Search Results (65)

Mpox, caused by the Mpox virus (MPXV), is a re-emerging zoonotic disease in the Poxviridae family. Since 2022, sub-Saharan Africa has experienced recurrent outbreaks, with the Democratic Republic of the Congo (DRC) accounting for 96% of the 567 confirmed cases reported in the African region by the World Health Organization as of June 2024. Despite MPXV’s endemic presence, its genomic diversity and evolutionary dynamics remain poorly characterized. We analyzed 270 MPXV genomes from 13 sub-Saharan African countries (2022–2024), representing the most geographically comprehensive regional dataset from the outbreak period. Phylogenetic analysis identified two geographically distinct clades: Clade I (East/Central Africa) and Clade II (West/Southern Africa). A marked disparity in APOBEC3-associated mutations was observed, with Clade IIb exhibiting significantly higher enrichment than Clade I, suggesting clade-specific host adaptation pressures. These mutations predominantly target genes involved in immune evasion and replication. Preliminary functional predictions indicated that selected missense mutations may impact on protein stability, underscoring the need for further experimental validation. Our findings provide the first pan–sub-Saharan analysis of MPXV clade divergence and reinforce the importance of sustained, regionally informed genomic surveillance to monitor viral evolution and guide outbreak response strategies across Africa. Full article

The human gut microbiome is intricately linked to systemic and organ-specific immune responses and is highly responsive to dietary modulation. As metagenomic techniques enable in-depth study of an ever-growing number of gut microbial species, it has become increasingly feasible to decipher the specific functions of the gut microbiome and how they may be modulated by diet. Diet exerts both supportive and selective pressures on the gut microbiome by regulating a multitude of factors, including energy density, macronutrient and micronutrient content, and circadian rhythm. The microbiome, in turn, contributes to local and systemic immune responses by providing colonization resistance against pathogens, shaping immune cell activity and differentiation, and facilitating the production of bioactive metabolites. Emerging research has strengthened the connections between the gut microbiome and cardiometabolic disorders (e.g., cardiovascular disease, obesity, type-2 diabetes), autoimmune conditions (e.g., type-1 diabetes, rheumatoid arthritis, celiac disease), respiratory disease, chronic kidney and liver disease, inflammatory bowel disease, and neurological disorders (e.g., Alzheimer’s, Parkinson’s disease, depressive disorders). Here, we outline ways in which dietary factors impact host response in diseases through alterations of gut microbiome functionality and composition. Consideration of diet-mediated microbial effects within the context of the diseases discussed highlights the potential of microbiome-targeted treatment strategies as alternative or adjunct therapies to improve patient outcomes. Full article

Phytoplasmas of the X-disease group (16SrIII) are economically significant pathogens in South America, causing severe crop losses. Traditional classification based on the 16S rRNA gene has limitations in resolving closely related strains, prompting the exploration of alternative markers. This study focuses on the immunodominant membrane proteins imp and idpA, which exhibit high variability and play crucial roles in host–pathogen interactions. Through molecular characterization of imp and idpA genes in 16SrIII subgroups, we identified significant genetic diversity and distinct evolutionary pressures. The imp gene, under positive selection, showed high variability in its hydrophilic extracellular domain, suggesting adaptation to host immune responses. In contrast, idpA exhibited strong negative selection, indicating functional conservation. Phylogenetic analyses revealed that imp and idpA provide higher resolution than the 16S rRNA gene, enabling finer differentiation within subgroups. These findings highlight the potential of imp and idpA as complementary markers for phytoplasma classification and diagnostics. Full article

The impact of hepatitis B virus (HBV) diversity and evolution on disease progression is not well-understood. This study aims to compare intra-individual viral evolution in two groups of chronic hepatitis B (CHB) patients, using antiviral treatment initiation as a measure of lack of immunological control. From the Danish Database for Hepatitis B and C (DANHEP), 25 CHB patients were included; 14 with antiviral treatment initiation (TI group), and 11 without (NTI group). For each patient, three serial plasma samples taken before potential treatment initiation were selected. HBV DNA was amplified by PCR and analyzed by next-generation sequencing. HBV DNA and alanine transaminase were elevated in the TI group throughout the study period. Significantly higher substitution rates in the NTI group versus the TI group were found both within the viral population and at consensus level. Putative predicted CD8⁺ T cell epitopes contained significantly more substitutions in the NTI group. Genome-wide association analysis revealed several amino acid residues in the HBV genome associated with treatment initiation. This study shows that HBV has a higher rate of substitutions in CHB patients not requiring treatment. This could be linked to host immune pressure leading to disease control. Full article

Infectious bronchitis virus (IBV) of the GI-23 lineage, which first emerged in the Middle East in the late 1990s, has since spread worldwide. The factors driving its expansion, whether human involvement, wild bird migration, or the virus’s biological traits, are still unclear. This study aimed to trace the genome evolution of GI-23 IBV in chickens and its adaptability to quails, which are susceptible to both gamma- and deltacoronaviruses. Thirty specific-pathogen-free (SPF) birds, aged between two and three weeks, were used. Initially, three birds were inoculated with the G052/2016 IBV via the oculo-nasal route. On the third day post-infection (dpi), oropharyngeal swabs were collected from the whole group, pooled, and subsequently used to infect three next birds. This process was repeated nine more times during consecutive IBV passages (P-I–P-X), and eventually, virus sequencing was performed using Next-Generation Sequencing (NGS). The obtained results showed that quails were not susceptible to the IBV GI-23 lineage, as the virus RNA was detected in low amounts only during the first passage (QP-I) with no further detections in later rounds of IBV passaging. In chickens, only mild diarrhea symptoms appeared in a few individuals. The NGS analysis identified sixty-two single nucleotide variants (SNVs), thirty of which caused amino acid changes, twenty-eight were synonymous, and one SNV introduced a stop codon. Three SNVs were found in untranslated regions. However, none of these SNVs lasted beyond seven passages, with forty-four being unique SNVs. The Shannon entropy values measured during passages varied for pol1a, pol1b, S, 5a, 5b, and N genes, with overall genome complexity peaking at CP-VI and CP-X. The highest complexity was observed in the pol1a (CP-X) and S genes (CP-IV, CP-VI, CP-VIII, and CP-X). Along with the S gene that was under positive selection, eight codons in pol1a were also positively selected. These findings suggest that even in an adapted host, IBV variability does not stabilize without immune pressure, indicating continuous molecular changes within its genome. Full article

The evolutionary arms race between host restriction factors and viral antagonists provides crucial insights into immune system evolution and viral adaptation. This study investigates the structural and evolutionary dynamics of the double-domain restriction factors A3F and A3G and their viral inhibitor, Vif, across diverse primate species. By constructing 3D structural homology models and integrating ancestral sequence reconstruction (ASR), we identified patterns of sequence diversity, structural conservation, and functional adaptation. Inactive CD1 (Catalytic Domain 1) domains displayed greater sequence diversity and more positive surface charges than active CD2 domains, aiding nucleotide chain binding and intersegmental transfer. Despite variability, the CD2 DNA-binding grooves remained structurally consistent with conserved residues maintaining critical functions. A3F and A3G diverged in loop 7’ interaction strategies, utilising distinct molecular interactions to facilitate their roles. Vif exhibited charge variation linked to host species, reflecting its coevolution with A3 proteins. These findings illuminate how structural adaptations and charge dynamics enable both restriction factors and their viral antagonists to adapt to selective pressures. Our results emphasize the importance of studying structural evolution in host–virus interactions, with implications for understanding immune defense mechanisms, zoonotic risks, and viral evolution. This work establishes a foundation for further exploration of restriction factor diversity and coevolution across species. Full article

Background/Objectives: Porcine reproductive and respiratory syndrome virus (PRRSV) is classified into various lineages based on the phylogenetic variation of orf5, which encodes a major surface glycoprotein GP5 containing both neutralizing and non-neutralizing linear epitopes. Several positively selected sites have been identified on the GP5 ectodomain, indicating host immune pressure on these sites. This present study aimed to investigate the kinetics of antibody responses to GP5 and to map the epitope-specific response to the GP5 ectodomain from different PRRSV lineages after vaccination with commercially available modified live virus (MLV) vaccines. Methods: Post-weaning pigs were vaccinated with MLV vaccines derived from either lineage 1D (Prevacent PRRS^®) or lineage 5 (Ingelvac PRRS^®). Animals were challenged with a heterologous (lineage 1A) strain at 64 days post-vaccination (dpv). Blood samples were collected at various times post-vaccination and challenge. Kinetics of antibody response to different PRRSV antigens were monitored and virus neutralization against archetypal and contemporary strains belonging to lineage 5 and 1A were evaluated. In addition, antibody responses to peptides derived from the GP5 ectodomain of different viral lineages were assessed. Results: Our results showed that the GP5-specific antibody response observed between 18 and 35 dpv was delayed compared to responses to the viral nucleocapsid protein. The polyclonal antibody response in both vaccinated groups showed similar levels of binding to variant GP5 peptides from different sub-lineages. Notably, in both vaccinated groups, the antibody directed to a peptide representing the GP5 ectodomain of a lineage 1C strain (variant 1C.5) displayed a rise in titer at 64 dpv, which was further increased by the challenge with the lineage 1A strain. Less than 50% of animals developed heterologous neutralizing antibodies post-vaccination with both MLV vaccines. However, higher neutralization titers were observed in all vaccinated animal post-challenge. Conclusions: Together, these data provide insights into the antibody responses to the GP5 ectodomain in MLV-vaccinated swine herds. Full article

Background/Objectives: Poxviruses are large DNA viruses that replicate in the host cytoplasm without a nuclear phase. As vaccine vectors, they can package and express large recombinant cassettes from different positions of their genomic core region. We present a comparison between wildtype modified vaccinia Ankara (MVA) and isolate CR19, which has significantly expanded inverted terminal repeats (ITRs). With this expansion, a site in wildtype MVA, called deletion site (DS) IV, has been duplicated at both ends of the genome and now occupies an almost central position in the newly formed ITRs. Methods: We inserted various reporter genes into this site and found that the ITRs can be used for transgene expression. However, ITRs are genomic structures that can rapidly adapt to selective pressure through transient duplication and contraction. To test the potential utility of insertions into viral telomers, we inserted a factor from the cellular innate immune system that interferes with viral replication as an example of a difficult transgene. Results: A site almost in the centre of the ITRs can be used for transgene expression, and both sides are mirrored into identical copies. The example of a challenging transgene, tetherin, proved to be surprisingly efficient in selecting candidate vectors against the large background of parental viruses. Conclusions: Insertion of transgenes into ITRs automatically doubles the gene doses. The functionalisation of viruses with tetherin may accelerate the identification and generation of recombinant vectors for personalised medicine and pandemic preparedness. Full article

In this review, we explore the underlying molecular biology of medullary thyroid carcinoma (MTC) and its interplay with the host immune system. MTC is consistently driven by a small number of specific pathogenic variants, beyond which few additional genetic events are required for tumorigenesis. This explains the exceedingly low tumour mutational burden seen in most MTC, in contrast to other cancers. However, because of the low tumour mutational burden (TMB), there is a correspondingly low level of tumour-associated neoantigens that are presented to the host immune system. This reduces tumour visibility and vigour of the anti-tumour immune response and suggests the efficacy of immunotherapy in MTC is likely to be poor, acknowledging this inference is largely based on the extrapolation of data from other tumour types. The dominance of specific RET (REarranged during Transfection) pathogenic variants in MTC tumorigenesis rationalizes the observed efficacy of the targeted RET-specific tyrosine kinase inhibitors (TKIs) in comparison to multi-kinase inhibitors (MKIs). Therapeutic durability of pathway inhibitors is an ongoing research focus. It may be limited by the selection pressure TKI treatment creates, promoting survival of resistant tumour cell clones that can escape pathway inhibition through binding-site mutations, activation of alternate pathways, and modulation of the cellular and cytokine milieu of the tumour microenvironment (TME). Full article

People living with HIV (PLWH) face a growing burden of chronic diseases, owing to the combinations of aging, environmental triggers, lifestyle choices, and virus-induced chronic inflammation. The rising incidence of pulmonary vascular diseases represents a major concern for PLWH. The study of HIV-associated pulmonary vascular complications ideally requires a strong understanding of pulmonary vascular cell biology and HIV pathogenesis at the molecular level for effective applications in infectious diseases and vascular medicine. Active HIV infection and/or HIV proteins disturb the delicate balance between vascular tone and constriction, which is pivotal for maintaining pulmonary vascular health. One of the defining features of HIV is its high genetic diversity owing to several factors including its high mutation rate, recombination between viral strains, immune selective pressures, or even geographical factors. The intrinsic HIV genetic diversity has several important implications for pathogenic outcomes of infection and the overall battle to combat HIV. Challenges in the field present themselves from two sides of the same coin: those imposed by the virus itself and those stemming from the host. The field may be advanced by further developing in vivo and in vitro models that are well described for both pulmonary vascular diseases and HIV for mechanistic studies. In essence, the study of HIV-associated pulmonary vascular complications requires a multidisciplinary approach, drawing upon insights from both infectious diseases and vascular medicine. In this review article, we discuss the fundamentals of HIV virology and their impact on pulmonary disease, aiming to enhance the understanding of either area or both simultaneously. Bridging the gap between preclinical research findings and clinical practice is essential for improving patient care. Addressing these knowledge gaps requires interdisciplinary collaborations, innovative research approaches, and dedicated efforts to prioritize HIV-related pulmonary complications on the global research agenda. Full article

The molecular mechanisms controlling the adaptation of viruses to host cells are generally poorly documented. An essential issue to resolve is whether host membranes, and especially lipid rafts, which are usually considered passive gateways for many enveloped viruses, also encode informational guidelines that could determine virus evolution. Due to their enrichment in gangliosides which confer an electronegative surface potential, lipid rafts impose a first control level favoring the selection of viruses with enhanced cationic areas, as illustrated by SARS-CoV-2 variants. Ganglioside clusters attract viral particles in a dynamic electrostatic funnel, the more cationic viruses of a viral population winning the race. However, electrostatic forces account for only a small part of the energy of raft-virus interaction, which depends mainly on the ability of viruses to form a network of hydrogen bonds with raft gangliosides. This fine tuning of virus-ganglioside interactions, which is essential to stabilize the virus on the host membrane, generates a second level of selection pressure driven by a typical induced-fit mechanism. Gangliosides play an active role in this process, wrapping around the virus spikes through a dynamic quicksand-like mechanism. Viruses are thus in an endless race for access to lipid rafts, and they are bound to evolve perpetually, combining speed (electrostatic potential) and precision (fine tuning of amino acids) under the selective pressure of the immune system. Deciphering the host membrane guidelines controlling virus evolution mechanisms may open new avenues for the design of innovative antivirals. Full article

Infectious diseases still threaten global human health, and host genetic factors have been indicated as determining risk factors for observed variations in disease susceptibility, severity, and outcome. We performed a genome-wide meta-analysis on 4624 subjects from the 10,001 Dalmatians cohort, with 14 infection-related traits. Despite a rather small number of cases in some instances, we detected 29 infection-related genetic associations, mostly belonging to rare variants. Notably, the list included the genes CD28, INPP5D, ITPKB, MACROD2, and RSF1, all of which have known roles in the immune response. Expanding our knowledge on rare variants could contribute to the development of genetic panels that could assist in predicting an individual’s life-long susceptibility to major infectious diseases. In addition, longitudinal biobanks are an interesting source of information for identifying the host genetic variants involved in infectious disease susceptibility and severity. Since infectious diseases continue to act as a selective pressure on our genomes, there is a constant need for a large consortium of biobanks with access to genetic and environmental data to further elucidate the complex mechanisms behind host–pathogen interactions and infectious disease susceptibility. Full article

Although very different, in terms of their genomic organization, their enzymatic proteins, and their structural proteins, HIV and SARS-CoV-2 have an extraordinary evolutionary potential in common. Faced with various selection pressures that may be generated by treatments or immune responses, these RNA viruses demonstrate very high adaptive capacities, which result in the continuous emergence of variants and quasi-species. In this retrospective analysis of viral proteins, ensuring the adhesion of these viruses to the plasma membrane of host cells, we highlight many common points that suggest the convergent mechanisms of evolution. HIV and SARS-CoV-2 first recognize a lipid raft microdomain that acts as a landing strip for viral particles on the host cell surface. In the case of mucosal cells, which are the primary targets of both viruses, these microdomains are enriched in anionic glycolipids (gangliosides) forming a global electronegative field. Both viruses use lipid rafts to surf on the cell surface in search of a protein receptor able to trigger the fusion process. This implies that viral envelope proteins are both geometrically and electrically compatible to the biomolecules they select to invade host cells. In the present study, we identify the surface electrostatic potential as a critical parameter controlling the convergent evolution dynamics of HIV-1 and SARS-CoV-2 surface envelope proteins, and we discuss the impact of this parameter on the phenotypic properties of both viruses. The virological data accumulated since the emergence of HIV in the early 1980s should help us to face present and future virus pandemics. Full article

Host immunity can exert a complex array of selective pressures on a pathogen, which can drive highly mutable RNA viruses towards viral escape. The plasticity of a virus depends on its rate of mutation, as well as the balance of fitness cost and benefit of mutations, including viral adaptations to the host’s immune response. Since its emergence, SARS-CoV-2 has diversified into genetically distinct variants, which are characterised often by clusters of mutations that bolster its capacity to escape human innate and adaptive immunity. Such viral escape is well documented in the context of other pandemic RNA viruses such as the human immunodeficiency virus (HIV) and influenza virus. This review describes the selection pressures the host’s antiviral immunity exerts on SARS-CoV-2 and other RNA viruses, resulting in divergence of viral strains into more adapted forms. As RNA viruses obscure themselves from host immunity, they uncover weak points in their own armoury that can inform more comprehensive, long-lasting, and potentially cross-protective vaccine coverage. Full article

Bactericidal/permeability-increasing protein, a primary factor of the innate immune system of mammals, participates in natural immune protection against invading bacteria. BPIFA1 actively contributes to host defense via multiple mechanisms, such as antibacterial, surfactant, airway surface liquid control, and immunomodulatory activities. However, the evolutionary history and selection forces on the BPIFA1 gene in mammals during adaptive evolution are poorly understood. This study examined the BPIFA1 gene of humans compared with that of other mammalian species to estimate the selective pressure derived by adaptive evolution. To assess whether or not positive selection occurred, we employed several different possibility tests (M1 vs. M2 and M7 vs. M8). The proportions of positively selected sites were significant, with a likelihood log value of 93.63 for the BPIFA1 protein. The Selecton server was used on the same dataset to reconfirm positive selection for specific sites by employing the Mechanistic-Empirical Combination model, thus providing additional evidence supporting the findings of positive selection. There was convincing evidence for positive selection signals in the BPIFA1 genes of mammalian species, which was more significant for selection signs and creating signals. We performed probability tests comparing various models based on dN/dS ratios to recognize specific codons under positive selection pressure. We identified positively selected sites in the LBP-BPI domain of BPIFA1 proteins in the mammalian genome, including a lipid-binding domain with a very high degree of selectivity for DPPC. BPIFA1 activates the upper airway’s innate immune system in response to numerous genetic signals in the mammalian genome. These findings highlight evolutionary advancements in immunoregulatory effects that play a significant role in the antibacterial and antiviral defenses of mammalian species. Full article