The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak in December 2019 has caused a global pandemic. The rapid mutation rate in the virus has created alarming situations worldwide ...and is being attributed to the false negativity in RT-PCR tests. It has also increased the chances of reinfection and immune escape. Recently various lineages namely, B.1.1.7 (Alpha), B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.617.3 have caused rapid infection around the globe. To understand the biophysical perspective, we have performed molecular dynamic simulations of four different spikes (receptor binding domain)-hACE2 complexes, namely wildtype (WT), Alpha variant (N501Y spike mutant), Kappa (L452R, E484Q) and Delta (L452R, T478K), and compared their dynamics, binding energy and molecular interactions. Our results show that mutation has caused significant increase in the binding energy between the spike and hACE2 in Alpha and Kappa variants. In the case of Kappa and Delta variants, the mutations at L452R, T478K and E484Q increased the stability and intra-chain interactions in the spike protein, which may change the interaction ability of neutralizing antibodies to these spike variants. Further, we found that the Alpha variant had increased hydrogen interaction with Lys353 of hACE2 and more binding affinity in comparison to WT. The current study provides the biophysical basis for understanding the molecular mechanism and rationale behind the increase in the transmissivity and infectivity of the mutants compared to wild-type SARS-CoV-2.
Biofilms: Survival and defense strategy for pathogens Kumar, Ashutosh; Alam, Anwar; Rani, Mamta ...
International journal of medical microbiology,
December 2017, 2017-Dec, 2017-12-00, 20171201, Letnik:
307, Številka:
8
Journal Article
Recenzirano
Studies on biofilm related infections are gaining prominence owing to their involvement in majority of clinical infections. Biofilm, considered as a generic mechanism for survival used by pathogenic ...as well as non-pathogenic microorganisms, involves surface attachment and growth of heterogeneous cells encapsulated within a matrix. The matrix provides ecological niche where partnership of cells endows a community like behaviour that not only enables the cohort to survive local microenvironment stress but also channelizes them to evolve, disseminate and cause resurgence of infections. In this mini-review we highlight the mechanisms used by microbes to develop and sustain biofilms, including the influence of the microbiota. Several strategies to target biofilms have been validated on certain groups of microorganisms and these basically target different stages in the life cycle of biofilm, however comprehensive methods to target microbial biofilms are relatively unknown. In the backdrop of recent reports suggesting that biofilms can harbour multiple species of organisms, we need to relook and devise newer strategies against biofilms. Effective anti-biofilm strategies cannot be confined to a single methodology that can disrupt one pathway but should simultaneously target the various routes adopted by the microorganisms for survival within their ecosystem. An overview of the currently available drugs, their mode of action, genomic targets and translational therapies against biofilm related infection are discussed.
SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus 2) has accumulated multiple mutations during its global circulation. Recently, three SARS-CoV-2 lineages, B.1.1.7 (501Y.V1), B.1.351 ...(501Y.V2) and B.1.1.28.1 (P.1), have emerged in the United Kingdom, South Africa and Brazil, respectively. Here, we have presented global viewpoint on implications of emerging SARS-CoV-2 variants based on structural-function impact of crucial mutations occurring in its spike (S), ORF8 and nucleocapsid (N) proteins. While the N501Y mutation was observed in all three lineages, the 501Y.V1 and P.1 accumulated a different set of mutations in the S protein. The missense mutational effects were predicted through a COVID-19 dedicated resource followed by atomistic molecular dynamics simulations. Current findings indicate that some mutations in the S protein might lead to higher affinity with host receptors and resistance against antibodies, but not all are due to different antibody binding (epitope) regions. Mutations may, however, result in diagnostic tests failures and possible interference with binding of newly identified anti-viral candidates against SARS-CoV-2, likely necessitating roll out of recurring "flu-like shots" annually for tackling COVID-19. The functional relevance of these mutations has been described in terms of modulation of host tropism, antibody resistance, diagnostic sensitivity and therapeutic candidates. Besides global economic losses, post-vaccine reinfections with emerging variants can have significant clinical, therapeutic and public health impacts.
Prior to coronavirus disease 2019 (COVID-19), tuberculosis (TB) was the worst killer among infectious diseases. The union of these two obnoxious respiratory diseases can be devastating, with severe ...public health implications. The COVID-19 pandemic has affected all TB-elimination programmes due to the severe burden on healthcare systems and the diversion of funds and attention towards controlling the pandemic. The emerging data show that the COVID-19 pandemic caused a marked decrease in case notifications and bacille Calmette-Guérin immunisations, ultimately promoting disease transmission and increasing the susceptible population. The similarity between the clinical characteristics of TB and COVID-19 adds to the public health complications, with evidence of immune dysregulation in both cases leading to severe consequences. Clinical evidence suggests that severe acute respiratory syndrome coronavirus 2 infection predisposes patients to TB infection or may lead to reactivation of latent disease. Similarly, underlying TB disease can worsen COVID-19. Treatment options are limited in COVID-19; therefore, using immunosuppressive and immunomodulatory regimens that can modulate the concomitant bacterial infection and interaction with anti-TB drugs requires caution. Thus, considering the synergistic impact of these two respiratory diseases, it is crucial to manage both diseases to combat the syndemic of TB and COVID-19.
In less than five months, COVID-19 has spread from a small focus in Wuhan, China, to more than 5 million people in almost every country in the world, dominating the concern of most governments and ...public health systems. The social and political distresses caused by this epidemic will certainly impact our world for a long time to come. Here, we synthesize lessons from a range of scientific perspectives rooted in epidemiology, virology, genetics, ecology and evolutionary biology so as to provide perspective on how this pandemic started, how it is developing, and how best we can stop it.
•A new coronavirus, SARS-CoV-2, emerged by the end of December 2019 in China.•In less than 3 months, it has spread worldwide causing a pandemic of COVID-19.•We review the genetic, virological, ecological, epidemiological and evolutionary factors of this viral pandemic.
(
) is a successful pathogen that can reside within the alveolar macrophages of the host and can survive in a latent stage. The pathogen has evolved and developed multiple strategies to resist the ...host immune responses.
escapes from host macrophage through evasion or subversion of immune effector functions.
genome codes for PE/PPE/PE_PGRS proteins, which are intrinsically disordered, redundant and antigenic in nature. These proteins perform multiple functions that intensify the virulence competence of
majorly by modulating immune responses, thereby affecting immune mediated clearance of the pathogen. The highly repetitive, redundant and antigenic nature of PE/PPE/PE_PGRS proteins provide a critical edge over other
proteins in terms of imparting a higher level of virulence and also as a decoy molecule that masks the effect of effector molecules, thereby modulating immuno-surveillance. An understanding of how these proteins subvert the host immunological machinery may add to the current knowledge about
virulence and pathogenesis. This can help in redirecting our strategies for tackling
infections.
Proteins are supposed to bind to their substrates/ligands in a specific manner via their pre-formed binding sites, according to classical biochemistry. In recent years, several types of deviations ...from this norm have been observed and called promiscuous behavior. Enzymatic promiscuities allow several biochemical functions to be carried out by the same enzyme. The promiscuous activity can also be the origin of “new proteins” via gene duplication. In more recent years, proteins from prokaryotes, eukaryotes and viruses have been found to have intrinsic disorder and lack a preformed binding site. Intrinsic disorder is exploited in regulatory proteins such as those that are involved in transcription and signal transduction. Such proteins function by folding locally while binding to their ligands or interacting with other proteins. These phenomena have also been classified as examples of protein promiscuity and encompass diverse kinds of ligands that can bind to a protein. Given the significant extent of structural homology in many protein families, it is not surprising that ligands also have been found to display promiscuity. Promiscuous behavior of proteins offers both challenges and opportunities to the drug discovery programs such as drug repurposing. Pathogens when exposed to antibiotics exploit protein promiscuity in several ways to develop resistance to the drug. There is increasing evidence now to support that the disorder in proteins is a major tool used by pathogens for virulence and evade drug action by exploiting protein promiscuity. This review provides a holistic view of this multi-faceted phenomenon called protein promiscuity.
•Types of enzyme promiscuity and role in evolution of new proteins.•Antibiotic resistance due to protein promiscuity.•Promiscuous behavior of Intrinsically disordered proteins and allosteric proteins.•Complications in drug design due to Protein promiscuity.•Drug repurposing due to promiscuous nature of drug binding.
Unlike DNA fingerprinting, which scores for differences in the genome that are phenotype neutral, epigenetic variations are gaining importance in forensic investigations. Methylation of DNA has a ...broad range of effects on the lifestyle, health status, and physical appearance of individuals. DNA methylation profiling of forensic samples is useful in determination of the cell or tissue type of the DNA source and also for estimation of age. The quality and quantity of the biosample available from the crime scene limits the possible number of DNA methylation tests and the selection of the technology that can be used. Several techniques have been used for DNA methylation analysis for epigenetic investigations of forensic biological samples. However, novel techniques are needed for multiplex analysis of epigenetic markers as the techniques that are currently available require a large amount of high-quality DNA and are also limited in their multiplexing capacities that are often insufficient to fully resolve a forensic query of interest.
The PE/PPE multigene family codes for approximately 10% of the Mycobacterium tuberculosis proteome and is encoded by 176 open reading frames. These proteins possess, and have been named after, the ...conserved proline-glutamate (PE) or proline-proline-glutamate (PPE) motifs at their N-terminus. Their genes have a conserved structure and repeat motifs that could be a potential source of antigenic variation in M. tuberculosis. PE/PPE genes are scattered throughout the genome and PE/PPE pairs are usually encoded in bicistronic operons although this is not universally so. This gene family has evolved by specific gene duplication events. PE/PPE proteins are either secreted or localized to the cell surface. Several are thought to be virulence factors, which participate in evasion of the host immune response. This review summarizes the current knowledge about the gene family in order to better understand its biological function.
► We present progress made in the field of PE/PPE proteins from Mycobacterium tuberculosis. ► They potentially provide virulence and antigenic variation. ► Many of them are secretory or cell surface localized. ► Several are thought to be vaccine and serodiagnostic marker candidates. ► Their genes are scattered but mostly exist in operons or together with Esx gene clusters.
PDF
