As the world faces the challenge of the COVID-19 pandemic, it has become an urgent need of the hour to understand how our immune system sense and respond to RNA viruses that are often ...life-threatening. While most vaccine strategies for these viruses are developed around a programmed antibody response, relatively less attention is paid to our innate immune defenses that can determine the outcome of a viral infection via the production of antiviral cytokines like Type I Interferons. However, it is becoming increasingly evident that the "cytokine storm" induced by aberrant activation of the innate immune response against a viral pathogen may sometimes offer replicative advantage to the virus thus promoting disease pathogenesis. Thus, it is important to fine tune the responses of the innate immune network that can be achieved via a deeper insight into the candidate molecules involved. Several pattern recognition receptors (PRRs) like the Toll like receptors (TLRs), NOD-like receptors (NLRs), and the retinoic acid inducible gene-I (RIG-I) like receptors (RLRs) recognize cytosolic RNA viruses and mount an antiviral immune response. RLRs recognize invasive viral RNA produced during infection and mediate the induction of Type I Interferons via the mitochondrial antiviral signaling (MAVS) molecule. It is an intriguing fact that the mitochondrion, one of the cell's most vital organelle, has evolved to be a central hub in this antiviral defense. However, cytokine responses and interferon signaling via MAVS signalosome at the mitochondria must be tightly regulated to prevent overactivation of the immune responses. This review focuses on our current understanding of the innate immune sensing of the host mitochondria by the RLR-MAVS signalosome and its specificity against some of the emerging/re-emerging RNA viruses like Ebola, Zika, Influenza A virus (IAV), and severe acute respiratory syndrome-coronavirus (SARS-CoV) that may expand our understanding for novel pharmaceutical development.
Warm and humid climate creates ideal conditions for mosquito breeding. The ability of these vectors to spread a number of diseases to humans causes millions of deaths every year. Indiscriminate use ...of synthetic insecticides leads to the development of resistance in vector mosquitoes and along with this, these pesticides cause biological magnification of toxic components and affects adversely the non-target organisms including human being. Commercially available, chemically manufactured mosquito repellent fast cards are convenient to use and quite effective but burning of such card generates a lot of smoke and might be hazardous to human health in the long run. Thus, alternative approaches are to be adopted to control the population load of vector mosquito. Like that, the present study also reveals the larvicidal effect of
Duranta
leaf extract against
Culex
mosquito. In the present study, mosquito repellent fast card has been developed by
Duranta
-algal mixture which has shown better result than commercially available fast card on the basis of mosquito mortality as well as the amount of gases emitted. Again, the ethanolic crude extract of
Duranta
leaves leads to 100% mortality of all instars (
Culex pipiens
) larvae at both 1000 ppm and 500 ppm concentration. Therefore, the active component of
Duranta
has also been investigated. In
Duranta
, highest area percentage and peak have been shown by propionic acid in the retention time 18.086 by GC–MS. So, it can be confirmed that the major active ingredient is propionic acid in
Duranta
which is responsible for the mosquitocidal properties. Occurrence of propionic acid in
Duranta
has also been confirmed by the HPLC analysis.
La Crosse virus (LACV), a zoonotic Bunyavirus, is a major cause of pediatric viral encephalitis in the United States. A hallmark of neurological diseases caused by LACV and other encephalitic viruses ...is the induction of neuronal cell death. Innate immune responses have been implicated in neuronal damage, but no mechanism has been elucidated. By using in vitro studies in primary neurons and in vivo studies in mice, we have shown that LACV infection induced the RNA helicase, RIG-I, and mitochondrial antiviral signaling protein (MAVS) signaling pathway, resulting in upregulation of the sterile alpha and TIR-containing motif 1 (SARM1), an adaptor molecule that we found to be directly involved in neuronal damage. SARM1-mediated cell death was associated with induced oxidative stress response and mitochondrial damage. These studies provide an innate-immune signaling mechanism for virus-induced neuronal death and reveal potential targets for development of therapeutics to treat encephalitic viral infections.
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► Bunyavirus infection induces SARM1 upregulation in neurons ► SARM1 mediates bunyavirus-induced cell death via oxidative stress response ► SARM1 upregulation following virus infection in neurons is MAVS dependent ► SARM1 localizes with MAVS at the mitochondria and induces apoptosis
The uncontrolled spread of drug-resistant tuberculosis (DR-TB) clinical cases necessitates the urgent discovery of newer chemotypes with novel mechanisms of action. Here, we report the chemical ...synthesis of rationally designed novel transition-state analogues (TSAs) by targeting the cyclization (Cy) domain of phenyloxazoline synthase (MbtB), a key enzyme of the conditionally essential siderophore biosynthesis pathway. Following bio-assay-guided evaluation of TSA analogues preferentially in iron-deprived and iron-rich media to understand target preferentiality against a panel of pathogenic and non-pathogenic mycobacteria strains, we identified a hit, i.e.,
. Molecular docking, dynamics, and MMPBSA calculations enabled us to comprehend
's stable binding at the active site pocket of
and the results imply that the
binding pocket has a strong affinity for electron-withdrawing functional groups and contributes to stable polar interactions between enzyme and ligand. Furthermore, enhanced intracellular killing efficacy (8 μg/mL) of
against
in infected macrophages is noted in comparison to moderate in vitro antimycobacterial efficacy (64 μg/mL) against
.
also demonstrates whole-cell efflux pump inhibitory activity against
. Identification of
by focusing on the modular
domain paves the way for accelerating novel anti-TB antibiotic discoveries.
•Each year, 200–300 people die from rabies in the Philippines.•Vaccines can be administered after bite exposure but also in prevention.•We evaluate the benefit of pre- vs post-exposure rabies ...vaccination.•A preventive program would prevent 297 deaths over 20 years in the Philippines.•It would also lead to a saving of 205 million Philippines Pesos (US$4.3 million).
Once symptoms appear, rabies is almost always fatal and accounts for 200–300 deaths annually in the Philippines. Available rabies vaccines can be administered either in pre- exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). After exposure, PrEP-immunized individuals require fewer doses of PEP and no rabies immunoglobulin.
A static decision-tree model was developed to assess cost-effectiveness of a PrEP+PEP program vs PEP alone. Philippines-specific data for people seeking medical advice at the Research Institute for Tropical Medicine between July 2015 and June 2016 were used in the model, together with data from published literature.
Over a 20-year period, in a cohort of 1 million 5-year-old children in the Philippines, PrEP+PEP was expected to prevent 297 deaths compared with PEP alone. From both payer and societal perspectives, the resulting incremental cost-effectiveness ratios were 36 035 (US$759; 2016 US$ conversion) and 18 663 (US$393) Philippine Pesos (PHP) — quality-adjusted life-years gained — respectively, which are both below the willingness-to-pay threshold of PHP140 255 (US$2 953).
These data suggest that a universal PrEP program targeting 5-year-olds would be cost-effective in the Philippines.
Despite the implementation of effective paediatric vaccination programmes, pertussis remains a global health problem. Disease epidemiology has changed over time, shifting towards the adolescent and ...adult populations. In adults, the true burden of pertussis is greatly underestimated and pertussis vaccine coverage rates are suboptimal, including individuals with chronic conditions. Here, we report the outcomes of a virtual international scientific workshop to assess the evidence on the burden of pertussis in older adults and identify potential solutions to improve uptake of pertussis vaccines. In adults, pertussis is underdiagnosed in part due to atypical or milder clinical presentation and the lack of testing and case confirmation. However, contemporary epidemiological data denoted an increase in the burden of pertussis among adolescents and adults. This might be related to a variety of reasons including the waning of immunity over time, the lack of booster vaccination, and the improved diagnostic methods that led to increased recognition of the disease in adults. Pertussis sequelae can be severe in older adults, particularly those with existing chronic medical conditions, and the vulnerability of these groups is further enhanced by low pertussis vaccine coverage. Possible measures to increase vaccine uptake include strengthening and harmonisation of immunisation guidelines, healthcare professionals taking a more active role in recommending pertussis vaccination, involvement of vaccination centres and pharmacies in the vaccination process, and improving knowledge of pertussis burden and vaccine efficacy among the general population.
The activation of astrocytes and microglia is often associated with diseases of the central nervous system (CNS). Understanding how activation alters the transcriptome of these cells may offer ...valuable insight regarding how activation of these cells mediate neurological damage. Furthermore, identifying common and unique pathways of gene expression during activation may provide new insight into the distinct roles these cells have in the CNS during infection and inflammation. Since recent studies indicate that TLR7 recognizes not only viral RNA but also microRNAs that are released by damaged neurons and elevated during neurological diseases, we first examined the response of glial cells to TLR7 stimulation using microarray analysis. Microglia were found to generate a much stronger response to TLR7 activation than astrocytes, both in the number of genes induced as well as fold induction. Although the primary pathways induced by both cell types were directly linked to immune responses, microglia also induced pathways associated with cellular proliferation, while astrocytes did not. Targeted analysis of a subset of the upregulated genes identified unique mRNA, including Ifi202b which was only upregulated by microglia and was found to be induced during both retroviral and bunyavirus infections in the CNS. In addition, other genes including Birc3 and Gpr84 as well as two expressed sequences AW112010 and BC023105 were found to be induced in both microglia and astrocytes and were upregulated in the CNS following virus infection. Thus, expression of these genes may a useful measurement of glial activation during insult or injury to the CNS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Eradication of Helicobacter pylori provides the most effective treatment for gastroduodenal diseases caused by H. pylori infection. Clarithromycin, a member of the macrolide family, still remains the ...most important antibiotic used in H. pylori eradication treatment. But the increasing prevalence of clarithromycin resistant H. pylori strains due to point mutations in the V region of the 23S rRNA, poses a great threat in treating the ailing patients. So, we aimed for PCR-mediated rapid detection of the point mutation at 2143 position of 23S rRNA gene in H. pylori that is relevant to clarithromycin resistance from culture and simultaneously from biopsy specimens to avoid the empirical treatment.
Newly developed PCR assay using DNA of pure culture detected point mutation in 23S rRNA gene in 21 (8.04%) of 261 clinical strains tested. The agar dilution method showed that all these 21 strains were resistant to clarithromycin indicating the perfect match of the PCR based results. Additionally, the sequencing study also identified the A to G mutation at 2143 position in 23S rRNA gene of the resistant strains only. Consequently, the newly developed Nested-ASP-PCR dealing directly with 50 biopsy specimens demonstrated 100% sensitivity and specificity with the findings of agar dilution method taken as Gold standard. Bioinformatics based analysis such as accessibility analysis and dot plot clearly stated that the base pairing probability has increased due to mutation. Computational studies revealed that the point mutation confers more stability in secondary structure due to conversion of loop to stem. Furthermore, interaction studies showed binding affinity of the CLR to the mutant type is weaker than that to the wild type.
This assay outlines a rapid, sensitive and simple approach to identify point mutation that confers clarithromycin resistance as well as clarithromycin sensitive strains, providing rapid initiation of effective antibiotic treatment. Additionally, it is simple to adopt for hospital based diagnostic laboratories to evaluate the degree of regional clarithromycin resistance from biopsy specimens itself. Furthermore, in silico studies provide evidence or a signal that the prevalence of clarithromycin resistance may rise in the near future as a result of this point mutation.
Group A streptococcal (GAS) strains causing severe, invasive infections often have mutations in the control of virulence two-component regulatory system (CovRS) which represses capsule production, ...and high-level capsule production is considered critical to the GAS hypervirulent phenotype. Additionally, based on studies in
GAS, hyperencapsulation is thought to limit transmission of CovRS-mutated strains by reducing GAS adherence to mucosal surfaces. It has recently been identified that about 30% of invasive GAS strains lacks capsule, but there are limited data regarding the impact of CovS inactivation in such acapsular strains. Using publicly available complete genomes (
= 2,455) of invasive GAS strains, we identified similar rates of CovRS inactivation and limited evidence for transmission of CovRS-mutated isolates for both encapsulated and acapsular
types. Relative to encapsulated GAS, CovS transcriptomes of the prevalent acapsular
types
,
, and
revealed unique impacts such as increased transcript levels of genes in the
/mga region along with decreased transcript levels of pilus operon-encoding genes and the streptokinase-encoding gene
. CovS inactivation in
and
strains, but not
, increased GAS survival in human blood. Moreover, CovS inactivation in acapsular GAS reduced adherence to host epithelial cells. These data suggest that the hypervirulence induced by CovS inactivation in acapsular GAS follows distinct pathways from the better studied encapsulated strains and that factors other than hyperencapsulation may account for the lack of transmission of CovRS-mutated strains. IMPORTANCE Devastating infections due to group A streptococci (GAS) tend to occur sporadically and are often caused by strains that contain mutations in the control of virulence regulatory system (CovRS). In well-studied
GAS, the increased production of capsule induced by CovRS mutation is considered key to both hypervirulence and limited transmissibility by interfering with proteins that mediate attachment to eukaryotic cells. Herein, we show that the rates of covRS mutations and genetic clustering of CovRS-mutated isolates are independent of capsule status. Moreover, we found that CovS inactivation in multiple acapsular GAS
types results in dramatically altered transcript levels of a diverse array of cell-surface protein-encoding genes and a unique transcriptome relative to encapsulated GAS. These data provide new insights into how a major human pathogen achieves hypervirulence and indicate that factors other than hyperencapsulation likely account for the sporadic nature of the severe GAS disease.
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