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Journal of Immunology (Baltimore, Md. :... May 2024Increased receptor binding affinity may allow viruses to escape from Ab-mediated inhibition. However, how high-affinity receptor binding affects innate immune escape and...
Increased receptor binding affinity may allow viruses to escape from Ab-mediated inhibition. However, how high-affinity receptor binding affects innate immune escape and T cell function is poorly understood. In this study, we used the lymphocytic choriomeningitis virus (LCMV) murine infection model system to create a mutated LCMV exhibiting higher affinity for the entry receptor α-dystroglycan (LCMV-GPH155Y). We show that high-affinity receptor binding results in increased viral entry, which is associated with type I IFN (IFN-I) resistance, whereas initial innate immune activation was not impaired during high-affinity virus infection in mice. Consequently, IFN-I resistance led to defective antiviral T cell immunity, reduced type II IFN, and prolonged viral replication in this murine model system. Taken together, we show that high-affinity receptor binding of viruses can trigger innate affinity escape including resistance to IFN-I resulting in prolonged viral replication.
Topics: Mice; Animals; Virus Internalization; Mice, Knockout; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Virus Replication; Mice, Inbred C57BL; Immunity, Innate
PubMed: 38497668
DOI: 10.4049/jimmunol.2300637 -
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 -
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 -
PLoS Neglected Tropical Diseases Feb 2024West African Mastomys rodents are the primary reservoir of the zoonotic Lassa virus (LASV). The virus causes haemorrhagic Lassa fever and considerable mortality in...
West African Mastomys rodents are the primary reservoir of the zoonotic Lassa virus (LASV). The virus causes haemorrhagic Lassa fever and considerable mortality in humans. To date, the role of Mastomys immunogenetics in resistance to, and persistence of, LASV infections is largely unknown. Here, we investigated the role of Major Histocompatibility Complex class I (MHC-I) on LASV infection status (i.e., active vs. cleared infection, determined via PCR and an immunofluorescence assay on IgG antibodies, respectively) in Mastomys natalensis and M. erythroleucus sampled within southwestern Nigeria. We identified more than 190 and 90 MHC-I alleles by Illumina high throughput-sequencing in M. natalensis and M. erythroleucus, respectively, with different MHC allele compositions and frequencies between LASV endemic and non-endemic sites. In M. natalensis, the MHC allele ManaMHC-I*006 was negatively associated with active infections (PCR-positive) and positively associated with cleared infections (IgG-positive) simultaneously, suggesting efficient immune responses that facilitate LASV clearance in animals carrying this allele. Contrarily, alleles ManaMHC-I*008 and ManaMHC-I*021 in M. natalensis, and MaerMHC-I*008 in M. erythroleucus, were positively associated with active infection, implying susceptibility. Alleles associated with susceptibility shared a glutamic acid at the positively selected codon 57, while ManaMHC-I*006 featured an arginine. There was no link between number of MHC alleles per Mastomys individual and LASV prevalence. Thus, specific alleles, but not MHC diversity per se, seem to mediate antibody responses to viremia. We conclude that co-evolution with LASV likely shaped the MHC-I diversity of the main LASV reservoirs in southwestern Nigeria, and that information on reservoir immunogenetics may hold insights into transmission dynamics and zoonotic spillover risks.
Topics: Animals; Humans; Lassa virus; Alleles; Antibody Formation; Kinetics; Lassa Fever; Immunoglobulin G
PubMed: 38421939
DOI: 10.1371/journal.pntd.0011984 -
Frontiers in Cellular and Infection... 2024Lassa virus (LASV) causes an acute multisystemic hemorrhagic fever in humans known as Lassa fever, which is endemic in several African countries. This manuscript focuses...
An atlas of gross and histologic lesions and immunohistochemical immunoreactivity during the temporal progression of aerosolized Lassa virus induced hemorrhagic fever in cynomolgus macaques.
Lassa virus (LASV) causes an acute multisystemic hemorrhagic fever in humans known as Lassa fever, which is endemic in several African countries. This manuscript focuses on the progression of disease in cynomolgus macaques challenged with aerosolized LASV and serially sampled for the development and progression of gross and histopathologic lesions. Gross lesions were first noted in tissues on day 6 and persisted throughout day 12. Viremia and histologic lesions were first noted on day 6 commencing with the pulmonary system and hemolymphatic system and progressing at later time points to include all systems. Immunoreactivity to LASV antigen was first observed in the lungs of one macaque on day 3 and appeared localized to macrophages with an increase at later time points to include immunoreactivity in all organ systems. Additionally, this manuscript will serve as a detailed atlas of histopathologic lesions and disease progression for comparison to other animal models of aerosolized Arenaviral disease.
Topics: Humans; Animals; Lassa virus; Lassa Fever; Macaca fascicularis; Antigens, Viral; Viremia
PubMed: 38404292
DOI: 10.3389/fcimb.2024.1341891 -
Viruses Feb 2024Lassa virus (LASV) is a zoonotic pathogen endemic throughout western Africa and is responsible for a human disease known as Lassa fever (LF). Historically, LASV has been... (Review)
Review
Lassa virus (LASV) is a zoonotic pathogen endemic throughout western Africa and is responsible for a human disease known as Lassa fever (LF). Historically, LASV has been emphasized as one of the greatest public health threats in West Africa, with up to 300,000 cases and 5000 associated deaths per year. This, and the fact that the disease has been reported in travelers, has driven a rapid production of various vaccine candidates. Several of these vaccines are currently in clinical development, despite limitations in understanding the immune response to infection. Alarmingly, the host immune response has been implicated in the induction of sensorineural hearing loss in LF survivors, legitimately raising safety questions about any future vaccines as well as efficacy in preventing potential hearing loss. The objective of this article is to revisit the importance and prevalence of LF in West Africa, with focus on Nigeria, and discuss current therapeutic approaches and ongoing vaccine development. In addition, we aim to emphasize the need for more scientific studies relating to LF-associated hearing loss, and to promote critical discussion about potential risks and benefits of vaccinating the population in endemic regions of West Africa.
Topics: Humans; Lassa Fever; Lassa virus; Africa, Western; Hearing Loss, Sensorineural; Viral Vaccines; Disease Management
PubMed: 38400041
DOI: 10.3390/v16020266 -
Vaccine Mar 2024Lassa fever (LF) is a zoonotic viral hemorrhagic disease endemic to several West African countries. Approximately 300-500,000 cases occur annually across all ages with...
Lassa fever (LF) is a zoonotic viral hemorrhagic disease endemic to several West African countries. Approximately 300-500,000 cases occur annually across all ages with 10-20% case fatality rates. A LF vaccine is a recognized public health priority, with several candidates entering clinical trials. However, the perspectives of regional experts regarding critical vaccine properties, ideal delivery methods, and priority target populations remain unclear. Using a mixed methods approach with a standardized questionnaire, we individually interviewed 8 West African stakeholders, each with extensive knowledge and experience of LF. They strongly favored the use of a mass, proactive campaign strategy to immunize a wide age range of people in high-risk areas, including pregnant women and health care workers. We estimated that these and other plausible delivery scenarios could result in an initial demand of anywhere from 1 to 100 million doses, with most demand coming from Nigeria. These findings may help inform LF vaccine development and deployment efforts.
Topics: Humans; Female; Pregnancy; Lassa Fever; Lassa virus; Africa, Western; Nigeria; Viral Vaccines
PubMed: 38369392
DOI: 10.1016/j.vaccine.2024.02.044 -
Frontiers in Immunology 2024The host immune response determines the differential outcome of acute or chronic viral infections. The comprehensive comparison of lymphoid tissue immune cells at the...
INTRODUCTION
The host immune response determines the differential outcome of acute or chronic viral infections. The comprehensive comparison of lymphoid tissue immune cells at the single-cell level between acute and chronic viral infections is largely insufficient.
METHODS
To explore the landscape of immune responses to acute and chronic viral infections, single-cell RNA sequencing(scRNA-seq), scTCR-seq and scBCR-seq were utilized to evaluate the longitudinal dynamics and heterogeneity of lymph node CD45 immune cells in mouse models of acute (LCMV Armstrong) and chronic (LCMV clone 13) viral infections.
RESULTS
In contrast with acute viral infection, chronic viral infection distinctly induced more robust NK cells and plasma cells at the early stage (Day 4 post-infection) and acute stage (Day 8 post-infection), respectively. Moreover, chronic viral infection exerted decreased but aberrantly activated plasmacytoid dendritic cells (pDCs) at the acute phase. Simultaneously, there were significantly increased IgA plasma cells (MALT B cells) but differential usage of B-cell receptors in chronic infection. In terms of T-cell responses, Gzma-high effector-like CD8 T cells were significantly induced at the early stage in chronic infection, which showed temporally reversed gene expression throughout viral infection and the differential usage of the most dominant TCR clonotype. Chronic infection also induced more robust CD4 T cell responses, including follicular helper T cells (Tfh) and regulatory T cells (Treg). In addition, chronic infection compromised the TCR diversity in both CD8 and CD4 T cells.
DISCUSSION
In conclusion, gene expression and TCR/BCR immune repertoire profiling at the single-cell level in this study provide new insights into the dynamic and differential immune responses to acute and chronic viral infections.
Topics: Mice; Animals; CD8-Positive T-Lymphocytes; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Persistent Infection; Receptors, Antigen, T-Cell; Lymph Nodes; Sequence Analysis, RNA
PubMed: 38352870
DOI: 10.3389/fimmu.2024.1341985 -
Journal of Virology Mar 2024Lymphocytic choriomeningitis virus (LCMV) is a bisegmented negative-sense RNA virus classified within the family of the order. LCMV is associated with fatal disease in...
UNLABELLED
Lymphocytic choriomeningitis virus (LCMV) is a bisegmented negative-sense RNA virus classified within the family of the order. LCMV is associated with fatal disease in immunocompromized populations, and as the prototypical arenavirus, acts as a model for the many serious human pathogens within this group. Here, we examined the dependence of LCMV multiplication on cellular trafficking components using a recombinant LCMV expressing enhanced green fluorescent protein in conjunction with a curated siRNA library. The screen revealed a requirement for subunits of both the coat protein 1 (COPI) coatomer and adapter protein 4 (AP-4) complexes. By rescuing a recombinant LCMV harboring a FLAG-tagged glycoprotein (GP-1) envelope spike (rLCMV-GP1-FLAG), we showed infection resulted in marked co-localization of individual COPI and AP-4 components with both LCMV nucleoprotein (NP) and GP-1, consistent with their involvement in viral processes. To further investigate the role of both COPI and AP-4 complexes during LCMV infection, we utilized the ARF-I inhibitor brefeldin A (BFA) that prevents complex formation. Within a single 12-h cycle of virus multiplication, BFA pre-treatment caused no significant change in LCMV-specific RNA synthesis, alongside no significant change in LCMV NP expression, as measured by BFA time-of-addition experiments. In contrast, BFA addition resulted in a significant drop in released virus titers, approaching 50-fold over the same 12-h period, rising to over 600-fold over 24 h. Taken together, these findings suggest COPI and AP-4 complexes are important host cell factors required for the formation and release of infectious LCMV.
IMPORTANCE
Arenaviruses are rodent-borne, segmented, negative-sense RNA viruses, with several members responsible for fatal human disease, with the prototypic member lymphocytic choriomeningitis virus (LCMV) being under-recognised as a pathogen capable of inflicting neurological infections with fatal outcome. A detailed understanding of how arenaviruses subvert host cell processes to complete their multiplication cycle is incomplete. Here, using a combination of gene ablation and pharmacological inhibition techniques, we showed that host cellular COPI and AP-4 complexes, with native roles in cellular vesicular transport, were required for efficient LCMV growth. We further showed these complexes acted on late stages of the multiplication cycle, post-gene expression, with a significant impact on infectious virus egress. Collectively, our findings improve the understanding of arenaviruses host-pathogen interactions and reveal critical cellular trafficking pathways required during infection.
Topics: Animals; Humans; Chlorocebus aethiops; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Vero Cells; Virus Replication; Adaptor Protein Complex 4; Coat Protein Complex I
PubMed: 38334330
DOI: 10.1128/jvi.02006-23 -
Nature Microbiology Mar 2024Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many...
Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis.
Topics: Humans; Lassa Fever; Genome-Wide Association Study; Seroepidemiologic Studies; Lassa virus; Fever; Human Genetics
PubMed: 38326571
DOI: 10.1038/s41564-023-01589-3