Infectious Disease-related Deaths Research Articles

Comparison of Molecular Testing Methods in Detecting Drug Resistance Tuberculosis

Tuberculosis (TB) is the leading cause of infectious disease-related deaths in Indonesia, and the COVID-19 pandemic has led to a decline in TB reporting and an increase in Drug-Resistant Tuberculosis (DR-TB). While traditional culture and Drug Susceptibility Testing (DST) takes 2-8 weeks, therefore, genotypic assays such as GeneXpert, Line Probe Assay (LPA), and sequencing offer faster and more precise diagnosis and drug resistance information.

Regulation of Type I Interferon and Autophagy in Immunity against Mycobacterium Tuberculosis: Role of CGAS and STING1.

Mycobacterium tuberculosis (M. tb) is a significant intracellular pathogen responsible for numerous infectious disease-related deaths worldwide. It uses ESX-1 T7SS to damage phagosomes and to enter the cytosol of host cells after phagocytosis. During infection, M. tb and host mitochondria release dsDNA, which activates the CGAS-STING1 pathway. This pathway leads to the production of type I interferons and proinflammatory cytokines and activates autophagy, which targets and degrades bacteria within autophagosomes. However, the role of type I IFNs in immunity against M. tb is controversial. While previous research has suggested a protective role, recent findings from cgas-sting1 knockout mouse studies have contradicted this. Additionally, a study using knockout mice and non-human primate models uncovered a new mechanism by which neutrophils recruited to lung infections form neutrophil extracellular traps. Activating plasmacytoid dendritic cells causes them to produce type I IFNs, which interfere with the function of interstitial macrophages and increase the likelihood of tuberculosis. Notably, M. tb uses its virulence proteins to disrupt the CGAS-STING1 signaling pathway leading to enhanced pathogenesis. Investigating the CGAS-STING1 pathway can help develop new ways to fight tuberculosis.

Exploring the use of exhaled breath as a diagnostic tool for pulmonary TB.

Despite its historical decline, TB remains a significant cause of infectious disease-related global deaths. The lack of reliable diagnostic tests for vulnerable groups, such as children and immunocompromised patients, remains a challenge for TB control. For decades, it has been recognised that exhaled breath has great potential as a non-invasive and universally accessible clinical alternative to sputum and invasive sampling methods. Although translation into clinical practice has not yet occurred, there has been significant progress with promising results in various applications, including diagnosis, estimation of infectiousness, and monitoring of treatment response. More recently, the COVID-19 pandemic reignited global interest in this field and technological advances have further accelerated its development. In the coming decade, breath sampling will enhance our understanding of respiratory infectious diseases and host-immune responses, which may lead to clinical applications. Here we discuss the diagnostic landscape of TB and the current state of the art of breath sampling.

An Aptamer-Based Proteomic Analysis of Plasma from Cats (Felis catus) with Clinical Feline Infectious Peritonitis.

Feline infectious peritonitis (FIP) is a systemic disease manifestation of feline coronavirus (FCoV) and is the most important cause of infectious disease-related deaths in domestic cats. FIP has a variable clinical manifestation but is most often characterized by widespread vasculitis with visceral involvement and/or neurological disease that is typically fatal in the absence of antiviral therapy. Using an aptamer-based proteomics assay, we analyzed the plasma protein profiles of cats who were naturally infected with FIP (n = 19) in comparison to the plasma protein profiles of cats who were clinically healthy and negative for FCoV (n = 17) and cats who were positive for the enteric form of FCoV (n = 9). We identified 442 proteins that were significantly differentiable; in total, 219 increased and 223 decreased in FIP plasma versus clinically healthy cat plasma. Pathway enrichment and associated analyses showed that differentiable proteins were related to immune system processes, including the innate immune response, cytokine signaling, and antigen presentation, as well as apoptosis and vascular integrity. The relevance of these findings is discussed in the context of previous studies. While these results have the potential to inform diagnostic, therapeutic, and preventative investigations, they represent only a first step, and will require further validation.

The nutritional well-being of children under five with HIV-positive parents at Bikurungu Health Center III in Rukungiri District

Families affected by HIV/AIDS often face food insecurity and malnutrition. In impoverished nations, over a third of infectious disease-related deaths in children under five result from poor nutrition. Household food insecurity and the impact of HIV/AIDS-related illnesses can hinder the growth of young children, leading to increased malnutrition. A study involving 310 mother/infant pairs from various households was conducted using a convenient sampling method. Information was gathered through a structured questionnaire. Analysis revealed that children in households affected by HIV had a significantly higher rate of stunting (height-for-age < –2 SD) compared to those in unaffected households (25.5% vs. 9.1%, p = .002). However, the rates of wasting and underweight did not significantly differ between HIV-affected and unaffected households. Living in households affected by HIV is associated with stunted growth in children under five. Keywords: HIV/AIDS, Children under 5 years of age, Malnutrition, Stunting

Depression and stigma experience among patients with tuberculosis in urban and rural settings

BackgroundTuberculosis is one of the leading causes of morbidity and mortality in the globe. The most common infectious disease-related death in the world is tuberculosis. In 2020, an estimated 9.9 million people became ill with tuberculosis (TB), translating to 127 cases per 100,000 people. The stigma associated with tuberculosis (TB) causes people to put off seeking treatment and adhering to their treatment regimen. India has the highest prevalence of tuberculosis in the world. Depression and stigma oftem co-exist in people with tuberculosis. ObjectiveTo estimate the prevalence of depression and stigma experience among patients with tuberculosis, and to determine the association of socio-demographic variables and stigma experience with depression in urban and rural field practice areas. MethodologyThis is a cross-sectional study where purposive sampling method was adopted. A house-to-house and phone interview was conducted using a pre-designed, pre-tested questionnaire. Depression was assessed using the PHQ-9 and stigma experience was assessed using the Stigma Scale for Chronic Illness - 8 items (SSCI -8 Items). SPSS version 25 was used (licensed to the institution)for analysis. Descriptive statistics was used to calculate proportions, mean, standard deviation. Inferential statistics like Chi-square analysis/Fisher's exact analysis were used to find the association between various socio-demographic variables with the depression among patients with tuberculosis and association between stigma experience and depression. (Yates continuity Highlights correction applied wherever required) p < 0.5 was considered to be statistically significant. ResultsThe overall prevalence of depression was 57.8%. The association between number of family members and type of tuberculosis with depression was statistically significant. 28.6% did not experience stigma, while 71.6% did. The association between depression score and stigma experience was not statistically significant. ConclusionMore than half of the study's participants had depression and had encountered stigma. There was significant association between depression scores with family size and type of tuberculosis.

Prevalence of tuberculosis/COVID-19 co-infection and factors associated with SARS-CoV-2 infection in pulmonary tuberculosis patients at a respiratory diseases center: a cross-sectional study.

currently, tuberculosis (TB) is the second cause of infectious disease-related deaths before COVID-19. These two infections have several similarities but little data is available on TB/COVID-19 co-infection, hence, we sought to investigate the prevalence of this co-infection and the factors associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in tuberculosis patients in a tuberculosis-endemic area. we conducted a prospective cross-sectional study from January to June 2022 at Respiratory Diseases Center in Douala, Cameroon by enrolling all consenting pulmonary tuberculosis patients. The presence of SARS-CoV-2 ribonucleic acid (RNA) and gamma-interferon levels were laboratory analyzed using the Reverse Transcriptase-Polymerase Chain Reaction and the enzyme-linked immunosorbent assay (ELISA) technique, respectively. The factors associated with COVID-19 carriage in pulmonary tuberculosis patients were analyzed by logistic regressions. overall, we enrolled 185 patients; 57.8% were males (sex ratio of 1.36) and their mean age was 43.70 ± 17.89 years. The prevalence of SARS-CoV-2 RNA in pulmonary TB patients was 24.3%. Asthma and sore throat were the factors favoring carriage (OR=3.74; 95% CI=1.271-11.017; p=0.017 and OR=4.05; 95%CI=1.204-13.600; p=0.024) and cough was a protective factor (OR=0.15; 95% CI = 0.034-0.690; p=0.015). the prevalence of SARS-CoV-2 carriage in tuberculosis patients is high and greater than the national prevalence. Asthma and sore throat would be associated factors.

Lower levels of small HDL particles associated with increased infectious disease morbidity and mortality: a population-based cohort study of 30 195 individuals.

Low levels of HDL cholesterol have been associated with increased risk of infectious disease morbidity and mortality. Nuclear magnetic resonance (NMR) spectroscopy permits the measurement of HDL particle count and allows further subclassification according to particle size. We tested the hypothesis that low number of different HDL subfractions is associated with increased infectious disease morbidity and mortality. HDL particle counts were measured using NMR spectroscopy in 30 195 individuals aged 22-99 years from the Copenhagen General Population Study. Using multiple-event Cox regression and cause-specific hazard models, we assessed risk of hospitalizations due to infection and infectious disease-related death, from 2003 through 2018. During follow-up, 9303 individuals had one or more infectious disease events, and 1558 experienced infectious disease-related death. In multifactorial adjusted analyses, low number of small and medium HDL particles was associated with increased risk of any infection and infectious disease-related death, whereas low number of large and extra-large HDL particles was not. A very high number of small and medium HDL particles was also associated with increased risk of any infection, but not with infectious disease-related death. For small and medium HDL particles and compared to individuals in the 91-95th percentile, hazard ratios (HRs) in individuals in the lowest percentile were 2.31 (95% confidence interval: 1.75, 3.05) for any infection and 3.23 (2.08, 5.02) for infectious disease-related death. For the highest percentile, corresponding HRs were 1.36 (1.07, 1.74) and 1.06 (0.57, 1.98), respectively. Individuals in the lowest percentile had increased risk of pneumonia (HR: 1.86; 95% confidence interval: 1.30, 2.65), sepsis (2.17; 1.37, 3.35), urinary tract infection (1.76; 1.17, 2.63), skin infection (1.87; 1.24, 2.81), gastroenteritis (1.78; 1.01, 3.16), and other infections (2.57; 1.28, 5.16). Low number of the small HDL particles was associated with increased infectious disease morbidity and mortality.

POS-043 The existence of Dibates mellitus in cases of Tuberculois patients. Findings in a Tribal population from Nikshay Data base

For more than 75,000 years, tuberculosis (TB) has plagued humans over the planet. It is the greatest cause of infectious disease-related death worldwide, surpassing out HIV, though COVID-19 may overtake it. Approximately 1,200,000 individuals died as a direct result of this disease, and an additional 250,000 people who were HIV-positive died as a result of it, according to WHO estimates for 2018. Only eight nations, India (28%) China (9%) Indonesia (8%), Pakistan 6%, Nigeria 4% and Bangladesh 4%, account for two thirds of the world's TB infections, according to the World Health Organization (WHO) (3 percent) Needless to highlight India remains the top contributor for the disease.

Performance Analysis of Different Convolutional Neural Network (CNN) Models with Optimizers in Detecting Tuberculosis (TB) from Various Chest X-ray Images

Tuberculosis (TB) is one of the top 10 infectious disease-related deaths. This paper uses Convolutional Neural Networks (CNN) to investigate the accuracy and performance of three pre-trained models with different optimizers and loss functions to diagnose tuberculosis based on the patient's chest X-ray scans. The odds of treating and curing tuberculosis (TB) are better if the disease is diagnosed early in a patient. Early detection of tuberculosis could lead to a decreased overall mortality rate. The best and quickest way to identify tuberculosis is to look at the patient's chest X-Ray image (CXR). A qualified professional Radiologist is required to make an accurate diagnosis. But do not have qualified doctor or radiologist everywhere. On the other hand, it is quite difficult for a doctor or radiologist to diagnose from any x-ray images with open eyes. 914 normal chest x-ray images and 892 TB infected images were used from different sources to train and evaluate these images to detect the exact x-ray of Tuberculosis infected people. Different famous pre-trained models like VGG16, InceptionV3 and Xception etc. were applied. Approximately 80% of the data was used for training and the remaining 20% was used for validation. From all of these datasets, randomly 190 images from normal and 180 images from TB chest x-ray images have been taken. Those randomized 370 (190 for TB and 180 for normal) images were used to evaluate the data finally. Performance of different algorithm like VGG16, InceptionV3 and Xception by applying different optimizers (Adam, Adadelta, Adagrad, Adamax, RMSprop, Nadam, SGD), different loss functions (Binary Cross Entropy, Hinge, Squared Hinge), varying input image size and also varying batch size were also been recorded. Note that, huge variations of performance for different combinations of algorithm, optimizer, loss function, input image size, batch size have been observed. Confusion matrix, precision, recall, f1-score value have also been recorded to understand and justify how accurately the model is predicting the disease from different angles.

Tools, Strains, and Strategies To Effectively Conduct Anaerobic and Aerobic Transcriptional Reporter Screens and Assays in Staphylococcus aureus.

Transcriptional reporters are reliable and time-tested tools to study gene regulation. In Staphylococcus aureus, β-galactosidase (lacZ)-based genetic screens are not widely used because of the necessity of selectable markers for strain construction and the production of staphyloxanthin pigment, which obfuscates results. We describe a series of vectors that allow for markerless insertion of codon-optimized lacZ-based transcriptional reporters. The vectors code for different ribosomal binding sites, allowing for tailored lacZ expression. A ΔcrtM::kanR deletion insertion mutant was constructed that prevents the synthesis of staphyloxanthin, thereby permitting blue-white screening without the interference of carotenoid production. We demonstrate the utility of these vectors to monitor aerobic and anaerobic transcriptional activities. For the latter, we describe the use of a ferrocyanide-ferricyanide redox system [Fe(CN)63-/4-] permitting blue-white screening in the absence of oxygen. We also describe additional reporter systems and methods for monitoring transcriptional activity during anaerobic culture, including an FAD-binding fluorescent protein (EcFbFP), alpha-hemolysin (hla), or lipase (geh). The systems and methods described are compatible with vectors utilized to create and screen high-density transposon mutant libraries. IMPORTANCE Staphylococcus aureus is a human pathogen and a leading cause of infectious disease-related illness and death worldwide. For S. aureus to successfully colonize and invade host tissues, it must tightly control the expression of genes encoding virulence factors. Oxygen tension varies greatly at infection sites, and many abscesses are devoid of oxygen. In this study, we have developed novel tools and methods to study how and when S. aureus alters transcription of genes. A key advantage of these methods and tools is that they can be utilized in the presence and absence of oxygen. A better understanding of anaerobic gene expression in S. aureus will provide important insights into the regulation of genes in low-oxygen environments.

HIV/AIDS, hepatitis and tuberculosis-related mortality among incarcerated people: a global scoping review

PurposePeople in prison are at a higher risk of preventable mortality from infectious disease such as human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), hepatitis B (HBV), hepatitis C (HCV) and tuberculosis (TB) than those in the community. The extent of infectious disease-related mortality within the prison setting remains unclear. The purpose of this paper was to collate available information on infectious disease-related mortality, including the number of deaths and calculate the person-time death rate.Design/methodology/approachThe authors searched databases between 1 January 2000 and 18 November 2020 for studies reporting HIV, HBV, HCV, TB and/or HIV/TB-related deaths among people in prison.FindingsThe authors identified 78 publications drawn from seven Joint United Nations Programme on HIV/AIDS’ regions encompassing 33 countries and reporting on 6,568 deaths in prison over a 20-year period. HIV/AIDS (n = 3,305) was associated with the highest number of deaths, followed by TB (n = 2,892), HCV (n = 189), HIV/TB (n = 173) and HBV (n = 9). Due to the limitations of the available published data, it was not possible to meta-analyse or in any other way synthesise the available evidence.Research limitations/implicationsTo inform targeted efforts to reduce mortality, there is a need for more, better quality data to understand infectious disease-related mortality in custodial settings. Increased investment in the prevention and management of infectious diseases in custodial settings, and in documenting infectious disease-related deaths in prison, is warranted and will yield public health benefits.Originality/valueTo the authors’ best knowledge, this is the first scoping review focussed on deaths due to these infections among people in prison internationally. The gaps identified form recommendations to improve the future collection and reporting of prison mortality data.

665 Insufficient sleep and mortality among persons who inject drugs (PWID)

Abstract Introduction Insufficient sleep is associated with all-cause mortality in the general population. Illicit drugs have pronounced effects upon sleep, and insomnia symptoms are common among people with HIV (PWH), suggesting persons who inject drugs (PWID) with HIV may be at higher risk of adverse outcomes from insufficient sleep. Methods Participants in the AIDS Linked to the IntraVenous Experience (ALIVE) study, a cohort of PWID with or without HIV, completed the Sleep Adequacy subscale of the Medical Outcomes Study (MOS) semi-annually from 2005-present. Two questions queried participants about the frequency over the past four-weeks of: 1. getting sufficient sleep to feel rested on awakening; 2. obtaining needed amount of sleep. Six-Item responses ranged from “all of the time” to “none of the time”. Participants with mean subscale scores below the sample median were considered to have insufficient sleep. Mortality data were obtained through the National Death Index through 2018. Hazards of all-cause and cause-specific mortality were evaluated using Cox-regressions accounting for repeated measurements of insufficient sleep, respectively. Models were adjusted for sociodemographics, HIV and HCV infection, severe depressive symptoms (Center for Epidemiological Studies Depression [CESD]≥23), number of comorbidities (0, 1, ≥2), active injection drug use, current tobacco and alcohol use. Results Of 2612 participants (33% HIV+), mean age at baseline was 45.8 years, 32.4% were female, 75% Black, 45% had ≥high school education, and 33% had an annual income &amp;gt;$5,000. At baseline, the majority were current smokers (84%), alcohol drinkers (59%), or actively injecting drugs (56%), while 25% had severe depressive symptoms and 21% had ≥2 comorbidities. After adjustment for covariates, insufficient sleep was associated with a 37% increased hazard of all-cause mortality (HR: 1.37, 95% confidence interval [CI]: 1.13–1.65). Insufficient sleep was associated with a 93% increased hazard of death from HIV or infectious disease-related deaths (HR: 1.93, 95% CI: 1.26–2.97). Conclusion Insufficient sleep was independently associated with all-cause mortality and specifically with death from HIV or infectious diseases-related causes among PWID. Interventions consider targeting sleep behaviors among PWID hold promise for improving health and longevity in this population. Support (if any) National Institutes of Health grants: U01-DA-036297; R01-DA-047064; R01-HL-90483; K24-AI-118591; T32-DA007292; R01-DA039408.

Mortal remains disposal in the wake of the COVID-19 pandemic.

When dealing with infectious disease-related deaths, it is important to handle the remains of the deceased in a respectful and safe manner. There is no known evidence of SARS-CoV-2 transmission through handling of COVID-19 victim remains. However, guidelines recommend appropriate precautions to ensure safety from any potential risk. Discussions of safe and dignified postmortem care in COVID-19 cases can guide future decision making to encourage safety, dignity, and respect for all.

Fatal Clostridium Perfringens Sepsis with Spleen Rupture and Intraabdominal Massive Bleeding in a 37-Week Pregnancy

The maternal death rate remains unacceptably high worldwide, predominantly in areas of poor access to quality health services. According to the WHO, in 2017, 810 women died from preventable causes related to pregnancy and childbirth. Causes of maternal death are plenty, including previous morbidity and unexpected causes. Among the latter are infectious disease-related deaths. Herein, we describe a case of a 29-year-old woman at 37 weeks’ gestation who presented with right upper quadrant pain, which was initially considered to be pregnancy-related. However, she collapsed shortly after the hospital admission. The physical examination revealed severe hypovolemic shock due to a large amount of intraperitoneal free fluid. The patient was immediately rushed into an emergency cesarean section followed by exploratory laparotomy, which demonstrated a large intra-abdominal hemorrhage. The patient and her fetus died in the operating room. An autopsy revealed acute gangrenous cholecystitis along with abundant rod-shaped bacteria within the mucosa and vessels of the gallbladder, gas gangrene and rupture of the spleen, and signs of shock.Clostridium perfringens (CP) was isolated in the culture of a splenic sample. Although CP is a well-known and dreadful infectious etiological agent, catastrophic cases still happen. The acquaintance of this infection by the caregivers is crucial for the early diagnosis and treatment. This is a quite unique way to provide a dismal chance of survival in sepsis cases by this agent.

Characterization of Tissue Distribution, Catabolism, and Elimination of an Anti-Staphylococcus aureus THIOMAB Antibody-Antibiotic Conjugate in Rats.

Invasive Staphylococcus aureus infection is a leading cause of infectious disease-related deaths because S. aureus survives within host phagocytic cells, from which the bacteria are not adequately eliminated using current antibiotic treatments. Anti-S. aureus THIOMAB antibody-antibiotic conjugate (TAC), an anti-S. aureus antibody conjugated with antibiotic payload dmDNA31, was designed to deliver antibiotics into phagocytes, thereby killing intracellular S. aureus Herein, we present the distribution, metabolism/catabolism, and elimination properties for this modality. The tissue distribution of TAC and the release and elimination of its payload dmDNA31 were characterized in rats using multiple approaches. Intravenous injection of unconjugated [14C]dmDNA31 to rats resulted in a rapid clearance in both systemic circulation and tissues, with biliary secretion as the major route of elimination. Six major metabolites were identified. When [14C]dmDNA31 was conjugated to an antibody as TAC and administered to rat intravenously, a sustained exposure was observed in both systemic circulation and tissues. The dmDNA31 in blood and tissues mainly remained in conjugated form after administering TAC, although minimal deconjugation of dmDNA31 from TAC was also observed. Several TAC catabolites were identified, which were mainly eliminated through the biliary-fecal route, with dmDNA31 and deacetylated dmDNA31 as the most abundant catabolites. In summary, these studies provide a comprehensive characterization of the distribution, metabolism/catabolism, and elimination properties of TAC. These data fully support further clinical development of TAC for the invasive and difficult-to-treat S. aureus infection. SIGNIFICANCE STATEMENT: The present studies provide a comprehensive investigation of the absorption, distribution, metabolism/catabolism, and elimination of the first antibody-antibiotic conjugate developed for the treatment of an infectious disease. Although many antibody-drug conjugates are in development for various disease indications, only a limited amount of absorption, distribution, metabolism/catabolism, and elimination information is available in the literature. This study demonstrates the use of radiolabeling technology to delineate the absorption, distribution, metabolism/catabolism, and elimination properties of a complex modality and help address the key questions related to clinical pharmacological studies.

Development of CART model for prediction of tuberculosis treatment loss to follow up in the state of São Paulo, Brazil: A case–control study

BackgroundTuberculosis is the leading cause of infectious disease-related death, surpassing even the immunodeficiency virus. Treatment loss to follow up and irregular medication use contribute to persistent morbidity and mortality. This increases bacillus drug resistance and has a negative impact on disease control. ObjectiveThis study aims to develop a computational model that predicts the loss to follow up treatment in tuberculosis patients, thereby increasing treatment adherence and cure, reducing efforts regarding treatment relapses and decreasing disease spread. MethodsThis is a case-controlled study. Included in the data set were 103,846 tuberculosis cases from the state of São Paulo. They were collected using the TBWEB, an information system used as a tuberculosis treatment monitor, containing samples from 2006 to 2016. This set was later resampled into 6 segments with a 1-1 ratio. This ratio was used to avoid any bias during the model construction. ResultsThe Classification and Regression Trees were used as the prediction model. Training and test sets accounted for 70% in the former and 30% in the latter of the tuberculosis cases. The model displayed an accuracy of 0.76, F-measure of 0.77, sensitivity of 0.80 and specificity of 0.71. The model emphasizes the relationship between several variables that had been identified in previous studies as related to patient cure or loss to follow up treatment in tuberculosis patients. ConclusionIt was possible to construct a predictive model for loss to follow up treatment in tuberculosis patients using Classification and Regression Trees. Although the fact that the ideal predictive ability was not achieved, it seems reasonable to propose the use of Classification and Regression Trees models to predict likelihood of treatment follow up to support healthcare professionals in minimising the loss to follow up.

Antifungal Drug Resistance: Molecular Mechanisms in Candida albicans and Beyond.

Fungal infections are a major contributor to infectious disease-related deaths across the globe. Candida species are among the most common causes of invasive mycotic disease, with Candida albicans reigning as the leading cause of invasive candidiasis. Given that fungi are eukaryotes like their human host, the number of unique molecular targets that can be exploited for antifungal development remains limited. Currently, there are only three major classes of drugs approved for the treatment of invasive mycoses, and the efficacy of these agents is compromised by the development of drug resistance in pathogen populations. Notably, the emergence of additional drug-resistant species, such as Candida auris and Candida glabrata, further threatens the limited armamentarium of antifungals available to treat these serious infections. Here, we describe our current arsenal of antifungals and elaborate on the resistance mechanisms Candida species possess that render them recalcitrant to therapeutic intervention. Finally, we highlight some of the most promising therapeutic strategies that may help combat antifungal resistance, including combination therapy, targeting fungal-virulence traits, and modulating host immunity. Overall, a thorough understanding of the mechanistic principles governing antifungal drug resistance is fundamental for the development of novel therapeutics to combat current and emerging fungal threats.

IL-7 shapes a multifaceted CD8 T cell response to airway Influenza/A infection

Abstract The lungs are a site vulnerable to diseases such as cancer, autoimmunity and infections. With each breath, we risk inhaling infectious agents, and as such, airborne diseases are the leading cause of infectious disease-related deaths in the world. In particular, various strains of Influenza virus can infect airway epithelial cells and activate a network of immune cells leading to clearance, or in cases of pandemic strains, an overzealous response that can be fatal. Adaptive immune cells, particularly cytotoxic CD8 T cell lymphocytes, play a crucial role in controlling viral replication by killing infected cells. Therefore, tight regulation of the cytokines that lead to the proper activation, proliferation and function of these immune cells is necessary to clear infections efficiently while minimizing damage to the host. Interleukin-7 (IL-7) is a cytokine known for its importance in T cell development and survival. While the function of IL-7 in T cell survival is well characterized, how IL-7 shapes T cell effector responses when a pathogen is encountered is less understood. Using IL-7Rα hypomorph mice in chimeric and adoptive transfer experiments we have found that IL-7 is cell-intrinsically important for the priming of antigen specific CD8 T cells in the draining lymph nodes. We found that IL-7 dictates terminal differentiation, cytokine production and degranulation of CD8 T cells locally in the airways. Drugs that manipulate IL-7 signaling are currently under clinical trial for multiple conditions. Our findings on IL-7 and its effects on lower respiratory diseases will be necessary for expanding the utility of these therapeutics.

A phase 1b randomized study of the safety and immunological responses to vaccination with H4:IC31, H56:IC31, and BCG revaccination in Mycobacterium tuberculosis-uninfected adolescents in Cape Town, South Africa

BackgroundTuberculosis (TB) remains the leading cause of infectious disease-related death. Recently, a trial of BCG revaccination and vaccination with H4:IC31, a recombinant protein vaccine, in South African adolescents (Aeras C-040-404) showed efficacy in preventing sustained QuantiFERON (QFT) conversion, a proxy for Mycobacterium tuberculosis (M.tb) infection. A phase 1b trial of 84 South African adolescents was conducted, concurrent with Aeras C-040-404, to assess the safety and immunogenicity of H4:IC31, H56:IC31 and BCG revaccination, and to identify and optimize immune assays for identification of candidate correlates of protection in efficacy trials. MethodsTwo doses of H4:IC31 and H56:IC31 vaccines were administered intramuscularly (IM) 56 days apart, and a single dose of BCG (2–8 × 105 CFU) was administered intradermally (ID). T-cell and antibody responses were measured using intracellular cytokine staining and binding antibody assays, respectively. Binding antibodies and CD4+/CD8+ T-cell responses to H4- and H56-matched antigens were measured in samples from all participants. The study was designed to characterize safety and immunogenicity and was not powered for group comparisons. (Clinicaltrials.gov NCT02378207). FindingsIn total, 481 adolescents (mean age 13·9 years) were screened; 84 were enrolled (54% female). The vaccines were generally safe and well-tolerated, with no reported severe adverse events related to the study vaccines. H4:IC31 and H56:IC31 elicited CD4+ T cells recognizing vaccine-matched antigens and H4- and H56-specific IgG binding antibodies. The highest vaccine-induced CD4+ T-cell response rates were for those recognizing Ag85B in the H4:IC31 and H56:IC31 vaccinated groups. BCG revaccination elicited robust, polyfunctional BCG-specific CD4+ T cells, with no increase in H4- or H56-specific IgG binding antibodies. There were few antigen-specific CD8+ T-cell responses detected in any group. InterpretationBCG revaccination administered as a single dose ID and both H4:IC31 and H56:IC31 administered as 2 doses IM had acceptable safety profiles in healthy, QFT-negative, previously BCG-vaccinated adolescents. Characterization of the assays and the immunogenicity of these vaccines may help to identify valuable markers of protection for upcoming immune correlates analyses of C-040-404 and future TB vaccine efficacy trials. FundingNIAID and Aeras.