Anti-Malarial Drug Resistance

Malaria is a life-threatening infectious disease caused by a protozoan parasite of the genus Plasmodium. It is transmitted through the bites of infected female Anopheles mosquitoes. The global burden is estimated to be around 219 million cases in 87 countries. Natural compounds have been used primarily in the traditional medicine for thousands of years. For the treatment of malaria, natural products were used until the development of synthetic drugs, and most of the currently available anti-malarial drugs have been derived based on the compounds from these traditional medicinal plants. The current chapter tries to briefly indicate the emerging resistance against anti-malarial drugs and to discuss the recent research on natural products that have been evaluated for anti-malarial activity. Rigorous evaluation of the efficacy and safety of traditional medicines is required along with identification of active constituents in order to develop new drugs with novel mechanisms of action.

Structure-Based Virtual Screening, Insilico Docking, ADME Prediction, and Molecular Dynamics Studies for Identification of Potential NMT Inhibitors Against Malaria

One of the major public health problems globally, malaria, is mainly caused protozoan parasites from the genus Plasmodium, and commonly spreads to people through the bites of infected female mosquitoes of the genus Anopheles. Strategies for treatment, prevention, and control are available for malaria but the eradication of malaria still poses great challenge due to plasmodium’s drug resistance over the past decades. Development of novel antimalarial drugs remains a significant task to protect people from malaria. N-Myristoyl transferase is responsible for the N-Myristoylation catalysis process and the survival of Plasmodium species. Thus, it is considered a therapeutic drug target in protozoans and was recently validated as a significant target for Plasmodium vivax. In this present scenario, we endeavour to identify effective NMT inhibitors to prevent the onset of malaria in the human species. Initially, the structure-based virtual screening was executed against ZINC database and four potential candidates for NMT were identified. Furthermore, the four identified compounds were subjected to ADME prediction and all the four compounds found within adequate range with predicted ADME properties. Eventually, we conducted the molecular dynamics simulation to investigate the binding stability of top three protein-ligand complexes at different time scale by employing the tool Desmond. The molecular dynamics simulation studies revealed the protein-ligand complexes were stable throughout the entire simulation. Besides, we noticed that the residues ASN 365, PHE 103 and HIS 213 of NMT were crucially involved in the formation of various intermolecular interactions, significantly contributing to the stability of protein-ligand complexes. From this computational investigation, we suggest that the three identified potential compounds are extremely useful for further lead optimization and drug development.

Pediococcus pentosaceus IM96 Exerts Protective Effects against Enterohemorrhagic Escherichia coli O157:H7 Infection In Vivo

Enterohemorrhagic Escherichia coli (EHEC) is a notorious and prevalent foodborne pathogen which can cause serious intestinal diseases. The antagonistic activity of probiotics against EHEC is promising, but most of the studies concerning this subject have been carried out in vitro. Specifically, the interaction between Pediococcus pentosaceus and EHEC O157:H7 in vivo has not been reported yet. In this study, we investigated the protective effect of P. pentosaceus IM96 on EHEC O157:H7-infected female mice in vivo. The results demonstrated that P. pentosaceus IM96 reduced the level of pro-inflammatory factors and increased the level of anti-inflammatory factors of EHEC O157:H7-infected mice. Furthermore, P. pentosaceus IM96 alleviated intestinal mucosal damage and increased the level of MUC-2, tight junction (TJ) proteins, and short chain fatty acids (SCFAs). The intestinal microbial community structure and the diversity and richness of the microbiota were also changed by P. pentosaceus IM96 treatment. In summary, P. pentosaceus IM96 exerted protective effects against EHEC O157:H7 via alleviating intestinal inflammation, strengthening the intestinal barrier function, and regulating intestinal microbiota, suggesting that P. pentosaceus IM96 might serve as a potential microbial agent to prevent and treat intestinal diseases caused by EHEC O157:H7 infection in the future.

Cutaneous leishmaniasis in protected environmental areas in the Eastern Amazon: the case of São Félix do Xingu, Pará, Brazil

Introduction: Cutaneous Leishmaniasis is a disease transmitted to men and animals by infected female phlebotomine sandflies and is considered a great environmental and public health problem in the Amazon region. Thus, the study aimed to analyze the spatial distribution of this disease in São Félix do Xingu, in the state of Pará, Brazil, and its relationship with epidemiological and environmental variables, in the period from 2012 to 2016. Methodology: The data used were from the Information System of the Pará State Secretariat of Health, the National Institute for Space Research and the Brazilian Institute of Geography and Statistics. The statistical and spatial analysis of the variables were done using non-parametric chi-square statistical test, kernel interpolation technique and the Bivariate Global Moran Index. Results: The municipality had 183 confirmed cases, non-homogeneously distributed in 5 administrative districts. The individuals most affected were adult males with brown skin, an elementary level of education and rural area residents. In the case series, a direct relationship was observed between the increase of the number of cases and deforestation in the study area. The spatial analysis showed different types of land use and cover related to case clusters in the municipality. Additionally, there was a presence of cases in protected areas and a great epidemiological silence in indigenous lands. Conclusions: Thus, this disease is a large and complex public health problem in the municipality, related to social and environmental risk factors.

Route of Zika virus infection in Aedes aegypti by transmission electron microscopy

Background Zika fever has been a global health security threat, especially in the tropical and subtropical regions where most of the cases occur. The disease is caused by Zika virus (ZIKV), which belongs to the family Flaviviridae, genus Flavivirus. The virus is transmitted by Aedes mosquitoes, mostly by Aedes aegypti, during its blood meal. In this study we present a descriptive analysis, by transmission electron microscopy (TEM), of ZIKV infection in A. aegypti elected tissues at the 3rd day of infection. ZIKV vertical transmission experiments by oral infection were conducted to explore an offspring of natural infection. Results Gut and ovary tissues harbored a higher number of viral particles. The ZIKV genome was also detected, by RT-qPCR technique, in the organism of orally infected female mosquitoes and in their eggs laid. Conclusions The data obtained suggest that the ovary is an organ susceptible to be infected with ZIKV and that virus can be transmitted from mother to a fraction of the progeny.

A pathogenic fungus uses volatiles to entice male flies into fatal matings with infected female cadavers

To ensure dispersal, many parasites and pathogens behaviourally manipulate infected hosts. Other pathogens and certain insect-pollinated flowers use sexual mimicry and release deceptive mating signals. However, it is unusual for pathogens to rely on both behavioural host manipulation and sexual mimicry. Here, we show that the host-specific and behaviourally manipulating pathogenic fungus, Entomophthora muscae, generates a chemical blend of volatile sesquiterpenes and alters the level of natural host cuticular hydrocarbons in dead infected female house fly (Musca domestica) cadavers. Healthy male house flies respond to the fungal compounds and are enticed into mating with dead female cadavers. This is advantageous for the fungus as close proximity between host individuals leads to an increased probability of infection. The fungus-emitted volatiles thus represent the evolution of an extended phenotypic trait that exploit male flies' willingness to mate and benefit the fungus by altering the behavioural phenotype of uninfected healthy male host flies.

Demographic characteristics of sources of HIV-1 transmission in Zambia

BACKGROUNDIn the last decade, universally available antiretroviral therapy has led to reduced HIV incidence in sub-Saharan Africa. Sources of remaining transmission need to be characterised to design effective prevention strategies.METHODSWe used phylogenetics to understand the population characteristics of people who are sources of infection. HIV samples from 6,864 individuals from Zambia were deep-sequenced as part of HPTN 071-02 (PopART) Phylogenetics between 2014 and 2018. We identified 300 likely directed transmission pairs and analysed their sources to better understand transmission in the general population.RESULTSAfter demographic weighting of the recipient population to match the estimated total population infected during the trial period, 59.4% (95% CI: 53.1%-65.8%) of transmissions were male-to-female, with 43.1% (36.6%-49.5%) of transmissions from males aged 25-40. Since the adult HIV prevalence was 2.0 times higher in women than men, the per-capita transmission rate was 2.93 times higher per infected male than per infected female. 25.6% (19.9%-31.3%) of sources were estimated to have themselves been infected less than a year before the transmission event. 16.8% (12%-21.7%) of sources transmitted viruses resistant to first-line ART. 13% (8.6%-17.4%) of transmissions occurred between individuals from different study communities.CONCLUSIONSOur findings suggest that HIV transmission in the study communities took place as part of common sexual mixing, and that there was no outsized contribution of importation, from drug resistance, or recent infection. Men aged 25-40 should be the focus of treatment for prevention interventions, even if linking them to care requires more effort.

Uterine Injury Caused by Genotype 4 Hepatitis E Virus Infection Based on a BALB/c Mice Model

To evaluate whether uterine injury caused by hepatitis E virus (HEV) infection is responsible for adverse pregnancy outcomes. HEV-infected female BALB/c mice were coupled with healthy male BALB/c mice at 0, 7, 14, 21, and 91 dpi to explore the uterine injury caused by HEV infection. Mice were euthanized after 10 days of copulation, and uteruses were collected for HEV RNA and antigen detection and histopathological analysis. Inflammatory responses; apoptosis; and estrogen receptor ɑ (ER-ɑ), endomethal antibody (ERAb), cytokeratin-7 (CK7), vimentin (VIM), and vascular endothelial growth factor (VEGF) expression levels were evaluated. After 10 days of copulation, miscarriage and nonpregnancy, as well as enlarged uteruses filled with inflammatory cytokines, were found in HEV-infected mice. HEV RNA and antigens were detected in the sera and uteruses of HEV-infected mice. Significant endometrial thickness (EMT) thinning, severe inflammatory responses, and aggravated apoptosis in the uteruses of HEV-infected mice that experienced miscarriage might contribute to adverse pregnancy outcomes. Furthermore, significantly suppressed ER-ɑ expression and increased ERAb, CK7, VIM, and VEGF expression levels were found in the uteruses of HEV-infected mice that had miscarried. However, uterine damage recovered after complete HEV clearance, and impaired fertility was improved. EMT injury, severe inflammatory responses, and aggravated apoptosis in the uterus caused by HEV infection are responsible for poor pregnancy outcomes.

Application of Deep Learning to Community-Science-Based Mosquito Monitoring and Detection of Novel Species

Mosquito-borne diseases account for human morbidity and mortality worldwide, caused by the parasites (e.g., malaria) or viruses (e.g., dengue, Zika) transmitted through bites of infected female mosquitoes. Globally, billions of people are at risk of infection, imposing significant economic and public health burdens. As such, efficient methods to monitor mosquito populations and prevent the spread of these diseases are at a premium. One proposed technique is to apply acoustic monitoring to the challenge of identifying wingbeats of individual mosquitoes. Although researchers have successfully used wingbeats to survey mosquito populations, implementation of these techniques in areas most affected by mosquito-borne diseases remains challenging. Here, methods utilizing easily accessible equipment and encouraging community-scientist participation are more likely to provide sufficient monitoring. We present a practical, community-science-based method of monitoring mosquito populations using smartphones. We applied deep-learning algorithms (TensorFlow Inception v3) to spectrogram images generated from smartphone recordings associated with six mosquito species to develop a multiclass mosquito identification system, and flag potential invasive vectors not present in our sound reference library. Though TensorFlow did not flag potential invasive species with high accuracy, it was able to identify species present in the reference library at an 85% correct identification rate, an identification rate markedly higher than similar studies employing expensive recording devices. Given that we used smartphone recordings with limited sample sizes, these results are promising. With further optimization, we propose this novel technique as a way to accurately and efficiently monitor mosquito populations in areas where doing so is most critical.