6, IL-10, and IP-10) efficiently classified tuberculosis patients with differential mycobacterial burden and especially IL-6 qualified as a biomarker candidate for early treatment response.

Restrained expression of canine glucocorticoid receptor splice variants \u03b1 and P prognosticates fatal disease outcome in SIRS

Glucocorticoids play a central role in the inflammatory response and alleviate the symptoms in critically ill patients. The glucocorticoid action relies on the glucocorticoid receptor (GR) which translocates into the nucleus upon ligand-binding and regulates transcription of a battery of genes. Although the GR is encoded by a single gene, dozens of its splice variants have been described in diverse species. The GRα isoform encodes the full, functionally active protein that is composed of a transactivation, a DNA-binding, and a C-terminal ligand-binding domain. The second most highly expressed receptor variant, the GR-P, is formed by an intron retention that introduces an early stop codon and results in a probably dysfunctional protein with truncated ligand-binding domain. We described the canine ortholog of GR-P and showed that this splice variant is highly abundant in the peripheral blood of dogs. The level of cGRα and cGR-P transcripts are elevated in patients of SIRS and the survival rate is increased with elevated cGRα and cGR-P expression. The ratio of cGRα and cGR-P mRNA did not differ between the survivor and non-survivor patients; thus, the total GR expression is more pertinent than the relative expression of GR isoforms in assessment of the disease outcome.

CD8+PD-L1+CXCR3+ polyfunctional T cell abundances are associated with survival in critical SARS-CoV-2-infected patients.

The importance of the adaptive T cell response in the control and resolution of viral infection has been well established. However, the nature of T cell–mediated viral control mechanisms in life-threatening stages of COVID-19 has yet to be determined. The aim of the present study was to determine the function and phenotype of T cell populations associated with survival or death of patients with COVID-19 in intensive care as a result of phenotypic and functional profiling by mass cytometry. Increased frequencies of circulating, polyfunctional CD4+CXCR5+HLA-DR+ stem cell memory T cells (Tscms) and decreased proportions of granzyme B–expressing and perforin-expressing effector memory T cells were detected in recovered and deceased patients, respectively. The higher abundance of polyfunctional PD-L1+CXCR3+CD8+ effector T cells (Teffs), CXCR5+HLA-DR+ Tscms, and anti-nucleocapsid (anti-NC) cytokine-producing T cells permitted us to differentiate between recovered and deceased patients. The results from a principal component analysis show an imbalance in the T cell compartment that allowed for the separation of recovered and deceased patients. The paucity of circulating PD-L1+CXCR3+CD8+ Teffs and NC-specific CD8+ T cells accurately forecasts fatal disease outcome. This study provides insight into the nature of the T cell populations involved in the control of COVID-19 and therefore might impact T cell–based vaccine designs for this infectious disease.

Abstract LB072: SARS-CoV-2 proteins and anti-COVID-19 drugs induce lytic reactivation of an oncogenic virus

Abstract An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of Coronavirus Disease-2019 (COVID-19), a respiratory disease, has infected over 75,000,000 people since the end of 2019, killed over 1,600,000, and caused worldwide social and economic disruption. Because the mechanisms of SARS-CoV-2 infection of host cells and its pathogenesis remain largely unclear, there are currently no antiviral drugs with proven efficacy. Besides severe respiratory and systematic symptoms, several comorbidities increase risk of fatal disease outcome. Therefore, it is required to investigate the impacts of COVID-19 on pre-existing diseases of patients, such as cancer and other infectious diseases. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, such as Kaposi's sarcoma (KS) and Primary effusion lymphoma (PEL), mostly seen in immunosuppressed patients especially people with HIV infection. In the current study, we for the first time report that SARS-CoV-2 encoded spike (S) and nucleocapsid (N) proteins and some currently used anti-COVID-19 drugs (especially Azithromycin and Nafamostat mesylate) are able to induce lytic reactivation of KSHV from virus infected normal and tumor cells, through manipulation of intracellular signaling pathways. In addition, we found the obvious upregulation of ACE2 expression, the major receptor of SARS-CoV-2, in AIDS-KS tissues, indicating that KSHV may potentially increase SARS-CoV-2 co-infection. Together, our data indicate that those KSHV+ patients especially in endemic areas exposure to COVID-19 or undergoing the treatment may have increased risks to develop these virus-associated cancers, even after they have fully recovered from COVID-19. Citation Format: Zhiqiang Qin, Jungang Chen, Lu Dai, Lindsey Barrett, Steven Post. SARS-CoV-2 proteins and anti-COVID-19 drugs induce lytic reactivation of an oncogenic virus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB072.

SARS-CoV-2 proteins and anti-COVID-19 drugs induce lytic reactivation of an oncogenic virus

An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of Coronavirus Disease-2019 (COVID-19), a respiratory disease, has infected almost one hundred million people since the end of 2019, killed over two million, and caused worldwide social and economic disruption. Because the mechanisms of SARS-CoV-2 infection of host cells and its pathogenesis remain largely unclear, there are currently no antiviral drugs with proven efficacy. Besides severe respiratory and systematic symptoms, several comorbidities increase risk of fatal disease outcome. Therefore, it is required to investigate the impacts of COVID-19 on pre-existing diseases of patients, such as cancer and other infectious diseases. In the current study, we report that SARS-CoV-2 encoded proteins and some currently used anti-COVID-19 drugs are able to induce lytic reactivation of Kaposi’s sarcoma-associated herpesvirus (KSHV), one of major human oncogenic viruses, through manipulation of intracellular signaling pathways. Our data indicate that those KSHV + patients especially in endemic areas exposure to COVID-19 or undergoing the treatment may have increased risks to develop virus-associated cancers, even after they have fully recovered from COVID-19.