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Infection, Genetics and Evolution :... Apr 2024This investigation delineates an exhaustive analysis of the clinical, immunological, and genomic landscapes of hepatitis B virus (HBV) infection across a cohort of 22...
This investigation delineates an exhaustive analysis of the clinical, immunological, and genomic landscapes of hepatitis B virus (HBV) infection across a cohort of 22 verified patients. The demographic analysis unveiled a pronounced male bias (77.27%), with patient ages spanning 20 to 85 years and durations of illness ranging from 10 days to 4 years. Predominant clinical manifestations included fever, fatigue, anorexia, abdominal discomfort, and arthralgia, alongside observed co-morbidities such as chronic renal disorders and hepatocellular carcinoma. Antigenic profiling of the HBV envelope proteins elucidated significant heterogeneity among the infected subjects, particularly highlighted by discordances in the detection capabilities of small and large HBsAg assays, suggesting antigenic diversity. Quantitative assessment of viral loads unveiled a broad spectrum, accompanied by atypical HBeAg reactivity patterns, challenging the reliability of existing serological markers. Correlative studies between viral burden and antigenicity of the envelope proteins unearthed phenomena indicative of diagnostic evasion. Notably, samples demonstrating robust viral replication were paradoxically undetectable by the large HBsAg ELISA kit, advocating for more sophisticated diagnostic methodologies. Genotypic examination of three HBV isolates classified them as genotype D (D2), with phylogenetic alignment to strains from various global origins. Mutational profiling identified pivotal mutations within the basic core promoter and preS2/S1 regions, associated with an augmented risk of hepatocellular carcinoma. Further, mutations discerned in the small HBsAg and RT/overlap regions were recognized as contributors to vaccine and/or diagnostic escape mechanisms. In summation, this scholarly discourse elucidates the intricate interplay of clinical presentations, antigenic diversity, and genomic attributes in HBV infection, accentuating the imperative for ongoing investigative endeavors to refine diagnostic and therapeutic modalities.
Topics: Humans; Male; Hepatitis B virus; Hepatitis B Surface Antigens; Carcinoma, Hepatocellular; Bangladesh; Phylogeny; Reproducibility of Results; Hepatitis B; Mutation; Genotype; Liver Neoplasms; Antigenic Variation; Genomics; DNA, Viral; Hepatitis B, Chronic
PubMed: 38367678
DOI: 10.1016/j.meegid.2024.105572 -
Virus Evolution 2024Respiratory syncytial virus (RSV) infection in immunocompromised individuals often leads to prolonged illness, progression to severe lower respiratory tract infection,...
Respiratory syncytial virus (RSV) infection in immunocompromised individuals often leads to prolonged illness, progression to severe lower respiratory tract infection, and even death. How the host immune environment of the hematopoietic stem cell transplant (HCT) adults can affect viral genetic variation during an acute infection is not understood well. In the present study, we performed whole genome sequencing of RSV/A or RSV/B from samples collected longitudinally from HCT adults with normal (<14 days) and delayed (≥14 days) RSV clearance who were enrolled in a ribavirin trial. We determined the inter-host and intra-host genetic variation of RSV and the effect of mutations on putative glycosylation sites. The inter-host variation of RSV is centered in the attachment (G) and fusion (F) glycoprotein genes followed by polymerase (L) and matrix (M) genes. Interestingly, the overall genetic variation was constant between normal and delayed clearance groups for both RSV/A and RSV/B. Intra-host variation primarily occurred in the G gene followed by non-structural protein (NS1) and L genes; however, gain or loss of stop codons and frameshift mutations appeared only in the G gene and only in the delayed viral clearance group. Potential gain or loss of O-linked glycosylation sites in the G gene occurred both in RSV/A and RSV/B isolates. For RSV F gene, loss of N-linked glycosylation site occurred in three RSV/B isolates within an antigenic epitope. Both oral and aerosolized ribavirin did not cause any mutations in the L gene. In summary, prolonged viral shedding and immune deficiency resulted in RSV variation, especially in structural mutations in the G gene, possibly associated with immune evasion. Therefore, sequencing and monitoring of RSV isolates from immunocompromised patients are crucial as they can create escape mutants that can impact the effectiveness of upcoming vaccines and treatments.
PubMed: 38361816
DOI: 10.1093/ve/vead086 -
Briefings in Bioinformatics Jan 2024Vaccination stands as the most effective and economical strategy for prevention and control of influenza. The primary target of neutralizing antibodies is the surface...
Vaccination stands as the most effective and economical strategy for prevention and control of influenza. The primary target of neutralizing antibodies is the surface antigen hemagglutinin (HA). However, ongoing mutations in the HA sequence result in antigenic drift. The success of a vaccine is contingent on its antigenic congruence with circulating strains. Thus, predicting antigenic variants and deducing antigenic clusters of influenza viruses are pivotal for recommendation of vaccine strains. The antigenicity of influenza A viruses is determined by the interplay of amino acids in the HA1 sequence. In this study, we exploit the ability of convolutional neural networks (CNNs) to extract spatial feature representations in the convolutional layers, which can discern interactions between amino acid sites. We introduce PREDAC-CNN, a model designed to track antigenic evolution of seasonal influenza A viruses. Accessible at http://predac-cnn.cloudna.cn, PREDAC-CNN formulates a spatially oriented representation of the HA1 sequence, optimized for the convolutional framework. It effectively probes interactions among amino acid sites in the HA1 sequence. Also, PREDAC-CNN focuses exclusively on physicochemical attributes crucial for the antigenicity of influenza viruses, thereby eliminating unnecessary amino acid embeddings. Together, PREDAC-CNN is adept at capturing interactions of amino acid sites within the HA1 sequence and examining the collective impact of point mutations on antigenic variation. Through 5-fold cross-validation and retrospective testing, PREDAC-CNN has shown superior performance in predicting antigenic variants compared to its counterparts. Additionally, PREDAC-CNN has been instrumental in identifying predominant antigenic clusters for A/H3N2 (1968-2023) and A/H1N1 (1977-2023) viruses, significantly aiding in vaccine strain recommendation.
Topics: Influenza A virus; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H1N1 Subtype; Hemagglutinin Glycoproteins, Influenza Virus; Seasons; Retrospective Studies; Antigens, Viral; Neural Networks, Computer; Amino Acids; Vaccines
PubMed: 38343322
DOI: 10.1093/bib/bbae033 -
Cureus Jan 2024For decades, tuberculosis (TB), caused by (MTB), has remained a global health challenge. Central to this issue are the proline-proline-glutamic acid (PPE) proteins,... (Review)
Review
For decades, tuberculosis (TB), caused by (MTB), has remained a global health challenge. Central to this issue are the proline-proline-glutamic acid (PPE) proteins, which play a pivotal role in the pathogenesis and persistence of MTB. This article explores the molecular mechanisms of PPE proteins and their roles in facilitating MTB's evasion of the host's immune system while enhancing virulence and transmission. Focusing on the structural and functional aspects of PPE proteins, this review provides a detailed analysis of antigenic variation, a crucial mechanism allowing MTB to elude immune detection. It also probes the genetic diversity of these PPE proteins and their complex interactions with host immunity, offering insights into the challenges they pose for therapeutic development. This review delves into the potential of targeting PPE proteins in novel therapeutic strategies, discussing the prospects of drug and vaccine development. The evidence reviewed in this article underscores the pressing need for innovative approaches to combat TB, especially in the face of increasing drug resistance. Ultimately, this review article highlights the untapped potential of PPE proteins in revolutionizing TB treatment, paving the way for breakthroughs in drug and vaccine development.
PubMed: 38333477
DOI: 10.7759/cureus.51955 -
Genome Jun 2024is a worldwide economically important pathogen of cattle that can cause or indirectly contribute to bovine respiratory disease. is also a primary etiological agent of...
is a worldwide economically important pathogen of cattle that can cause or indirectly contribute to bovine respiratory disease. is also a primary etiological agent of respiratory disease in bison with high mortality rates. A major challenge in the development of an efficacious vaccine is the design of antigens that contain both MHC-1 and MHC-2 T-cell epitopes, and that account for population level diversity within the species. Publicly available genomes and sequence read archive libraries of 381 strains isolated from cattle ( = 202) and bison ( = 179) in North America were used to identify a core genome of 575 genes, including 38 that encode either known or predicted secreted or outer membrane proteins. The antigenic potentials of the proteins were characterized by the presence and strength of their T-cell epitopes, and their protein variant diversity at the population-level. The proteins had surprisingly low diversity and varying predictive levels of T-cell antigenicity. These results provide a reference for the selection or design of antigens for vaccine testing against strains infecting North American cattle and bison.
Topics: Animals; Bison; Cattle; North America; Epitopes, T-Lymphocyte; Genetic Variation; Mycoplasma bovis; Bacterial Outer Membrane Proteins; Genome, Bacterial; Antigens, Bacterial; Cattle Diseases
PubMed: 38330385
DOI: 10.1139/gen-2023-0084 -
Frontiers in Neurology 2024Congenital dysfibrinogenemia (CD) is a rare hereditary coagulation disorder resulting from mutations in fibrinogen genes. CD primarily presents with bleeding symptoms,...
BACKGROUND
Congenital dysfibrinogenemia (CD) is a rare hereditary coagulation disorder resulting from mutations in fibrinogen genes. CD primarily presents with bleeding symptoms, but it can also lead to thrombotic events, including ischemic stroke.
CASE PRESENTATION
This report describes the case of a 52-year-old Chinese man who was admitted to the hospital twice due to recurrent cerebral infarction, characterized by sudden speech impairment and weakness in the right upper extremity. Brain MRI revealed multiple ischemic changes, predominantly in the left frontal and parietal lobes. Coagulation tests demonstrated reduced plasma fibrinogen (Clauss method), prolonged prothrombin time and thrombin time, and an elevated international normalized ratio. However, the ELISA assay indicated elevated levels of fibrinogen γ-chain protein. Despite a 2-month-old treatment regimen with aspirin, clopidogrel, and atorvastatin after the first hospitalization, the patient experienced a second ischemic stroke. Genetic analysis using whole-exome sequencing (WES) and Sanger sequencing identified a rare heterozygous missense variation, c.952G>A (rs267606810), in both the stroke patient and his asymptomatic sister. Both individuals exhibited the same alterations in fibrinogen, characterized by reduced functional levels but increased antigenic protein. Subsequently, the patient was diagnosed with ischemic stroke associated with congenital dysfibrinogenemia.
CONCLUSION
This case report expands the clinical phenotype spectrum associated with c.952G>A (rs267606810) and underscores the significance of considering CD as a potential etiology for unexplained ischemic stroke, particularly in patients with a family history of coagulation disorders.
PubMed: 38327620
DOI: 10.3389/fneur.2024.1272802 -
Biomedical Journal Feb 2024Epigenetic machinery has emerged as a central player in gene regulation and chromatin organization in Plasmodium spp. Epigenetic modifications on histones and their role...
Epigenetic machinery has emerged as a central player in gene regulation and chromatin organization in Plasmodium spp. Epigenetic modifications on histones and their role in antigenic variation in P. falciparum are widely studied. Recent discoveries on nucleic acid methylome are exciting and provide a new dimension to the apicomplexan protozoan parasite's gene regulatory process. Reports have confirmed that N6-methyl adenosine (m6A) methylation plays a crucial role in the translational plasticity of the human malaria parasite during its development in RBC. The YTH domain (YT521-B Homology) protein in P. falciparum binds to m6A epitranscriptome modifications on the mRNA and regulates protein translation. The binding of the PfYTH domain protein to the m6A-modified mRNA is mediated through a binding pocket formed by aromatic amino acids. The P. falciparum genome encodes two members of YTH domain proteins, i.e., YTH1 and YTH2, and both have distinct roles in dictating the epitranscriptome in human malaria parasites. This review highlights recent advancements in the functions and mechanisms of YTH domain protein's role in translational plasticity in the various developmental stages of the parasite.
PubMed: 38316392
DOI: 10.1016/j.bj.2024.100703 -
Viruses Jan 2024Seoul (SEOV) and Hantaan (HTNV) orthohantaviruses are significant zoonotic pathogens responsible for hemorrhagic fever with renal syndrome. Here, we investigated the...
Seoul (SEOV) and Hantaan (HTNV) orthohantaviruses are significant zoonotic pathogens responsible for hemorrhagic fever with renal syndrome. Here, we investigated the molecular evolution of SEOV and HTNV through phylogenetic and bioinformatic analyses using complete genome sequences of their large (L), medium (M), and small (S) gene segments. Despite similar epizootic cycles and clinical symptoms, SEOV and HTNV exhibited distinct genetic and evolutionary dynamics. The phylogenetic trees of each segment consistently showed major genetic clades associated with the geographical distribution of both viruses. Remarkably, SEOV M and S segments exhibit higher evolutionary rates, rapidly increasing genetic diversity, and a more recent origin in contrast to HTNV. Reassortment events were infrequent, but both viruses appear to utilize the M gene segment in genetic exchanges. SEOV favors the L or M segment reassortment, while HTNV prefers the M or S segment exchange. Purifying selection dominates in all three gene segments of both viruses, yet SEOV experiences an elevated positive selection in its glycoprotein Gc ectodomain. Key amino acid differences, including a positive 'lysine fence' (through residues K77, K82, K231, K307, and K310) located at the tip of the Gn, alongside the physical stability around an RGD-like motif through M108-F334 interaction, may contribute to the unique antigenic properties of SEOV. With the increasing global dispersion and potential implications of SEOV for the global public health landscape, this study highlights the unique evolutionary dynamics and antigenic properties of SEOV and HTNV in informing vaccine design and public health preparedness.
Topics: Phylogeny; Seoul; RNA Viruses; Evolution, Molecular; Genetic Variation; Orthohantavirus
PubMed: 38257805
DOI: 10.3390/v16010105 -
Biomolecules Jan 2024Although located at the chromosome end, telomeres are an essential chromosome component that helps maintain genome integrity and chromosome stability from protozoa to... (Review)
Review
Although located at the chromosome end, telomeres are an essential chromosome component that helps maintain genome integrity and chromosome stability from protozoa to mammals. The role of telomere proteins in chromosome end protection is conserved, where they suppress various DNA damage response machineries and block nucleolytic degradation of the natural chromosome ends, although the detailed underlying mechanisms are not identical. In addition, the specialized telomere structure exerts a repressive epigenetic effect on expression of genes located at subtelomeres in a number of eukaryotic organisms. This so-called telomeric silencing also affects virulence of a number of microbial pathogens that undergo antigenic variation/phenotypic switching. Telomere proteins, particularly the RAP1 homologs, have been shown to be a key player for telomeric silencing. RAP1 homologs also suppress the expression of Telomere Repeat-containing RNA (TERRA), which is linked to their roles in telomere stability maintenance. The functions of RAP1s in suppressing telomere recombination are largely conserved from kinetoplastids to mammals. However, the underlying mechanisms of RAP1-mediated telomeric silencing have many species-specific features. In this review, I will focus on RAP1's functions in suppressing telomeric/subtelomeric DNA recombination and in the regulation of monoallelic expression of subtelomere-located major surface antigen genes. Common and unique mechanisms will be compared among RAP1 homologs, and their implications will be discussed.
Topics: Animals; Telomere; Epigenomics; Eukaryota; RNA, Long Noncoding; Mammals
PubMed: 38254667
DOI: 10.3390/biom14010067 -
Infection, Genetics and Evolution :... Mar 2024Plasmodium vivax is the most geographically widespread malaria parasite in human presently. The ookinete surface proteins of sexual stage of malaria parasites, Pvs25 and...
Plasmodium vivax is the most geographically widespread malaria parasite in human presently. The ookinete surface proteins of sexual stage of malaria parasites, Pvs25 and Pvs28, are candidates for the transmission blocking vaccine. The antigenic variation in population might be barrier for vaccine development. The objective of this study was to investigate the genetic diversity of Pvs25 and Pvs28 in endemic areas of Thailand. P. vivax clinical isolates collected from Thai-neighboring border areas were analyzed using polymerase chain reaction and sequencing method. Three and 14 amino acid substitutions were observed in 43 Pvs25 and 48 Pvs28 sequences, respectively. Three haplotypes in Pvs25 and 14 haplotypes with 5-7 GSGGE/D tandem repeats in Pvs28 were identified. The nucleotide diversity of pvs25 (π = 0.00059) had lower level than pvs28 (π = 0.00517). Tajima's D value for both pvs25 and pvs28 genes were negative while no significant difference was found (P > 0.10). Low genetic diversity was found in pvs25 and pvs28 genes in Thailand. The finding of the most frequent amino acid substitutions was consistent with global isolates. Therefore, the data could be helpful in developing of effective transmission blocking vaccine in malaria endemic areas.
Topics: Humans; Plasmodium vivax; Thailand; Polymorphism, Genetic; Malaria, Vivax; Membrane Proteins; Vaccines
PubMed: 38244749
DOI: 10.1016/j.meegid.2024.105558