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Proceedings of the National Academy of... Mar 2024Viral mimicry of host cell structures has been postulated to curtail the B cell receptor (BCR) repertoire against persisting viruses through tolerance mechanisms. This...
Viral mimicry of host cell structures has been postulated to curtail the B cell receptor (BCR) repertoire against persisting viruses through tolerance mechanisms. This concept awaits, however, experimental testing in a setting of natural virus-host relationship. We engineered mouse models expressing a monoclonal BCR specific for the envelope glycoprotein of lymphocytic choriomeningitis virus (LCMV), a naturally persisting mouse pathogen. When the heavy chain of the LCMV-neutralizing antibody KL25 was paired with its unmutated ancestor light chain, most B cells underwent receptor editing, a behavior reminiscent of autoreactive clones. In contrast, monoclonal B cells expressing the same heavy chain in conjunction with the hypermutated KL25 light chain did not undergo receptor editing but exhibited low levels of surface IgM, suggesting that light chain hypermutation had lessened KL25 autoreactivity. Upon viral challenge, these IgM cells were not anergic but up-regulated IgM, participated in germinal center reactions, produced antiviral antibodies, and underwent immunoglobulin class switch as well as further affinity maturation. These studies on a persisting virus in its natural host species suggest that central tolerance mechanisms prune the protective antiviral B cell repertoire.
Topics: Animals; Mice; Central Tolerance; B-Lymphocytes; Antibodies, Viral; Lymphocytic choriomeningitis virus; Antiviral Agents; Immunoglobulin M
PubMed: 38446855
DOI: 10.1073/pnas.2318657121 -
Virology Journal Nov 2023The global decline in biodiversity is a matter of great concern for members of the class Reptilia. Reptarenaviruses infect snakes, and have been linked to various...
The global decline in biodiversity is a matter of great concern for members of the class Reptilia. Reptarenaviruses infect snakes, and have been linked to various clinical conditions, such as Boid Inclusion Body Disease (BIBD) in snakes belonging to the families Boidae and Pythonidae. However, there is a scarcity of information regarding reptarenaviruses found in snakes in both the United States and globally. This study aimed to contribute to the understanding of reptarenavirus diversity by molecularly characterizing a reptarenavirus detected in a Colombian Red-Tailed Boa (Boa constrictor imperator). Using a metagenomics approach, we successfully identified, and de novo assembled the whole genomic sequences of a reptarenavirus in a Colombian Red-Tailed Boa manifesting clinically relevant symptoms consistent with BIBD. The analysis showed that the Colombian Red-Tailed Boa in this study carried the University of Giessen virus (UGV-1) S or S6 (UGV/S6) segment and L genotype 7. The prevalence of the UGV/S6 genotype, in line with prior research findings, implies that this genotype may possess specific advantageous characteristics or adaptations that give it a competitive edge over other genotypes in the host population. This research underscores the importance of monitoring and characterizing viral pathogens in captive and wild snake populations. Knowledge of such viruses is crucial for the development of effective diagnostic methods, potential intervention strategies, and the conservation of vulnerable reptilian species. Additionally, our study provides valuable insights for future studies focusing on the evolutionary history, molecular epidemiology, and biological properties of reptarenaviruses in boas and other snake species.
Topics: Humans; Animals; Arenaviridae; Boidae; Colombia; Biological Evolution; Genotype
PubMed: 37968659
DOI: 10.1186/s12985-023-02237-2 -
BMC Infectious Diseases Mar 2024Lassa fever is a hemorrhagic disease caused by Lassa virus (LASV), which has been classified by the World Health Organization as one of the top infectious diseases...
BACKGROUND
Lassa fever is a hemorrhagic disease caused by Lassa virus (LASV), which has been classified by the World Health Organization as one of the top infectious diseases requiring prioritized research. Previous studies have provided insights into the classification and geographic characteristics of LASV lineages. However, the factor of the distribution and evolution characteristics and phylodynamics of the virus was still limited.
METHODS
To enhance comprehensive understanding of LASV, we employed phylogenetic analysis, reassortment and recombination detection, and variation evaluation utilizing publicly available viral genome sequences.
RESULTS
The results showed the estimated the root of time of the most recent common ancestor (TMRCA) for large (L) segment was approximately 634 (95% HPD: [385879]), whereas the TMRCA for small (S) segment was around 1224 (95% HPD: [10301401]). LASV primarily spread from east to west in West Africa through two routes, and in route 2, the virus independently spread to surrounding countries through Liberia, resulting in a wider spread of LASV. From 1969 to 2018, the effective population size experienced two significant increased, indicating the enhanced genetic diversity of LASV. We also found the evolution rate of L segment was faster than S segment, further results showed zinc-binding protein had the fastest evolution rate. Reassortment events were detected in multiple lineages including sub-lineage IIg, while recombination events were observed within lineage V. Significant amino acid changes in the glycoprotein precursor of LASV were identified, demonstrating sequence diversity among lineages in LASV.
CONCLUSION
This study comprehensively elucidated the transmission and evolution of LASV in West Africa, providing detailed insights into reassortment events, recombination events, and amino acid variations.
Topics: Humans; Lassa virus; Phylogeny; Lassa Fever; Amino Acids; Liberia
PubMed: 38486143
DOI: 10.1186/s12879-024-09200-8 -
Emerging Microbes & Infections Dec 2023We phylogenetically compared sequences of the zoonotic Lassa virus (LASV) obtained from rodents in seven localities across the highly endemic Edo and Ondo States within...
We phylogenetically compared sequences of the zoonotic Lassa virus (LASV) obtained from rodents in seven localities across the highly endemic Edo and Ondo States within Nigeria. Sequencing 1641 nt from the S segment of the virus genome, we resolved clades within lineage II that were either limited to Ebudin and Okhuesan in Edo state (2g-beta) or along Owo-Okeluse-Ifon in Ondo state (2g-gamma). We also found clades within Ekpoma, a relatively large cosmopolitan town in Edo state, that extended into other localities within Edo (2g-alpha) and Ondo (2g-delta). LASV variants from within Ebudin and Ekpoma in Edo State (dated approximately 1961) were more ancient compared to those from Ondo state (approximately 1977), suggesting a broadly east-west virus migration across south-western Nigeria; a pattern not always consistent with LASV sequences derived from humans in the same localities. Additionally, in Ebudin and Ekpoma, LASV sequences between and were interspersed on the phylogenetic tree, but those from were estimated to emerge more recently (approximately 2005). Overall, our results show that LASV amplification in certain localities (reaching a prevalence as high as 76% in Okeluse), anthropogenically-aided spread of rodent-borne variants amidst the larger towns (involving communal accommodation such as student hostels), and virus-exchange between syntopic and rodents (as the latter, a savanna species, encroaches southward into the degraded forest) pose perpetual zoonotic hazard across the Edo-Ondo Lassa fever belt, threatening to accelerate the dissemination of the virus into non endemic areas.
Topics: Humans; Mice; Animals; Lassa virus; Nigeria; Phylogeny; Lassa Fever; Murinae
PubMed: 37288752
DOI: 10.1080/22221751.2023.2219350 -
Journal of Virology Jun 2024The mammarenavirus Lassa virus (LASV) causes the life-threatening hemorrhagic fever disease, Lassa fever. The lack of licensed medical countermeasures against LASV...
The mammarenavirus Lassa virus (LASV) causes the life-threatening hemorrhagic fever disease, Lassa fever. The lack of licensed medical countermeasures against LASV underscores the urgent need for the development of novel LASV vaccines, which has been hampered by the requirement for a biosafety level 4 facility to handle live LASV. Here, we investigated the efficacy of mRNA-lipid nanoparticle (mRNA-LNP)-based vaccines expressing the LASV glycoprotein precursor (LASgpc) or nucleoprotein (LCMnp) of the prototypic mammarenavirus, lymphocytic choriomeningitis virus (LCMV), in mice. Two doses of LASgpc- or LCMnp-mRNA-LNP administered intravenously (i.v.) protected C57BL/6 mice from a lethal challenge with a recombinant (r) LCMV expressing a modified LASgpc (rLCMV/LASgpc) inoculated intracranially. Intramuscular (i.m.) immunization with two doses of LASgpc- or LCMnp-mRNA-LNP significantly reduced the viral load in C57BL/6 mice inoculated i.v. with rLCMV/LASgpc. High levels of viremia and lethality were observed in CBA mice inoculated i.v. with rLCMV/LASgpc, which were abrogated by i.m. immunization with two doses of LASgpc-mRNA-LNP. The protective efficacy of two i.m. doses of LCMnp-mRNA-LNP was confirmed in a lethal hemorrhagic disease model of FVB mice i.v. inoculated with wild-type rLCMV. In all conditions tested, negligible and high levels of LASgpc- and LCMnp-specific antibodies were detected in mRNA-LNP-immunized mice, respectively, but robust LASgpc- and LCMnp-specific CD8 T cell responses were induced. Accordingly, plasma from LASgpc-mRNA-LNP-immunized mice did not exhibit neutralizing activity. Our findings and surrogate mouse models of LASV infection, which can be studied at a reduced biocontainment level, provide a critical foundation for the rapid development of mRNA-LNP-based LASV vaccines.IMPORTANCELassa virus (LASV) is a highly pathogenic mammarenavirus responsible for several hundred thousand infections annually in West African countries, causing a high number of lethal Lassa fever (LF) cases. Despite its significant impact on human health, clinically approved, safe, and effective medical countermeasures against LF are not available. The requirement of a biosafety level 4 facility to handle live LASV has been one of the main obstacles to the research and development of LASV countermeasures. Here, we report that two doses of mRNA-lipid nanoparticle-based vaccines expressing the LASV glycoprotein precursor (LASgpc) or nucleoprotein (LCMnp) of lymphocytic choriomeningitis virus (LCMV), a mammarenavirus genetically closely related to LASV, conferred protection to recombinant LCMV-based surrogate mouse models of lethal LASV infection. Notably, robust LASgpc- and LCMnp-specific CD8 T cell responses were detected in mRNA-LNP-immunized mice, whereas no virus-neutralizing activity was observed.
Topics: Animals; Female; Mice; Antibodies, Neutralizing; Antibodies, Viral; Disease Models, Animal; Glycoproteins; Lassa Fever; Lassa virus; Liposomes; Lymphocytic choriomeningitis virus; Mice, Inbred C57BL; Nanoparticles; Nucleoproteins; RNA, Messenger; Viral Load; Viral Vaccines
PubMed: 38767352
DOI: 10.1128/jvi.00578-24 -
Viruses Feb 2024Following an Argentine Hemorrhagic Fever (AHF) outbreak in the early 1990s, a rodent survey for Junín virus, a New World Clade B arenavirus, in endemic areas of...
Following an Argentine Hemorrhagic Fever (AHF) outbreak in the early 1990s, a rodent survey for Junín virus, a New World Clade B arenavirus, in endemic areas of Argentina was conducted. Since 1990, INEVH has been developing eco-epidemiological surveillance of rodents, inside and outside the Argentine Hemorrhagic Fever endemic area. Samples from rodents captured between 1993 and 2019 that were positive for Arenavirus infection underwent Sanger and unbiased, Illumina-based high-throughput sequencing, which yielded 5 complete and 88 partial genomes. Previously, 11 genomes representing four species of New World arenavirus Clade C existed in public records. This work has generated 13 novel genomes, expanding the New World arenavirus Clade C to 24 total genomes. Additionally, two genomes exhibit sufficient genetic diversity to be considered a new species, as per ICTV guidelines (proposed name ). The 13 novel genomes exhibited reassortment between the small and large segments in New World . This work demonstrates that Clade C infections circulate broadly among species in the Argentine Hemorrhagic Fever endemic area; however, the risk for Clade C human infection is currently unknown.
Topics: Animals; Humans; Arenaviridae; Rodentia; Hemorrhagic Fever, American; Argentina; Arenaviruses, New World; Junin virus; Arenavirus
PubMed: 38543706
DOI: 10.3390/v16030340 -
Viruses Apr 2024Lymphocytic choriomeningitis virus (LCMV) and Lassa virus (LASV) share many genetic and biological features including subtle differences between pathogenic and...
Lymphocytic choriomeningitis virus (LCMV) and Lassa virus (LASV) share many genetic and biological features including subtle differences between pathogenic and apathogenic strains. Despite remarkable genetic similarity, the viscerotropic WE strain of LCMV causes a fatal LASV fever-like hepatitis in non-human primates (NHPs) while the mouse-adapted Armstrong (ARM) strain of LCMV is deeply attenuated in NHPs and can vaccinate against LCMV-WE challenge. Here, we demonstrate that internalization of WE is more sensitive to the depletion of membrane cholesterol than ARM infection while ARM infection is more reliant on endosomal acidification. LCMV-ARM induces robust NF-κB and interferon response factor (IRF) activation while LCMV-WE seems to avoid early innate sensing and failed to induce strong NF-κB and IRF responses in dual-reporter monocyte and epithelial cells. Toll-like receptor 2 (TLR-2) signaling appears to play a critical role in NF-κB activation and the silencing of TLR-2 shuts down IL-6 production in ARM but not in WE-infected cells. Pathogenic LCMV-WE infection is poorly recognized in early endosomes and failed to induce TLR-2/Mal-dependent pro-inflammatory cytokines. Following infection, Interleukin-1 receptor-associated kinase 1 (IRAK-1) expression is diminished in LCMV-ARM- but not LCMV-WE-infected cells, which indicates it is likely involved in the LCMV-ARM NF-κB activation. By confocal microscopy, ARM and WE strains have similar intracellular trafficking although LCMV-ARM infection appears to coincide with greater co-localization of early endosome marker EEA1 with TLR-2. Both strains co-localize with Rab-7, a late endosome marker, but the interaction with LCMV-WE seems to be more prolonged. These findings suggest that LCMV-ARM's intracellular trafficking pathway may facilitate interaction with innate immune sensors, which promotes the induction of effective innate and adaptive immune responses.
Topics: Lymphocytic choriomeningitis virus; Immunity, Innate; Animals; Virus Internalization; Humans; Mice; Toll-Like Receptor 2; Endosomes; NF-kappa B; Signal Transduction; Cell Line; Lymphocytic Choriomeningitis; Epithelial Cells
PubMed: 38675975
DOI: 10.3390/v16040635 -
Frontiers in Immunology 2024Blindness or vision loss due to neuroretinal and photoreceptor degeneration affects millions of individuals worldwide. In numerous neurodegenerative diseases, including...
Blindness or vision loss due to neuroretinal and photoreceptor degeneration affects millions of individuals worldwide. In numerous neurodegenerative diseases, including age-related macular degeneration, dysregulated immune response-mediated retinal degeneration has been found to play a critical role in the disease pathogenesis. To better understand the pathogenic mechanisms underlying the retinal degeneration, we used a mouse model of systemic immune activation where we infected mice with lymphocytic choriomeningitis virus (LCMV) clone 13. Here, we evaluated the effects of LCMV infection and present a comprehensive discovery-based proteomic investigation using tandem mass tag (TMT) labeling and high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS). Changes in protein regulation in the posterior part of the eye, neuroretina, and RPE/choroid were compared to those in the spleen as a secondary lymphoid organ and to the kidney as a non-lymphoid but encapsulated organ at 1, 8, and 28 weeks of infection. Using bioinformatic tools, we found several proteins responsible for maintaining normal tissue homeostasis to be differentially regulated in the neuroretina and the RPE/choroid during the degenerative process. Additionally, in the organs we observed, several important protein pathways contributing to cellular homeostasis and tissue development were perturbed and associated with LCMV-mediated inflammation, promoting disease progression. Our findings suggest that the response to a systemic chronic infection differs between the neuroretina and the RPE/choroid, and the processes induced by chronic systemic infection in the RPE/choroid are not unlike those induced in non-immune-privileged organs such as the kidney and spleen. Overall, our data provide detailed insight into several molecular mechanisms of neuroretinal degeneration and highlight various novel protein pathways that further suggest that the posterior part of the eye is not an isolated immunological entity despite the existence of neuroretinal immune privilege.
Topics: Animals; Mice; Proteomics; Disease Models, Animal; Retinal Degeneration; Lymphocytic choriomeningitis virus; Mice, Inbred C57BL; Lymphocytic Choriomeningitis; Tandem Mass Spectrometry; Proteome; Retina; Chromatography, Liquid; Choroid
PubMed: 38665911
DOI: 10.3389/fimmu.2024.1374617 -
Viruses Nov 2023Mammalian arenaviruses are rodent-borne zoonotic viruses, some of which can cause fatal hemorrhagic diseases in humans. The first discovered arenavirus, lymphocytic...
Mammalian arenaviruses are rodent-borne zoonotic viruses, some of which can cause fatal hemorrhagic diseases in humans. The first discovered arenavirus, lymphocytic choriomeningitis virus (LCMV), has a worldwide distribution and can be fatal for transplant recipients. However, no FDA-approved drugs or vaccines are currently available. In this study, using a quantitative proteomic analysis, we identified a variety of host factors that could be needed for LCMV infection, among which we found that protein disulfide isomerase A4 (PDIA4), a downstream factor of endoplasmic reticulum stress (ERS), is important for LCMV infection. Biochemical analysis revealed that LCMV glycoprotein was the main viral component accounting for PDIA4 upregulation. The inhibition of ATF6-mediated ERS could prevent the upregulation of PDIA4 that was stimulated by LCMV infection. We further found that PDIA4 can affect the LCMV viral RNA synthesis processes and release. In summary, we conclude that PDIA4 could be a new target for antiviral drugs against LCMV.
Topics: Animals; Humans; Glycoproteins; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Mammals; Protein Disulfide-Isomerases; Proteomics
PubMed: 38140584
DOI: 10.3390/v15122343 -
Scientific Reports Nov 2023Lassa fever (LF) is prevalent in many West African countries, including Nigeria. Efforts to combat LF have primarily focused on rural areas where interactions between...
Lassa fever (LF) is prevalent in many West African countries, including Nigeria. Efforts to combat LF have primarily focused on rural areas where interactions between rodents and humans are common. However, recent studies indicate a shift in its occurrence from rural to urban areas. We analysed secondary data of reported LF outbreaks from 2017 to 2021 in Ondo State, Nigeria to identify the distribution pattern, ecological variations, and other determinants of disease spread from the ward level using nearest neighbour statistics and regression analysis. Data utilised include LF incidence, ecological variables involving population, nighttime light intensity, vegetation, temperature, market presence, road length, and building area coverage. ArcGIS Pro 3.0 software was employed for spatial analysis. Results revealed spatio-temporal clustering of LF incidents between 2017 and 2021, with an increasing trend followed by a decline in 2021. All wards in Owo Local Government Area were identified as LF hotspots. The ecological variables exhibited significant correlations with the number of LF cases in the wards, except for maximum temperature. Notably, these variables varied significantly between wards with confirmed LF and those without. Therefore, it is important to prioritise strategies for mitigating LF outbreaks in urban areas of Nigeria and other LF-endemic countries.
Topics: Humans; Animals; Lassa Fever; Nigeria; Incidence; Africa, Western; Disease Outbreaks; Rodentia; Lassa virus
PubMed: 38012226
DOI: 10.1038/s41598-023-47820-3