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Health Science Reports Oct 2023The Lassa virus is an RNA virus belonging to the family. It is responsible for Lassa fever, an acute viral zoonosis of the severe hemorrhagic fever type with... (Review)
Review
The Lassa virus is an RNA virus belonging to the family. It is responsible for Lassa fever, an acute viral zoonosis of the severe hemorrhagic fever type with manifestations of fever, muscle pain, sore throat, nausea, vomiting, and chest and abdominal pain. Lassa fever is endemic in West Africa, where the first case was reported in 1969 in Lassa, a town in Nigeria, more than 50 years ago, and it is estimated that nearly 5000 deaths occur in West Africa each year. Nigeria is one of the endemic hotspots and has experienced numerous recurrent outbreaks of Lassa fever due to the increased multiplication of the host reservoir, . For the Lassa epidemics in 2022 and January 2023 alone, Nigeria accounts for a quarter of the annual deaths from this disease. Poor lifestyle and hygiene, difficulty in diagnosis due to nonspecific symptomatology, lack of effective treatment based on clinical evidence, an ineffective human immunization program combined with a health system that is not adapted or equipped to control and prevent recurrent deadly epidemics, and an outdated regional disease surveillance system in West Africa are some of the challenges that must be overcome to rapidly and effectively eradicate this disease, whose area of spread is constantly expanding as a result of the movement of populations in the context of economic and socio-cultural activities.
PubMed: 37885466
DOI: 10.1002/hsr2.1628 -
Frontiers in Immunology 2023The IL-6 cytokine family signals through the common signal transduction molecule gp130 combined with a cytokine-specific receptor. Gp130 signaling on CD4 T cells is...
The IL-6 cytokine family signals through the common signal transduction molecule gp130 combined with a cytokine-specific receptor. Gp130 signaling on CD4 T cells is vital in controlling chronic infection of mice with lymphocytic choriomeningitis virus clone 13 (LCMV Cl13), but the precise role of individual members of the IL-6 cytokine family is not fully understood. Transcriptional analysis highlighted the importance of gp130 signaling in promoting key processes in CD4 T cells after LCMV Cl13 infection, particularly genes associated with T follicular helper (Tfh) cell differentiation and IL-21 production. Further, mice failed to generate antibody or CD8 T-cell immunity and to control LCMV Cl13. Transcriptomics and phenotypic analyses of Tfh cells revealed that IL-6R and IL-27R signaling was required to activate key pathways within CD4 T cells. IL-6 and IL-27 signaling has distinct and overlapping roles, with IL-6 regulating Tfh differentiation, IL-27 regulating CD4 T cell survival, and both redundantly promoting IL-21.
Topics: Mice; Animals; CD4-Positive T-Lymphocytes; Interleukin-27; Interleukin-6; Cytokine Receptor gp130; Persistent Infection; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Receptors, Cytokine
PubMed: 37583704
DOI: 10.3389/fimmu.2023.1221562 -
Journal of Immunology (Baltimore, Md. :... Mar 2024Chronic viral infections, such as HIV and hepatitis C virus, represent a major public health problem. Although it is well understood that neonates and adults respond...
Chronic viral infections, such as HIV and hepatitis C virus, represent a major public health problem. Although it is well understood that neonates and adults respond differently to chronic viral infections, the underlying mechanisms remain unknown. In this study, we transferred neonatal and adult CD8+ T cells into a mouse model of chronic infection (lymphocytic choriomeningitis virus clone 13) and dissected out the key cell-intrinsic differences that alter their ability to protect the host. Interestingly, we found that neonatal CD8+ T cells preferentially became effector cells early in chronic infection compared with adult CD8+ T cells and expressed higher levels of genes associated with cell migration and effector cell differentiation. During the chronic phase of infection, the neonatal cells retained more immune functionality and expressed lower levels of surface markers and genes related to exhaustion. Because the neonatal cells protect from viral replication early in chronic infection, the altered differentiation trajectories of neonatal and adult CD8+ T cells is functionally significant. Together, our work demonstrates how cell-intrinsic differences between neonatal and adult CD8+ T cells influence key cell fate decisions during chronic infection.
Topics: Mice; Animals; Lymphocytic Choriomeningitis; Persistent Infection; Lymphocytic choriomeningitis virus; CD8-Positive T-Lymphocytes; Cell Differentiation; Mice, Inbred C57BL; Chronic Disease
PubMed: 38231127
DOI: 10.4049/jimmunol.2300396 -
Emerging Infectious Diseases Nov 2023Lassa fever, caused by Lassa virus (LASV), is endemic to West Africa, where ≈300,000 illnesses and ≈5,000 deaths occur annually. LASV is primarily spread by infected...
Lassa fever, caused by Lassa virus (LASV), is endemic to West Africa, where ≈300,000 illnesses and ≈5,000 deaths occur annually. LASV is primarily spread by infected multimammate rats via urine and fomites, highlighting the need to understand the environmental fate of LASV. We evaluated persistence of LASV Josiah and Sauerwald strains on surfaces, in aqueous solutions, and with sodium hypochlorite disinfection. Tested strains were more stable in deionized water (first-order rate constant [k] for Josiah, 0.23 days; for Sauerwald, k = 0.34 days) than primary influent wastewater (Josiah, k = 1.3 days; Sauerwald, k = 1.9 days). Both strains had similar decay rates on high-density polyethylene (Josiah, k = 4.3 days; Sauerwald, k = 2.3 days) and stainless steel (Josiah, k = 5.3 days; Sauerwald, k = 2.7 days). Sodium hypochlorite was highly effective at inactivating both strains. Our findings can inform future risk assessment and management efforts for Lassa fever.
Topics: Animals; Rats; Lassa virus; Lassa Fever; Disinfection; Sodium Hypochlorite; Africa, Western
PubMed: 37877545
DOI: 10.3201/eid2911.230678 -
Immunity May 2024Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How...
Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How chronic viral infection disrupts MBC development and whether such changes are reversible remain unknown. Through single-cell (sc)ATAC-seq and scRNA-seq during acute versus chronic lymphocytic choriomeningitis viral infection, we identified a memory subset enriched for interferon (IFN)-stimulated genes (ISGs) during chronic infection that was distinct from the T-bet subset normally associated with chronic infection. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic MBCs, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing phenotypic changes in the dominating MBC subset, with a decrease in the ISG subset and an increase in CD11cCD80 cells. However, timing was critical, with MBCs resistant to intervention at 4 weeks post-infection. Together, our research identifies a key mechanism to instruct MBC identity during viral infection.
Topics: Animals; Interferon Type I; Lymphocytic Choriomeningitis; Mice; Lymphocytic choriomeningitis virus; Memory B Cells; Epigenesis, Genetic; Mice, Inbred C57BL; Receptor, Interferon alpha-beta; Immunologic Memory; Chronic Disease; B-Lymphocyte Subsets; Single-Cell Analysis
PubMed: 38593796
DOI: 10.1016/j.immuni.2024.03.016 -
Nature Communications Nov 2023During infection, virus-specific CD8 T cells undergo rapid bursts of proliferation and differentiate into effector cells that kill virus-infected cells and reduce viral...
During infection, virus-specific CD8 T cells undergo rapid bursts of proliferation and differentiate into effector cells that kill virus-infected cells and reduce viral load. This rapid clonal expansion can put T cells at significant risk for replication-induced DNA damage. Here, we find that c-Myc links CD8 T cell expansion to DNA damage response pathways though the E3 ubiquitin ligase, Cullin 4b (Cul4b). Following activation, c-Myc increases the levels of Cul4b and other members of the Cullin RING Ligase 4 (CRL4) complex. Despite expressing c-Myc at high levels, Cul4b-deficient CD8 T cells do not expand and clear the Armstrong strain of lymphocytic choriomeningitis virus (LCMV) in vivo. Cul4b-deficient CD8 T cells accrue DNA damage and succumb to proliferative catastrophe early after antigen encounter. Mechanistically, Cul4b knockout induces an accumulation of p21 and Cyclin E2, resulting in replication stress. Our data show that c-Myc supports cell proliferation by maintaining genome stability via Cul4b, thereby directly coupling these two interdependent pathways. These data clarify how CD8 T cells use c-Myc and Cul4b to sustain their potential for extraordinary population expansion, longevity and antiviral responses.
Topics: CD8-Positive T-Lymphocytes; Cell Cycle; Cullin Proteins; Lymphocytic choriomeningitis virus; Ubiquitin-Protein Ligases; Proto-Oncogene Proteins c-myc
PubMed: 37925424
DOI: 10.1038/s41467-023-42765-7 -
Pediatric Research Jan 2024Congenital infections can have devastating short- and long-term impacts on the developing fetus. Lymphocytic choriomeningitis virus (LCMV) is a zoonotic pathogen of... (Review)
Review
Congenital infections can have devastating short- and long-term impacts on the developing fetus. Lymphocytic choriomeningitis virus (LCMV) is a zoonotic pathogen of concern that causes a severe congenital syndrome but is under-recognized and under-studied. Herein we review data on the natural animal reservoirs of LCMV, modes of transmission to humans, seroprevalence of LCMV worldwide in both pregnant and non-pregnant individuals, mechanisms of viral dissemination to placenta and fetus, and impact of climate change on viral transmission. We highlight opportunities to enhance awareness of congenital LCMV and provide recommendations for prevention and monitoring among at-risk pregnant people. IMPACT: Key message of the article: LCMV is a zoonotic virus that poses a major threat to maternal-fetal health. Adds to the existing literature: We comprehensively address transmission of LCMV from the natural reservoir to the pregnant individual, placenta, and fetus. Impact: Available data call for enhanced patient and provider awareness about congenital LCMV during pregnancy, as well as a need for efforts to better define the seroprevalence and impact of congenital LCMV worldwide.
Topics: Pregnancy; Animals; Female; Humans; Lymphocytic choriomeningitis virus; Lymphocytic Choriomeningitis; Seroepidemiologic Studies; Placenta; Fetal Diseases
PubMed: 37857846
DOI: 10.1038/s41390-023-02859-w -
Blood Dec 2023Viral hemorrhagic fevers (HF) are a group of acute febrile diseases with high mortality rates. Although hemostatic dysfunction appears to be a major determinant of the...
Viral hemorrhagic fevers (HF) are a group of acute febrile diseases with high mortality rates. Although hemostatic dysfunction appears to be a major determinant of the severity of the disease, it is still unclear what pathogenic mechanisms lead to it. In clinical studies it is found that arenaviruses, such as Lassa, Machupo, and Guanarito viruses cause HF that vary in symptoms and biological alterations. In this study we aimed to characterize the hemostatic dysfunction induced by arenaviral HF to determine its implication in the severity of the disease and to elucidate the origin of this syndrome. We found that lethal infection with Machupo, Guanarito, and Lassa viruses is associated with cutaneomucosal, cerebral, digestive, and pulmonary hemorrhages. The affected animals developed a severe alteration of the coagulation system, which was concomitant with acute hepatitis, minor deficit of hepatic factor synthesis, presence of a plasmatic inhibitor of coagulation, and dysfunction of the fibrinolytic system. Despite signs of increased vascular permeability, endothelial cell infection was not a determinant factor of the hemorrhagic syndrome. There were also alterations of the primary hemostasis during lethal infection, with moderate to severe thrombocytopenia and platelet dysfunction. Finally, we show that lethal infection is accompanied by a reduced hematopoietic potential of the bone marrow. This study provides an unprecedented characterization of the hemostasis defects induced by several highly pathogenic arenaviruses.
Topics: Animals; Arenaviridae; Arenavirus; Hemorrhagic Fevers, Viral; Hemorrhage; Hemostasis; Hemostatics; Macaca
PubMed: 37699247
DOI: 10.1182/blood.2023020351 -
Nature Communications Jan 2024Lassa virus (LASV) infection is expanding outside its traditionally endemic areas in West Africa, posing a pandemic biothreat. LASV-neutralizing antibodies, moreover,...
Lassa virus (LASV) infection is expanding outside its traditionally endemic areas in West Africa, posing a pandemic biothreat. LASV-neutralizing antibodies, moreover, have proven difficult to elicit. To gain insight into LASV neutralization, here we develop a prefusion-stabilized LASV glycoprotein trimer (GPC), pan it against phage libraries comprising single-domain antibodies (nanobodies) from shark and camel, and identify one, D5, which neutralizes LASV. Cryo-EM analyses reveal D5 to recognize a cleavage-dependent site-of-vulnerability at the trimer apex. The recognized site appears specific to GPC intermediates, with protomers lacking full cleavage between GP1 and GP2 subunits. Guinea pig immunizations with the prefusion-stabilized cleavage-intermediate LASV GPC, first as trimer and then as a nanoparticle, induce neutralizing responses, targeting multiple epitopes including that of D5; we identify a neutralizing antibody (GP23) from the immunized guinea pigs. Collectively, our findings define a prefusion-stabilized GPC trimer, reveal an apex-situated site-of-vulnerability, and demonstrate elicitation of LASV-neutralizing responses by a cleavage-intermediate LASV trimer.
Topics: Animals; Guinea Pigs; Lassa virus; Single-Domain Antibodies; Lassa Fever; Antibodies, Viral; Antibodies, Neutralizing
PubMed: 38177144
DOI: 10.1038/s41467-023-44534-y -
Cell Death & Disease Dec 2023Acute infection and chronic infection are the two most common fates of pathogenic virus infections. While several factors that contribute to these fates are described,...
Acute infection and chronic infection are the two most common fates of pathogenic virus infections. While several factors that contribute to these fates are described, the critical control points and the mechanisms that underlie infection fate regulation are incompletely understood. Using the acute and chronic lymphocytic choriomeningitis virus (LCMV) infection model of mice, we find that the early dynamic pattern of the IFN-I response is a differentiating trait between both infection fates. Acute-infected mice generate a 2-wave IFN-I response while chronic-infected mice generate only a 1-wave response. The underlying cause is a temporal difference in CD8 T cell-mediated killing of splenic marginal zone CD169+ macrophages. It occurs later in acute infection and thus enables CD169+ marginal zone macrophages to produce the 2nd IFN-I wave. This is required for subsequent immune events including induction of inflammatory macrophages, generation of effector CD8+ T cells and virus clearance. Importantly, these benefits come at a cost for the host in the form of spleen fibrosis. Due to an earlier marginal zone destruction, these ordered immune events are deregulated in chronic infection. Our findings demonstrate the critical importance of kinetically well-coordinated sequential immune events for acute infection control and highlights that it may come at a cost for the host organism.
Topics: Mice; Animals; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Persistent Infection; Mice, Inbred C57BL; CD8-Positive T-Lymphocytes; Macrophages
PubMed: 38110339
DOI: 10.1038/s41419-023-06374-y