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BMC Microbiology Apr 2024Despite repeated spillover transmission and their potential to cause significant morbidity and mortality in human hosts, the New World mammarenaviruses remain largely... (Review)
Review
Despite repeated spillover transmission and their potential to cause significant morbidity and mortality in human hosts, the New World mammarenaviruses remain largely understudied. These viruses are endemic to South America, with animal reservoir hosts covering large geographic areas and whose transmission ecology and spillover potential are driven in part by land use change and agriculture that put humans in regular contact with zoonotic hosts.We compiled published studies about Guanarito virus, Junin virus, Machupo virus, Chapare virus, Sabia virus, and Lymphocytic Choriomeningitis virus to review the state of knowledge about the viral hemorrhagic fevers caused by New World mammarenaviruses. We summarize what is known about rodent reservoirs, the conditions of spillover transmission for each of these pathogens, and the characteristics of human populations at greatest risk for hemorrhagic fever diseases. We also review the implications of repeated outbreaks and biosecurity concerns where these diseases are endemic, and steps that countries can take to strengthen surveillance and increase capacity of local healthcare systems. While there are unique risks posed by each of these six viruses, their ecological and epidemiological similarities suggest common steps to mitigate spillover transmission and better contain future outbreaks.
Topics: Animals; Humans; Arenaviridae; Arenaviruses, New World; South America
PubMed: 38575867
DOI: 10.1186/s12866-024-03257-w -
PLoS Pathogens Mar 2024Chronic viral infections cause T cell dysfunction in both animal models and human clinical settings, thereby affecting the ability of the host immune system to clear...
Chronic viral infections cause T cell dysfunction in both animal models and human clinical settings, thereby affecting the ability of the host immune system to clear viral pathogens and develop proper virus-specific immune memory. However, the impact of chronic viral infections on the host's immune memory to other pathogens has not been well described. In this study, we immunized mice with recombinant Listeria monocytogenes expressing OVA (Lm-OVA) to generate immunity to Lm and allow analysis of OVA-specific memory T (Tm) cells. We then infected these mice with lymphocytic choriomeningitis virus (LCMV) strain Cl-13 which establishes a chronic infection. We found that chronically infected mice were unable to protect against Listeria re-challenge. OVA-specific Tm cells showed a progressive loss in total numbers and in their ability to produce effector cytokines in the context of chronic LCMV infection. Unlike virus-specific T cells, OVA-specific Tm cells from chronically infected mice did not up-regulate the expression of inhibitory receptors, a hallmark feature of exhaustion in virus-specific T cells. Finally, OVA-specific Tm cells failed to mount a robust recall response after bacteria re-challenge both in the chronically infected and adoptively transferred naïve hosts. These results show that previously established bacteria-specific Tm cells become functionally impaired in the setting of an unrelated bystander chronic viral infection, which may contribute to poor immunity against other pathogens in the host with chronic viral infection.
Topics: Humans; Animals; Mice; CD8-Positive T-Lymphocytes; Immunologic Memory; Lymphocytic choriomeningitis virus; Cytokines; Virus Diseases; Lymphocytic Choriomeningitis; Mice, Inbred C57BL
PubMed: 38547316
DOI: 10.1371/journal.ppat.1012113 -
Viruses Mar 2024The order includes at least fourteen families with diverse but related viruses, which are transmitted to vertebrate hosts by arthropod or rodent vectors. These viruses... (Review)
Review
The order includes at least fourteen families with diverse but related viruses, which are transmitted to vertebrate hosts by arthropod or rodent vectors. These viruses are responsible for an increasing number of outbreaks worldwide and represent a threat to public health. Infection in humans can be asymptomatic, or it may present with a range of conditions from a mild, febrile illness to severe hemorrhagic syndromes and/or neurological complications. There is a need to develop safe and effective vaccines, a process requiring better understanding of the adaptive immune responses involved during infection. This review highlights the most recent findings regarding T cell and antibody responses to the five families with known human pathogens (, , , , and ). Future studies that define and characterize mechanistic correlates of protection against infections or disease will help inform the development of effective vaccines.
Topics: Humans; RNA Viruses; Arenaviridae; Adaptive Immunity; Vaccines
PubMed: 38543848
DOI: 10.3390/v16030483 -
Viruses Mar 2024CD8 T cells are critical to the adaptive immune response against viral pathogens. However, overwhelming antigen exposure can result in their exhaustion, characterised by...
CD8 T cells are critical to the adaptive immune response against viral pathogens. However, overwhelming antigen exposure can result in their exhaustion, characterised by reduced effector function, failure to clear virus, and the upregulation of inhibitory receptors, including programmed cell death 1 (PD-1). However, exhausted T cell responses can be "re-invigorated" by inhibiting PD-1 or the primary ligand of PD-1: PD-L1. Further, the absence of the type I interferon receptor IFNAR1 also results in T cell exhaustion and virus persistence in lymphocytic choriomeningitis virus Armstrong (LCMV-Arm)-infected mice. In this study, utilizing single- and double-knockout mice, we aimed to determine whether ablation of PD-1 could restore T cell functionality in the absence of IFNAR1 signalling in LCMV-Arm-infected mice. Surprisingly, this did not re-invigorate the T cell response and instead, it converted chronic LCMV-Arm infection into a lethal disease characterized by severe lung inflammation with an infiltration of neutrophils and T cells. Depletion of CD8 T cells, but not neutrophils, rescued mice from lethal disease, demonstrating that IFNAR1 is required to prevent T cell exhaustion and virus persistence in LCMV-Arm infection, and in the absence of IFNAR1, PD-L1 is required for survival. This reveals an important interplay between IFNAR1 and PD-L1 with implications for therapeutics targeting these pathways.
Topics: Mice; Animals; Lymphocytic choriomeningitis virus; CD8-Positive T-Lymphocytes; Lymphocytic Choriomeningitis; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Mice, Knockout; Interferon Type I; Mice, Inbred C57BL
PubMed: 38543756
DOI: 10.3390/v16030390 -
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 -
International Journal of Biological... Apr 2024The interactions between bovine serum albumin (BSA) and mycophenolic acid (MPA) were investigated in silico through molecular docking and in vitro, using fluorescence...
The interactions between bovine serum albumin (BSA) and mycophenolic acid (MPA) were investigated in silico through molecular docking and in vitro, using fluorescence spectroscopy. Dynamic light scattering and scanning electron microscopy were used to figure out the structure of MPA-Complex (MPA-C). The binding affinity between MPA and BSA was determined, yielding a Kd value of (12.0 ± 0.7) μM, and establishing a distance of 17 Å between the BSA and MPA molecules. The presence of MPA prompted protein aggregation, leading to the formation of MPA-C. The cytotoxicity of MPA-C and its ability to fight Junín virus (JUNV) were tested in A549 and Vero cell lines. It was found that treating infected cells with MPA-C decreased the JUNV yield and was more effective than free MPA in both cell line models for prolonged time treatments. Our results represent the first report of the antiviral activity of this type of BSA-MPA complex against JUNV, as assessed in cell culture model systems. MPA-C shows promise as a candidate for drug formulation against human pathogenic arenaviruses.
Topics: Humans; Serum Albumin, Bovine; Mycophenolic Acid; Molecular Docking Simulation; Virus Replication; Junin virus; Antiviral Agents
PubMed: 38513897
DOI: 10.1016/j.ijbiomac.2024.131023 -
Journal of Virology Apr 2024Live-attenuated virus vaccines provide long-lived protection against viral disease but carry inherent risks of residual pathogenicity and genetic reversion. The...
Live-attenuated virus vaccines provide long-lived protection against viral disease but carry inherent risks of residual pathogenicity and genetic reversion. The live-attenuated Candid#1 vaccine was developed to protect Argentines against lethal infection by the Argentine hemorrhagic fever arenavirus, Junín virus. Despite its safety and efficacy in Phase III clinical study, the vaccine is not licensed in the US, in part due to concerns regarding the genetic stability of attenuation. Previous studies had identified a single F427I mutation in the transmembrane domain of the Candid#1 envelope glycoprotein GPC as the key determinant of attenuation, as well as the propensity of this mutation to revert upon passage in cell culture and neonatal mice. To ascertain the consequences of this reversion event, we introduced the I427F mutation into recombinant Candid#1 (I427F rCan) and investigated the effects in two validated small-animal models: in mice expressing the essential virus receptor (human transferrin receptor 1; huTfR1) and in the conventional guinea pig model. We report that I427F rCan displays only modest virulence in huTfR1 mice and appears attenuated in guinea pigs. Reversion at another attenuating locus in Candid#1 GPC (T168A) was also examined, and a similar pattern was observed. By contrast, virus bearing both revertant mutations (A168T+I427F rCan) approached the lethal virulence of the pathogenic Romero strain in huTfR1 mice. Virulence was less extreme in guinea pigs. Our findings suggest that genetic stabilization at both positions is required to minimize the likelihood of reversion to virulence in a second-generation Candid#1 vaccine.IMPORTANCELive-attenuated virus vaccines, such as measles/mumps/rubella and oral poliovirus, provide robust protection against disease but carry with them the risk of genetic reversion to the virulent form. Here, we analyze the genetics of reversion in the live-attenuated Candid#1 vaccine that is used to protect against Argentine hemorrhagic fever, an often-lethal disease caused by the Junín arenavirus. In two validated small-animal models, we find that restoration of virulence in recombinant Candid#1 viruses requires back-mutation at two positions specific to the Candid#1 envelope glycoprotein GPC, at positions 168 and 427. Viruses bearing only a single change showed only modest virulence. We discuss strategies to genetically harden Candid#1 GPC against these two reversion events in order to develop a safer second-generation Candid#1 vaccine virus.
Topics: Animals; Guinea Pigs; Humans; Mice; Glycoproteins; Hemorrhagic Fever, American; Junin virus; South American People; Vaccines, Attenuated; Viral Vaccines; Virulence
PubMed: 38506509
DOI: 10.1128/jvi.00112-24 -
European Journal of Immunology May 2024Resident memory T (T) cells have been recently established as an important subset of memory T cells that provide early and essential protection against reinfection in...
Resident memory T (T) cells have been recently established as an important subset of memory T cells that provide early and essential protection against reinfection in the absence of circulating memory T cells. Recent findings showing that T expand in vivo after repeated antigenic stimulation indicate that these memory T cells are not terminally differentiated. This suggests an opportunity for in vitro T expansion to apply in an immunotherapy setting. However, it has also been shown that T may not maintain their identity and form circulating memory T cells after in vivo restimulation. Therefore, we set out to determine how T respond to antigenic activation in culture. Using Listeria monocytogenes and LCMV infection models, we found that T from the intraepithelial compartment of the small intestine expand in vitro after antigenic stimulation and subsequent resting in homeostatic cytokines. A large fraction of the expanded T retained their phenotype, including the expression of key T markers CD69 and CD103 (ITGAE). The optimal culture of T required low O pressure to maintain the expression of these and other T-associated molecules. Expanded T retained their effector capacity to produce cytokines after restimulation, but did not acquire a highly glycolytic profile indicative of effector T cells. The proteomic analysis confirmed T profile retention, including expression of T-related transcription factors, tissue retention factors, adhesion molecules, and enzymes involved in fatty acid metabolism. Collectively, our data indicate that limiting oxygen conditions supports in vitro expansion of T cells that maintain their T phenotype, at least in part, suggesting an opportunity for therapeutic strategies that require in vitro expansion of T.
Topics: Animals; Memory T Cells; Immunologic Memory; Mice; Listeria monocytogenes; Antigens, CD; Integrin alpha Chains; Mice, Inbred C57BL; Listeriosis; Lectins, C-Type; Antigens, Differentiation, T-Lymphocyte; Cytokines; Lymphocyte Activation; Lymphocytic choriomeningitis virus; Intestinal Mucosa; CD8-Positive T-Lymphocytes; Intestine, Small; Cells, Cultured
PubMed: 38501878
DOI: 10.1002/eji.202350873 -
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