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Viruses Nov 2022Lassa virus (LASV) is a highly pathogenic virus that is categorized as a biosafety level-4 pathogen. Currently, there are no approved drugs or vaccines specific to LASV....
Lassa virus (LASV) is a highly pathogenic virus that is categorized as a biosafety level-4 pathogen. Currently, there are no approved drugs or vaccines specific to LASV. In this study, high-throughput screening of a fragment-based drug discovery library was performed against LASV entry using a pseudotype virus bearing the LASV envelope glycoprotein complex (GPC). Two compounds, F1920 and F1965, were identified as LASV entry inhibitors that block GPC-mediated membrane fusion. Analysis of adaptive mutants demonstrated that the transient mutants L442F and I445S, as well as the constant mutant F446L, were located on the same side on the transmembrane domain of the subunit GP2 of GPC, and all the mutants conferred resistance to both F1920 and F1965. Furthermore, F1920 antiviral activity extended to other highly pathogenic mammarenaviruses, whereas F1965 was LASV-specific. Our study showed that both F1920 and F1965 provide a potential backbone for the development of lead drugs for preventing LASV infection.
Topics: Humans; Lassa virus; Lassa Fever; Arenaviridae; Antiviral Agents; Drug Discovery; HIV Fusion Inhibitors
PubMed: 36560653
DOI: 10.3390/v14122649 -
Virulence Dec 2022The area of Lassa virus (LASV) circulation is expanding, with the emergence of highly pathogenic new LASV lineages. Benin recently became an endemic country for LASV and...
The area of Lassa virus (LASV) circulation is expanding, with the emergence of highly pathogenic new LASV lineages. Benin recently became an endemic country for LASV and has seen the emergence of a new LASV lineage (VII). The first two outbreaks in 2014 and 2016 showed a relatively high mortality rate compared to other outbreaks. We infected cynomolgus monkeys with two strains belonging to lineage II and lineage VII that were isolated from deceased patients during the 2016 outbreak in Benin. The lineage VII strain (L7) caused uniform mortality. Death was associated with uncontrolled viral replication, unbalanced inflammatory responses characterized by increased concentrations of pro- and anti-inflammatory mediators, and the absence of efficient immune responses, resembling the pathogenesis associated with the prototypic Josiah strain in monkeys. The lineage II strain (L2) showed apparently lower virulence than its counterpart, with a prolonged time to death and a lower mortality rate. Prolonged survival was associated with better control of viral replication, a moderate inflammatory response, and efficient -cell responses. Transcriptomic analyses also highlighted important differences in the immune responses associated with the outcome. Both strains caused strong inflammation in several organs. Notably, meningitis and encephalitis were observed in the cerebral cortex and cerebellum in all monkeys, independently of the outcome. Due to their apparently high pathogenicity, emerging strains from lineage VII should be considered in preclinical vaccine testing. Lineage II would also be beneficial in pathogenesis studies to study the entire spectrum of Lassa fever severity.
Topics: Animals; Humans; Lassa Fever; Lassa virus; Macaca fascicularis; Virus Replication
PubMed: 35437094
DOI: 10.1080/21505594.2022.2060170 -
MBio Aug 2022Lassa virus (LASV) is the causative agent of the deadly Lassa fever (LF). Seven distinct LASV lineages circulate through western Africa, among which lineage I (LI), the...
Lassa virus (LASV) is the causative agent of the deadly Lassa fever (LF). Seven distinct LASV lineages circulate through western Africa, among which lineage I (LI), the first to be identified, is particularly resistant to antibody neutralization. Lineage I LASV evades neutralization by half of known antibodies in the GPC-A antibody competition group and all but one of the antibodies in the GPC-B competition group. Here, we solve two cryo-electron microscopy (cryo-EM) structures of LI GP in complex with a GPC-A and a GPC-B antibody. We used complementary structural and biochemical techniques to identify single-amino-acid substitutions in LI that are responsible for immune evasion by each antibody group. Further, we show that LI infection is more dependent on the endosomal receptor lysosome-associated membrane protein 1 (LAMP1) for viral entry relative to LIV. In the absence of LAMP1, LI requires a more acidic fusion pH to initiate membrane fusion with the host cell relative to LIV. No vaccine or therapeutics are approved to prevent LASV infection or treat LF. All vaccine platforms currently under development present only the LIV GP sequence. However, our data suggest that the high genetic diversity of LASV may be problematic for designing both a broadly reactive immunogen and therapeutic. Here, we examine antibodies that are highly potent against LIV yet are ineffective against LI. By pinpointing LI mutations responsible for this decrease in antibody efficacy, we suggest that future vaccine platforms may need to incorporate specific LI-like mutations in order to generate a broadly neutralizing antibody response against all LASV lineages.
Topics: Antibodies, Neutralizing; Cryoelectron Microscopy; Humans; Lassa Fever; Lassa virus; Virus Internalization
PubMed: 35730904
DOI: 10.1128/mbio.01278-22 -
Immunology Letters Nov 2019Lassa fever is an acute viral haemorrhagic illness caused by Lassa virus (LASV), which is endemic throughout much of West Africa. The virus primarily circulates in the... (Review)
Review
Lassa fever is an acute viral haemorrhagic illness caused by Lassa virus (LASV), which is endemic throughout much of West Africa. The virus primarily circulates in the Mastomys natalensis reservoir and is transmitted to humans through contact with infectious rodents or their secretions; human-to-human transmission is documented as well. With the exception of Dengue fever, LASV has the highest human impact of any haemorrhagic fever virus. On-going outbreaks in Nigeria have resulted in unprecedented mortality. Consequently, the World Health Organization (WHO) has listed LASV as a high priority pathogen for the development of treatments and prophylactics. Currently, there are no licensed vaccines to protect against LASV infection. Although numerous candidates have demonstrated efficacy in animal models, to date, only a single candidate has advanced to clinical trials. Lassa fever vaccine development efforts have been hindered by the high cost of biocontainment requirements, the absence of established correlates of protection, and uncertainty regarding the extent to which animal models are predictive of vaccine efficacy in humans. This review briefly discusses the epidemiology and biology of LASV infection and highlights recent progress in vaccine development.
Topics: Animals; Humans; Lassa Fever; Lassa virus; Murinae; Viral Vaccines
PubMed: 31026485
DOI: 10.1016/j.imlet.2019.03.008 -
Biochimica Et Biophysica Acta.... Nov 2022Mammarenaviruses include many significant worldwide-widespread human pathogens, among them Lassa virus (LASV), having a dramatic morbidity and mortality rate. They are a...
Mammarenaviruses include many significant worldwide-widespread human pathogens, among them Lassa virus (LASV), having a dramatic morbidity and mortality rate. They are a potential high-risk menace to the worldwide public health since there are no treatments and there is a high possibility of animal-to-human and human-to-human viral transmission. These viruses enter into the cells by endocytosis fusing its membrane envelope with the late endosomal membrane thanks to the glycoprotein GP2, a membrane fusion protein of class I. This protein contains different domains, among them the N-terminal fusion peptide (NFP), the internal fusion loop (IFL), the membrane proximal external region (MPER) and the transmembrane domain (TMD). All these domains are implicated in the membrane fusion process. In this work, we have used an all-atom molecular dynamics study to know the binding of these protein domains with a complex membrane mimicking the late endosome one. We show that the NFP/IFL domain is capable of spontaneously inserting into the membrane without a significant change of secondary structure, the MPER domain locates at the bilayer interface with an orientation parallel to the membrane surface and tends to interact with other MPER domains, and the TMD domain tilts inside the bilayer. Moreover, they predominantly interact with negatively charged phospholipids. Overall, these membrane-interacting domains would characterise a target that would make possible to find effective antiviral molecules against LASV in particular and Mammarenaviruses in general.
Topics: Animals; Endosomes; Humans; Lassa virus; Membrane Fusion; Peptides; Virus Internalization
PubMed: 35964711
DOI: 10.1016/j.bbamem.2022.184031 -
The Pan African Medical Journal 2020Lassa virus (LASV), the causative agent of Lassa fever (LF), an endemic acute viral haemorrhagic illness in Nigeria, is transmitted by direct contact with the rodent,...
INTRODUCTION
Lassa virus (LASV), the causative agent of Lassa fever (LF), an endemic acute viral haemorrhagic illness in Nigeria, is transmitted by direct contact with the rodent, contaminated food or household items. Person-to-person transmission also occurs and sexual transmission has been reported. Thus, this study investigated the presence of LASV in body fluids of suspected and confirmed cases.
METHODS
this was a cross-sectional study between March 2018 and April 2019 involving 112 consenting suspected and post ribavirin confirmed cases attending the Lassa fever treatment center in Ondo State. Whole blood was collected from 57 suspected and 29 confirmed cases. Other samples from confirmed cases were 5 each of High Vaginal Swab (HVS) and seminal fluid; 12 breast milk and 4 urine. All samples were analyzed using reverse transcription-PCR (RT-PCR) targeting the S-gene of LASV.
RESULTS
analysis of whole blood by RT-PCR showed that 1/57 (1.8%) suspected and 1/29 (3.4%) confirmed post ribavirin treated cases were positive. While LASV was detected in 2/5 (40%) post ribavirin treated seminal fluids and 1/11 (8.3%) breast milk. However, LASV was not detected in any of the HVS and urine samples.
CONCLUSION
the detection of LASV in seminal fluid and breast milk of discharged post ribavirin treated cases suggests its persistence in these fluids of recovering Nigerians. The role of postnatal and sexual transmissions in the perennial outbreak of LF needs to be further evaluated.
Topics: Adult; Antiviral Agents; Cross-Sectional Studies; Disease Outbreaks; Female; Humans; Lassa Fever; Lassa virus; Male; Middle Aged; Milk, Human; Nigeria; Reverse Transcriptase Polymerase Chain Reaction; Ribavirin; Semen
PubMed: 33014249
DOI: 10.11604/pamj.2020.36.253.22104 -
BMC Infectious Diseases Feb 2021Lassa fever (LF) is a zoonotic infectious disease of public concern in Nigeria. The infection dynamics of the disease is not well elucidated in Nigeria. This study was...
BACKGROUND
Lassa fever (LF) is a zoonotic infectious disease of public concern in Nigeria. The infection dynamics of the disease is not well elucidated in Nigeria. This study was carried out to describe the pattern of infection, case fatality rate and spread of lassa virus (LASV) from 2017 to 2020.
METHODS
Weekly epidemiological data on LF from December, 2016 to September, 2020 were obtained from Nigeria Centre for Disease Control. The number of confirmed cases and deaths were computed according to months and states. Descriptive statistics was performed and case fatality rate was calculated. Distribution and spread maps of LF over the four years period was performed on ArcMap 10.7.
RESULTS
A total of 2787 confirmed cases and 516 deaths were reported in Nigeria from December, 2016 to September, 2020. Increase in number of cases and deaths were observed with 298, 528, 796 and 1165 confirmed cases and 79, 125, 158 and 158 deaths in 2017, 2018, 2019 and 2020 respectively. Over 60% of the cases were reported in two states, Edo and Ondo states. The LF cases spread from 19 states in 2017 to 32 states and Federal Capital Territory (FCT) in 2020. Ondo state (25.39%) had the highest of deaths rate from LF over the four years. Case fatality rate (CFR) of LF was highest in 2017 (26.5%) with CFR of 23.7, 19.6 and 13.4% in 2018, 2019 and 2020 respectively. The peak of infection was in the month of February for the four years. Infections increases at the onset of dry season in November and decline till April when the wet season sets-in.
CONCLUSION
There is an annual increase in the number of LASV infection across the states in Nigeria. There is need to heighten control strategies through the use of integrated approach, ranging from vector control, health education and early diagnosis.
Topics: Animals; Geography; Humans; Lassa Fever; Lassa virus; Mortality; Nigeria; Seasons; Zoonoses
PubMed: 33546623
DOI: 10.1186/s12879-021-05837-x -
Viruses Jan 2021Defective interfering particles (DIPs) are naturally occurring products during virus replication in infected cells. DIPs contain defective viral genomes (DVGs) and...
Defective interfering particles (DIPs) are naturally occurring products during virus replication in infected cells. DIPs contain defective viral genomes (DVGs) and interfere with replication and propagation of their corresponding standard viral genomes by competing for viral and cellular resources, as well as promoting innate immune antiviral responses. Consequently, for many different viruses, including mammarenaviruses, DIPs play key roles in the outcome of infection. Due to their ability to broadly interfere with viral replication, DIPs are attractive tools for the development of a new generation of biologics to target genetically diverse and rapidly evolving viruses. Here, we provide evidence that in cells infected with the Lassa fever (LF) vaccine candidate ML29, a reassortant that carries the nucleoprotein (NP) and glycoprotein (GP) dominant antigens of the pathogenic Lassa virus (LASV) together with the L polymerase and Z matrix protein of the non-pathogenic genetically related Mopeia virus (MOPV), L-derived truncated RNA species are readily detected following infection at low multiplicity of infection (MOI) or in persistently-infected cells originally infected at high MOI. In the present study, we show that expression of green fluorescent protein (GFP) driven by a tri-segmented form of the mammarenavirus lymphocytic choriomeningitis virus (r3LCMV-GFP/GFP) was strongly inhibited in ML29-persistently infected cells, and that the magnitude of GFP suppression was dependent on the passage history of the ML29-persistently infected cells. In addition, we found that DIP-enriched ML29 was highly attenuated in immunocompetent CBA/J mice and in Hartley guinea pigs. Likewise, STAT-1 mice, a validated small animal model for human LF associated hearing loss sequelae, infected with DIP-enriched ML29 did not exhibit any hearing abnormalities throughout the observation period (62 days).
Topics: Animals; Female; Genome, Viral; Guinea Pigs; Humans; Lassa Fever; Lassa virus; Mice; Mice, Inbred CBA; RNA, Viral; Viral Vaccines; Virus Replication
PubMed: 33573250
DOI: 10.3390/v13020214 -
Emerging Microbes & Infections Dec 2024Identification of the diverse animal hosts responsible for spill-over events from animals to humans is crucial for comprehending the transmission patterns of emerging...
Identification of the diverse animal hosts responsible for spill-over events from animals to humans is crucial for comprehending the transmission patterns of emerging infectious diseases, which pose significant public health risks. To better characterize potential animal hosts of Lassa virus (LASV), we assessed domestic and non-domestic animals from 2021-2022 in four locations in southern Nigeria with reported cases of Lassa fever (LF). Birds, lizards, and domestic mammals (dogs, pigs, cattle and goats) were screened using RT-qPCR, and whole genome sequencing was performed for lineage identification on selected LASV positive samples. Animals were also screened for exposure to LASV by enzyme-linked immunosorbent assay (ELISA). Among these animals, lizards had the highest positivity rate by PCR. Genomic sequencing of samples in most infected animals showed sub-lineage 2 g of LASV. Seropositivity was highest among cattle and lowest in pigs. Though the specific impact these additional hosts may have in the broader virus-host context are still unknown - specifically relating to pathogen diversity, evolution, and transmission - the detection of LASV in non-rodent hosts living in proximity to confirmed human LF cases suggests their involvement during transmission as potential reservoirs. Additional epidemiological data comparing viral genomes from humans and animals, as well as those circulating within the environment will be critical in understanding LASV transmission dynamics and will ultimately guide the development of countermeasures for this zoonotic health threat.
Topics: Humans; Animals; Cattle; Dogs; Swine; Lassa virus; Lassa Fever; Nigeria; Genome, Viral; Public Health; Mammals
PubMed: 38088796
DOI: 10.1080/22221751.2023.2294859 -
Clinical Infectious Diseases : An... May 2022Lassa fever is a zoonotic, acute viral illness first identified in Nigeria in 1969. An estimate shows that the "at risk" seronegative population (in Sierra Leone,...
BACKGROUND
Lassa fever is a zoonotic, acute viral illness first identified in Nigeria in 1969. An estimate shows that the "at risk" seronegative population (in Sierra Leone, Guinea, and Nigeria) may be as high as 59 million, with an annual incidence of all illnesses of 3 million, and fatalities up to 67 000, demonstrating the serious impact of the disease on the region and global health.
METHODS
Histopathologic evaluation, immunohistochemical assay, and electron microscopic examination were performed on postmortem tissue samples from 12 confirmed Lassa fever cases.
RESULTS
Lassa fever virus antigens and viral particles were observed in multiple organ systems and cells, including cells in the mononuclear phagocytic system and other specialized cells where it had not been described previously.
CONCLUSIONS
The immunolocalization of Lassa fever virus antigens in fatal cases provides novel insightful information with clinical and pathogenetic implications. The extensive involvement of the mononuclear phagocytic system, including tissue macrophages and endothelial cells, suggests participation of inflammatory mediators from this lineage with the resulting vascular dilatation and increasing permeability. Other findings indicate the pathogenesis of Lassa fever is multifactorial and additional studies are needed.
Topics: Endothelial Cells; Humans; Incidence; Lassa Fever; Lassa virus; Virus Diseases
PubMed: 34463715
DOI: 10.1093/cid/ciab719