Special Issue "Lassa Fever: Viral Replication, Disease Pathogenesis, and Host Immune Modulations"

A special issue of Pathogens (ISSN 2076-0817).

Deadline for manuscript submissions: 1 December 2019.

Special Issue Editor

Prof. Hinh Ly
E-Mail Website
Guest Editor
Department of Veterinary & Biomedical SciencesUniversity of Minnesota, Twin Cities, MN, USA
Interests: hemorrhagic fever viruses, arenaviruses, Lassa fever, host-virus interactions, innate immunity, viral pathogenesis and host defense
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Special Issue Information

Dear Colleagues,

In a relatively short period of time, starting in the beginning of the year until early March 2018, the Nigeria Center for Disease Control reported unusually high number of cases of Lassa virus (LASV) infection (>700 suspected cases with >350 confirmed cases and >110 deaths) [1]. In other words, more cases of LASV infections had been recorded in the first two months of this year across 18 states of Nigeria than in all of the previous year. Without a vaccine and effective drugs, LASV can kill up to 50% of those hospitalized for the infection. LASV causes Lassa fever disease in several countries, including Nigeria, Guinea, Liberia, Sierra Leone, Togo, and perhaps other countries in West Africa, where it is estimated to infect up to half million people causing roughly five thousand deaths each year in these endemic regions. LASV infection, which is often misdiagnosed, can lead to a wide range of disease symptoms ranging from asymptomatic or mild flu-like symptoms to mucosal bleeding, multi-organ failure and death [2]. Some of the more severe symptoms of LASV infection include pleural effusion, pulmonary edema, respiratory distress, seizures, thrombocytopenia, leukopenia, coagulopathy, encephalopathy, terminal shock syndrome that culminates in death of the patients. About one third of the patients, even those who recovered from the infection, experienced permanent sensorineural hearing loss [3]. Lassa fever disease can be particularly severe in pregnant women (especially when they are infected during the third trimester of pregnancy) and neonates with close to 90% fatality rate, as well as in infants and toddlers [4]. The molecular mechanisms contributing to virus virulence and disease pathogenesis are currently not well understood [5]. LASV genome structure is relatively simple with two ambisense RNA segments that encode for four proteins (nucleoprotein NP, matrix protein Z, polymerase protein L, and the envelope glycoprotein complex GPC) [6]. Recent studies have uncovered the multi-functional roles that each of the viral proteins play in mediating virus replication and host-virus interactions, including how they modulate the host innate immune responses to the infection [7]. Despite major discoveries made in last few decades of research on Lassa fever, there are still many unresolved key issues that hamper the development of effective vaccines and therapies. Some of these issues include a detail understanding of the viral and participating host factors in completing the virus life cycle, in mediating disease pathogenesis or protection from disease, and in activating or suppressing host innate and cellular immunity against virus infection. This Special Issue is devoted to understanding these important issues. Timely contributions in the form of original research and review articles on Lassa fever viral replication, disease pathogenesis and protection, host immune modulations, and other related hot topics are hereby solicited for consideration of publication in this Special Issue.

Bibliography:

  1. Roberts, L. Nigeria hit by unprecedented Lassa fever outbreak. Science 2018, in press.
  2. Shao, J.; Liang, Y.; Ly, H. Human hemorrhagic fever causing arenaviruses: molecular mechanisms contributing to virus virulence and disease pathogenesis. Pathogens 2015, 4, 283–306.
  3. Mateer, E.J.; Huang, C.; Shehu, N.Y.; Paessler, S. Lassa fever-induced sensorineural hearing loss: A neglected public heath and social burden. PLOS Negl. Trop. Dis. 2018, in press.
  4. Greenky, D.; Knust, B.; Dziuban, E.J. What pediatricians should know about Lassa virus. JAMA Pediatrics 2018, in press.
  5. McLay, L.; Liang, Y.; Ly, H. Comparative analysis of disease pathogenesis and molecular mechanisms of New World and Old World arenavirus infections. J. Gen. Virol. 2014, 95, 1–15.
  6. McLay, L.; Ansari, T.; Liang, Y.; Ly, H. Targeting virulence mechanisms for the prevention and therapy of arenaviral hemorrhagic fever. Antiviral Res. 2013, 97, 81–92.
  7. Meyer, B.; Ly, H. Inhibition of innate immune responses is key to pathogenesis by arenaviruses. J. Virol. 2016, 90, 3810–3818.

Dr. Hinh Ly
Guest Editor

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Keywords

  • Basic biology of Lassa virus
  • Lassa virus entry, replication, and assembly
  • Lassa fever disease pathogenesis
  • Virulence factor(s)
  • Immune activation and evasion mechanisms
  • Lassa virus immunity and vaccine
  • Lassa virus transmission
  • Antivirals against Lassa fever
  • Animal models of Lassa fever
  • Viral hemorrhagic fevers

Published Papers (6 papers)

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Research

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Open AccessArticle
A Single Dose of Modified Vaccinia Ankara Expressing Lassa Virus-like Particles Protects Mice from Lethal Intra-cerebral Virus Challenge
Pathogens 2019, 8(3), 133; https://doi.org/10.3390/pathogens8030133 - 28 Aug 2019
Abstract
Lassa fever surpasses Ebola, Marburg, and all other hemorrhagic fevers except Dengue in its public health impact. Caused by Lassa virus (LASV), the disease is a scourge on populations in endemic areas of West Africa, where reported incidence is higher. Here, we report [...] Read more.
Lassa fever surpasses Ebola, Marburg, and all other hemorrhagic fevers except Dengue in its public health impact. Caused by Lassa virus (LASV), the disease is a scourge on populations in endemic areas of West Africa, where reported incidence is higher. Here, we report construction, characterization, and preclinical efficacy of a novel recombinant vaccine candidate GEO-LM01. Constructed in the Modified Vaccinia Ankara (MVA) vector, GEO-LM01 expresses the glycoprotein precursor (GPC) and zinc-binding matrix protein (Z) from the prototype Josiah strain lineage IV. When expressed together, GP and Z form Virus-Like Particles (VLPs) in cell culture. Immunogenicity and efficacy of GEO-LM01 was tested in a mouse challenge model. A single intramuscular dose of GEO-LM01 protected 100% of CBA/J mice challenged with a lethal dose of ML29, a Mopeia/Lassa reassortant virus, delivered directly into the brain. In contrast, all control animals died within one week. The vaccine induced low levels of antibodies but Lassa-specific CD4+ and CD8+ T cell responses. This is the first report showing that a single dose of a replication-deficient MVA vector can confer full protection against a lethal challenge with ML29 virus. Full article
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Open AccessArticle
Attenuated Replication of Lassa Virus Vaccine Candidate ML29 in STAT-1-/- Mice
Pathogens 2019, 8(1), 9; https://doi.org/10.3390/pathogens8010009 - 15 Jan 2019
Cited by 2
Abstract
Lassa virus (LASV), a highly prevalent mammalian arenavirus endemic in West Africa, can cause Lassa fever (LF), which is responsible for thousands of deaths annually. LASV is transmitted to humans from naturally infected rodents. At present, there is not an effective vaccine nor [...] Read more.
Lassa virus (LASV), a highly prevalent mammalian arenavirus endemic in West Africa, can cause Lassa fever (LF), which is responsible for thousands of deaths annually. LASV is transmitted to humans from naturally infected rodents. At present, there is not an effective vaccine nor treatment. The genetic diversity of LASV is the greatest challenge for vaccine development. The reassortant ML29 carrying the L segment from the nonpathogenic Mopeia virus (MOPV) and the S segment from LASV is a vaccine candidate under current development. ML29 demonstrated complete protection in validated animal models against a Nigerian strain from clade II, which was responsible for the worst outbreak on record in 2018. This study demonstrated that ML29 was more attenuated than MOPV in STAT1-/- mice, a small animal model of human LF and its sequelae. ML29 infection of these mice resulted in more than a thousand-fold reduction in viremia and viral load in tissues and strong LASV-specific adaptive T cell responses compared to MOPV-infected mice. Persistent infection of Vero cells with ML29 resulted in generation of interfering particles (IPs), which strongly interfered with the replication of LASV, MOPV and LCMV, the prototype of the Arenaviridae. ML29 IPs induced potent cell-mediated immunity and were fully attenuated in STAT1-/- mice. Formulation of ML29 with IPs will improve the breadth of the host’s immune responses and further contribute to development of a pan-LASV vaccine with full coverage meeting the WHO requirements. Full article
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Open AccessArticle
Identification of Residues in Lassa Virus Glycoprotein Subunit 2 That Are Critical for Protein Function
Pathogens 2019, 8(1), 1; https://doi.org/10.3390/pathogens8010001 - 26 Dec 2018
Cited by 2
Abstract
Lassa virus (LASV) is an Old World arenavirus, endemic to West Africa, capable of causing hemorrhagic fever. Currently, there are no approved vaccines or effective antivirals for LASV. However, thorough understanding of the LASV glycoprotein and entry into host cells could accelerate therapeutic [...] Read more.
Lassa virus (LASV) is an Old World arenavirus, endemic to West Africa, capable of causing hemorrhagic fever. Currently, there are no approved vaccines or effective antivirals for LASV. However, thorough understanding of the LASV glycoprotein and entry into host cells could accelerate therapeutic design. LASV entry is a two-step process involving the viral glycoprotein (GP). First, the GP subunit 1 (GP1) binds to the cell surface receptor and the viral particle is engulfed into an endosome. Next, the drop in pH triggers GP rearrangements, which ultimately leads to the GP subunit 2 (GP2) forming a six-helix-bundle (6HB). The process of GP2 forming 6HB fuses the lysosomal membrane with the LASV envelope, allowing the LASV genome to enter the host cell. The aim of this study was to identify residues in GP2 that are crucial for LASV entry. To achieve this, we performed alanine scanning mutagenesis on GP2 residues. We tested these mutant GPs for efficient GP1-GP2 cleavage, cell-to-cell membrane fusion, and transduction into cells expressing α-dystroglycan and secondary LASV receptors. In total, we identified seven GP2 mutants that were cleaved efficiently but were unable to effectively transduce cells: GP-L280A, GP-L285A/I286A, GP-I323A, GP-L394A, GP-I403A, GP-L415A, and GP-R422A. Therefore, the data suggest these residues are critical for GP2 function in LASV entry. Full article
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Open AccessCommunication
Host-Driven Phosphorylation Appears to Regulate the Budding Activity of the Lassa Virus Matrix Protein
Pathogens 2018, 7(4), 97; https://doi.org/10.3390/pathogens7040097 - 09 Dec 2018
Cited by 1
Abstract
Lassa mammarenavirus (LASV) is an enveloped RNA virus that can cause Lassa fever, an acute hemorrhagic fever syndrome associated with significant morbidity and high rates of fatality in endemic regions of western Africa. The arenavirus matrix protein Z has several functions during the [...] Read more.
Lassa mammarenavirus (LASV) is an enveloped RNA virus that can cause Lassa fever, an acute hemorrhagic fever syndrome associated with significant morbidity and high rates of fatality in endemic regions of western Africa. The arenavirus matrix protein Z has several functions during the virus life cycle, including coordinating viral assembly, driving the release of new virus particles, regulating viral polymerase activity, and antagonizing the host antiviral response. There is limited knowledge regarding how the various functions of Z are regulated. To investigate possible means of regulation, mass spectrometry was used to identify potential sites of phosphorylation in the LASV Z protein. This analysis revealed that two serines (S18, S98) and one tyrosine (Y97) are phosphorylated in the flexible N- and C-terminal regions of the protein. Notably, two of these sites, Y97 and S98, are located in (Y97) or directly adjacent to (S98) the PPXY late domain, an important motif for virus release. Studies with non-phosphorylatable and phosphomimetic Z proteins revealed that these sites are important regulators of the release of LASV particles and that host-driven, reversible phosphorylation may play an important role in the regulation of LASV Z protein function. Full article
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Review

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Open AccessReview
Virus–Host Interactions Involved in Lassa Virus Entry and Genome Replication
Pathogens 2019, 8(1), 17; https://doi.org/10.3390/pathogens8010017 - 29 Jan 2019
Cited by 1
Abstract
Lassa virus (LASV) is the causative agent of Lassa fever, a human hemorrhagic disease associated with high mortality and morbidity rates, particularly prevalent in West Africa. Over the past few years, a significant amount of novel information has been provided on cellular factors [...] Read more.
Lassa virus (LASV) is the causative agent of Lassa fever, a human hemorrhagic disease associated with high mortality and morbidity rates, particularly prevalent in West Africa. Over the past few years, a significant amount of novel information has been provided on cellular factors that are determinant elements playing a role in arenavirus multiplication. In this review, we focus on host proteins that intersect with the initial steps of the LASV replication cycle: virus entry and genome replication. A better understanding of relevant virus–host interactions essential for sustaining these critical steps may help to identify possible targets for the rational design of novel therapeutic approaches against LASV and other arenaviruses that cause severe human disease. Full article
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Open AccessReview
Improving the Breadth of the Host’s Immune Response to Lassa Virus
Pathogens 2018, 7(4), 84; https://doi.org/10.3390/pathogens7040084 - 28 Oct 2018
Cited by 6
Abstract
In 2017, the global Coalition for Epidemic Preparedness (CEPI) declared Lassa virus disease to be one of the world’s foremost biothreats. In January 2018, World Health Organization experts met to address the Lassa biothreat. It was commonly recognized that the diversity of Lassa [...] Read more.
In 2017, the global Coalition for Epidemic Preparedness (CEPI) declared Lassa virus disease to be one of the world’s foremost biothreats. In January 2018, World Health Organization experts met to address the Lassa biothreat. It was commonly recognized that the diversity of Lassa virus (LASV) isolated from West African patient samples was far greater than that of the Ebola isolates from the West African epidemic of 2013–2016. Thus, vaccines produced against Lassa virus disease face the added challenge that they must be broadly-protective against a wide variety of LASV. In this review, we discuss what is known about the immune response to Lassa infection. We also discuss the approaches used to make broadly-protective influenza vaccines and how they could be applied to developing broad vaccine coverage against LASV disease. Recent advances in AIDS research are also potentially applicable to the design of broadly-protective medical countermeasures against LASV disease. Full article
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