Small molecule-directed immunotherapy against recurrent infection by Mycobacterium tuberculosis

Tuberculosis remains the biggest infectious threat to humanity with one-third of the population infected and 1.4 million deaths and 8.7 million new cases annually. Current tuberculosis therapy is lengthy and consists of multiple antimicrobials, which causes poor compliance and high treatment dropout, resulting in the development of drug-resistant variants of tuberculosis. Therefore, alternate methods to treat tuberculosis are urgently needed. Mycobacterium tuberculosis evades host immune responses by inducing T helper (Th)2 and regulatory T (Treg) cell responses, which diminish protective Th1 responses. Here, we show that animals (Stat-6−/−CD4-TGFβRIIDN mice) that are unable to generate both Th2 cells and Tregs are highly resistant to M. tuberculosis infection. Furthermore, simultaneous inhibition of these two subsets of Th cells by therapeutic compounds dramatically reduced bacterial burden in different organs. This treatment was associated with the generation of protective Th1 immune responses. As these therapeutic agents are not directed to the harbored organisms, they should avoid the risk of promoting the development of drug-resistant M. tuberculosis variants

Changing Ecotypes of Dengue Virus 2 Serotype in Nigeria and the Emergence of Cosmopolitan and Asian I Lineages, 1966–2019

Dengue virus (DENV) is a leading mosquito-borne virus with a wide geographical spread and a major public health concern. DENV serotype 1 (DENV-1) and serotype 2 (DENV-2) were first reported in Africa in 1964 in Ibadan, Nigeria. Although the burden of dengue is unknown in many African countries, DENV-2 is responsible for major epidemics. In this study, we investigated the activities of DENV-2 to determine the circulating strains and to appraise the changing dynamics in the epidemiology of the virus in Nigeria. Nineteen DENV-2 sequences from 1966–2019 in Nigeria were retrieved from the GenBank of the National Center of Biotechnology Information (NCBI). A DENV genotyping tool was used to identify the specific genotypes. The evolutionary history procedure was performed on 54 DENV-2 sequences using MEGA 7. There is a deviation from Sylvatic DENV-2 to other genotypes in Nigeria. In 2019, the Asian I genotype of DENV-2 was predominant in southern Edo State, located in the tropical rainforest region, with the first report of the DENV-2 Cosmopolitan strain. We confirmed the circulation of other non-assigned genotypes of DENV-2 in Nigeria. Collectively, this shows that DENV-2 dynamics have changed from Sylvatic transmission reported in the 1960s with the identification of the Cosmopolitan strain and Asian lineages. Sustained surveillance, including vectorial studies, is required to fully establish the trend and determine the role of these vectors

Modelling Energy Consumption based on Resource Utilization

Power management is an expensive and important issue for large computational infrastructures such as datacenters, large clusters, and computational grids. However, measuring energy consumption of scalable systems may be impractical due to both cost and complexity for deploying power metering devices on a large number of machines. In this paper, we propose the use of information about resource utilization (e.g. processor, memory, disk operations, and network traffic) as proxies for estimating power consumption. We employ machine learning techniques to estimate power consumption using such information which are provided by common operating systems. Experiments with linear regression, regression tree, and multilayer perceptron on data from different hardware resulted into a model with 99.94\% of accuracy and 6.32 watts of error in the best case.Comment: Submitted to Journal of Supercomputing on 14th June, 201

Antiretroviral-induced adverse drug reactions in HIV-infected patients in Mali: a resource-limited setting experience

Background: There are few reports in the literature from sub-Saharan Africa (SSA) regarding antiretroviral-induced adverse drug reactions (ADRs). Antiretroviral therapy (ART) is now widely available in SSA, and ADRs during HIV infection are also frequent. In this study, we reported the frequency and risk factors of ART-induced ADRs in a Malian population.Methods: This prospective cohort study was performed in the HIV Care and Counseling Centre (CESAC) of Mali from 2011 to 2012. Adult patients infected with HIV and who had recently started ART were included and followed-up clinically Were included in this study, adult patients living with HIV and had recently started ART who were followed up for at least 6 months to determine the incidence of ADRs using Naranjo’s classification scale.Results: During this study, 357 (42.3%) patients presented ADRs (40.1% of our patients (n=338) experienced at least one ADR, and 2.2% (n=19) experienced at least two ADRs). The prevalence of ADRs by organ system was: 45.9% neurological (n=164); 29.4% metabolic (blood chemistry) (n=105); 15.4% hematological (n=55). High probable rate of ADR was observed as indicated by the Naranjo score in 83.7% of the cases. Zidovudine (AZT) and stavudine (d4T) use was identified as a risk factor for either anaemia or peripheral neuropathy whereas nevirapine (NVP) and female gender were risk factors for skin reactions. Patients with advance disease had the highest rate of ADRs compared to the others.Conclusions: Based on the Naranjo probability scale, our data show that ADRs such as peripheral neuropathy and anemia are very frequent. These ADR was linked to AZT and D4T. Our findings highlight the need for active monitoring, continuous pharmacovigilance of ART and change of some ART drug in this population

Evaluation of antimycobacterial activity of medicinal plants used by Malian traditional medicine practitioners to treat tuberculosis

Global Tuberculosis (TB) control is facing major challenges such as occurrence of multidrug-resistant (MDR) and extensively drug-resistant tuberculosis (XDR). The current TB drugs are getting less effective and associated with side effects limiting their use, especially with MDR and XDR infected patients. In Mali, many medicinal plants are used against various diseases including bacterial infections. The study aimed at studying the antimycobacterial activities of 60 extracts from 22 Malian medicinal. The antibacterial activity against Mycobacterium tuberculosis H37Rv was assessed employing micro-broth dilution method. Out of 60 extracts evaluated, eleven from nine different plants were found to be active against H37Rv strain. The minimal inhibitory concentrations (MICs) ranked from 125 μg/mL to 1250 μg/mL. The most active extracts (125 μg/mL) were represented by ethanolic extract of Saba senegalensis and Vitellaria paradoxa leaves, dichloromethane extract of Cola cordifolia leaves, Strychnos spinosa and Ximenia Americana roots. Ethanolic extract of Zizyphus mauritiana, Guiera senegalensis and methanolic extract of Anthocleista djalonensis also prevented the growth of H37Rv at 250 μg/mL. The results suggest that Saba senegalensis, Vitellaria paradoxa, Cola cordifolia, Strychnos spinosa and Ximenia Americana could be potential sources of antimycobacterial molecule

Successful Shortening of Tuberculosis Treatment Using Adjuvant Host-Directed Therapy with FDA-Approved Phosphodiesterase Inhibitors in the Mouse Model

Global control of tuberculosis (TB), an infectious disease that claims nearly 2 million lives annually, is hindered by the long duration of chemotherapy required for curative treatment. Lack of adherence to this intense treatment regimen leads to poor patient outcomes, development of new or additional drug resistance, and continued spread of M.tb. within communities. Hence, shortening the duration of TB therapy could increase drug adherence and cure in TB patients. Here, we report that addition of the United Stated Food and Drug Administration-approved phosphodiesterase inhibitors (PDE-Is) cilostazol and sildenafil to the standard TB treatment regimen reduces tissue pathology, leads to faster bacterial clearance and shortens the time to lung sterilization by one month, compared to standard treatment alone, in a murine model of TB. Our data suggest that these PDE-Is could be repurposed for use as adjunctive drugs to shorten TB treatment in humans

Failure to Recognize Nontuberculous Mycobacteria Leads to Misdiagnosis of Chronic Pulmonary Tuberculosis

BACKGROUND: Nontuberculous mycobacterial (NTM) infections cause morbidity worldwide. They are difficult to diagnose in resource-limited regions, and most patients receive empiric treatment for tuberculosis (TB). Our objective here is to evaluate the potential impact of NTM diseases among patients treated presumptively for tuberculosis in Mali. METHODS: We re-evaluated sputum specimens among patients newly diagnosed with TB (naïve) and those previously treated for TB disease (chronic cases). Sputum microscopy, culture and Mycobacterium tuberculosis drug susceptibility testing were performed. Identification of strains was performed using molecular probes or sequencing of secA1 and/or 16S rRNA genes. RESULTS: Of 142 patients enrolled, 61 (43%) were clinically classified as chronic cases and 17 (12%) were infected with NTM. Eleven of the 142 (8%) patients had NTM disease alone (8 M. avium, 2 M. simiae and 1 M. palustre). All these 11 were from the chronic TB group, comprising 11/61 (18%) of that group and all were identified as candidates for second line treatment. The remaining 6/17 (35.30%) NTM infected patients had coinfection with M. tuberculosis and all 6 were from the TB treatment naïve group. These 6 were candidates for the standard first line treatment regimen of TB. M. avium was identified in 11 of the 142 (8%) patients, only 3/11 (27.27%) of whom were HIV positive. CONCLUSIONS: NTM infections should be considered a cause of morbidity in TB endemic environments especially when managing chronic TB cases to limit morbidity and provide appropriate treatment

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century