Lymphocytic Choriomeningitis Virus (LCMV) infection of CNS glial cells results in TLR2-MyD88/Mal-dependent inflammatory responses

Lymphocytic choriomeningitis virus (LCMV), an arenavirus, is a prevalent pathogen and an important and underrecognized cause of neurologic birth defects. LCMV utilizes rodents as its principal reservoir. Rodents that acquire the virus transplacentally often remain asymptomatic because congenital infection provides immunological tolerance for the virus. Humans typically acquire LCMV by direct contact with fomites contaminated with infectious virus, from rodents, or by inhalation of aerosolized virus. Congenital LCMV infection occurs when a woman acquires the virus during pregnancy. The virus is passed to the fetus transplacentally, presumably during maternal viremia. Published reports of LCMV infection during pregnancy make it clear that LCMV can be a severe neuroteratogen. Prospective epidemiological or clinical studies of congenital LCMV infection are needed to gain more knowledge about the incidence and spectrum of LCMV-induced teratogenicity. The clinical presentation of congenital LCMV is reviewed, along with recommendations for diagnostic studies and information about long-term prognosis.

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The CD8+ T-Cell Response to Lymphocytic Choriomeningitis Virus Involves the L Antigen: Uncovering New Tricks for an Old Virus

Journal of Virology ◽

10.1128/jvi.02632-06 ◽

2007 ◽

Vol 81 (10) ◽

pp. 4928-4940 ◽

Cited By ~ 74

Author(s):

Maya F. Kotturi ◽

Bjoern Peters ◽

Fernando Buendia-Laysa ◽

John Sidney ◽

Carla Oseroff ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Response ◽

Cellular Response ◽

Lymphocytic Choriomeningitis ◽

Lymphocytic Choriomeningitis Virus ◽

T Cell Response ◽

Ifn Γ ◽

Lcmv Infection

ABSTRACT CD8+ T-cell responses control lymphocytic choriomeningitis virus (LCMV) infection in H-2b mice. Although antigen-specific responses against LCMV infection are well studied, we found that a significant fraction of the CD8+ CD44hi T-cell response to LCMV in H-2b mice was not accounted for by known epitopes. We screened peptides predicted to bind major histocompatibility complex class I and overlapping 15-mer peptides spanning the complete LCMV proteome for gamma interferon (IFN-γ) induction from CD8+ T cells derived from LCMV-infected H-2b mice. We identified 19 novel epitopes. Together with the 9 previously known, these epitopes account for the total CD8+ CD44hi response. Thus, bystander T-cell activation does not contribute appreciably to the CD8+ CD44hi pool. Strikingly, 15 of the 19 new epitopes were derived from the viral L polymerase, which, until now, was not recognized as a target of the cellular response induced by LCMV infection. The L epitopes induced significant levels of in vivo cytotoxicity and conferred protection against LCMV challenge. Interestingly, protection from viral challenge was best correlated with the cytolytic potential of CD8+ T cells, whereas IFN-γ production and peptide avidity appear to play a lesser role. Taken together, these findings illustrate that the LCMV-specific CD8+ T-cell response is more complex than previously appreciated.

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55 Lethal Lymphocytic Choriomeningitis Virus (LCMV) Infection in STAT1 KO Mice is Associated with Dysregulated PD1/B7-H1 and A Phenotypic Switch in the T-cell Response

Cytokine ◽

10.1016/j.cyto.2007.07.060 ◽

2007 ◽

Vol 39 (1) ◽

pp. 16

Author(s):

Markus J. Hofer ◽

Marcus Mueller ◽

Clare O’Sullivan ◽

Pete Manders ◽

Iain L. Campbell

Keyword(s):

T Cell ◽

Cell Response ◽

Lymphocytic Choriomeningitis ◽

Lymphocytic Choriomeningitis Virus ◽

T Cell Response ◽

Phenotypic Switch ◽

Lcmv Infection

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Virus-induced Transient Bone Marrow Aplasia: Major Role of Interferon-α/β during Acute Infection with the Noncytopathic Lymphocytic Choriomeningitis Virus

Journal of Experimental Medicine ◽

10.1084/jem.185.3.517 ◽

1997 ◽

Vol 185 (3) ◽

pp. 517-530 ◽

Cited By ~ 132

Author(s):

Daniel Binder ◽

Jörg Fehr ◽

Hans Hengartner ◽

Rolf M. Zinkernagel

Keyword(s):

Bone Marrow ◽

Nk Cells ◽

Acute Infection ◽

Lymphocytic Choriomeningitis ◽

Lymphocytic Choriomeningitis Virus ◽

Mouse Strains ◽

Interferon Α ◽

Wild Type ◽

Ifn Γ ◽

Lcmv Infection

The hematologic consequences of infection with the noncytopathic lymphocytic choriomeningitis virus (LCMV) were studied in wild-type mice with inherent variations in their interferon (IFN)-α/β responder ability and in mutant mice lacking α/β (IFN-α/β R0/0) or γ IFN (IFN-γ R0/0) receptors. During the first week of infection, wild type mice demonstrated a transient pancytopenia. Within a given genetic background, the extent of the blood cell abnormalities did not correlate with the virulence of the LCMV isolate but variations were detected between different mouse strains; they were found to depend on their IFN-α/β responder phenotype. Whereas IFN-γ R0/0 mice were comparable to wild-type mice, IFN-α/β R0/0 mice exhibited unchanged peripheral blood values during acute LCMV infection. In parallel, the bone marrow (BM) cellularity, the pluripotential and committed progenitor compartments were up to 30-fold reduced in wild type and IFN-γ R0/0, but remained unchanged in IFN-α/β R0/0 mice. Viral titers in BM 3 d after LCMV infection were similar in these mice, but antigen localization was different. Viral antigen was predominantly confined to stromal BM in normal mice and IFN-γ R0/0 knockouts, whereas, in IFN-α/β R0/0 mice, LCMV was detected in >90% of megakaryocytes and 10–15% of myeloid precursors, but not in erythroblasts. Although IFN-α/β efficiently prevented viral replication in potentially susceptible hematopoietic cells, even in overwhelming LCMV infection, unlimited virus multiplication in platelet and myeloid precursors in IFN-α/β R0/0 mice did not interfere with the number of circulating blood cells. Natural killer (NK) cell expansion and activity in the BM was comparable on day 3 after infection in mutant and control mice. Adaptive immune responses did not play a major role because comparable kinetics of LCMV-induced pancytopenia and transient depletion of the pluripotential and committed progenitor compartments were observed in CD80/0 and CD40/0 mice, in mice depleted of NK cells, in lpr mice, and in perforin-deficient (P0/0) mice lacking lytic NK cells. Thus, the reversible depression of hematopoiesis during early LCMV infection was not mediated by LCMV-WE–specific cytotoxic T lymphocyte, cytolysis, or secreted IFN-γ from virally induced NK cells but was a direct effect of IFN-α/β.

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Thymic Tolerance to Only One Viral Protein Reduces Lymphocytic Choriomeningitis Virus-Induced Immunopathology and Increases Survival in Perforin-Deficient Mice

Journal of Virology ◽

10.1128/jvi.73.7.5918-5925.1999 ◽

1999 ◽

Vol 73 (7) ◽

pp. 5918-5925 ◽

Cited By ~ 9

Author(s):

Matthias von Herrath ◽

Bryan Coon ◽

Dirk Homann ◽

Tom Wolfe ◽

Luca G. Guidotti

Keyword(s):

Immune Response ◽

Viral Protein ◽

Selective Reduction ◽

Lymphocytic Choriomeningitis ◽

Lymphocytic Choriomeningitis Virus ◽

Term Survival ◽

Tnf Α ◽

Ifn Γ ◽

Deficient Mice ◽

Lcmv Infection

ABSTRACT The outcome of viral infections is dependent on the amount of tissue destruction caused either by direct lysis of infected cells and/or by immunopathology resulting from the immune response to the virus. We investigated whether induction of tolerance to only one viral protein could reduce immunopathology caused by nonlytic lymphocytic choriomeningitis virus (LCMV) in perforin-deficient hosts. Earlier studies had shown that LCMV infection results in aplastic anemia and death in most of these mice and that this is associated with bone marrow infiltration by antiviral cytotoxic T lymphocytes (CTL) that secrete inflammatory cytokines. We report here that perforin-deficient mice exhibit severe immunopathology in multiple organs that is characterized by infiltration of anti-LCMV CTL that secrete large amounts of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). Importantly, this immunopathology is significantly reduced and long-term survival of LCMV infection is increased in perforin-deficient mice expressing LCMV nucleoprotein (NP) in the thymus (and therefore deleting most of their LCMV-NP CTL) compared to the situation in thymus nonexpressors. This is due to the selective reduction of NP-specific CTL responses and their inflammatory-cytokine (IFN-γ and TNF-α) secretion and to a lack of pathogenetically relevant compensatory responses to other viral proteins. Thus, “selective reduction” of the antiviral immune response to only one viral protein can significantly reduce inflammatory immunopathology and might be a therapeutic possibility for certain nonlytic infections.

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Interleukin-18 and cytotoxic impairment are independent and synergistic causes of murine virus-induced hyperinflammation

Blood ◽

10.1182/blood.2019003846 ◽

2020 ◽

Vol 136 (19) ◽

pp. 2162-2174 ◽

Cited By ~ 1

Author(s):

Paul Tsoukas ◽

Emily Rapp ◽

Lauren Van Der Kraak ◽

Eric S. Weiss ◽

Vinh Dang ◽

...

Keyword(s):

Macrophage Activation ◽

Inflammatory Responses ◽

Interferon Γ ◽

Lymphocytic Choriomeningitis ◽

Wild Type ◽

Interleukin 18 ◽

Promising Therapeutic Target ◽

Life Threatening ◽

Cd8 Depletion ◽

Lcmv Infection

Abstract Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperinflammatory syndromes typically associated with underlying hematologic and rheumatic diseases, respectively. Familial HLH is associated with genetic cytotoxic impairment and thereby to excessive antigen presentation. Extreme elevation of serum interleukin-18 (IL-18) has been observed specifically in patients with MAS, making it a promising therapeutic target, but how IL-18 promotes hyperinflammation remains unknown. In an adjuvant-induced MAS model, excess IL-18 promoted immunopathology, whereas perforin deficiency had no effect. To determine the effects of excess IL-18 on virus-induced immunopathology, we infected Il18-transgenic (Il18tg) mice with lymphocytic choriomeningitis virus (LCMV; strain Armstrong). LCMV infection is self-limited in wild-type mice, but Prf1−/− mice develop prolonged viremia and fatal HLH. LCMV-infected Il18-transgenic (Il18tg) mice developed cachexia and hyperinflammation comparable to Prf1−/− mice, albeit with minimal mortality. Like Prf1−/− mice, immunopathology was largely rescued by CD8 depletion or interferon-γ (IFNg) blockade. Unlike Prf1−/− mice, they showed normal target cell killing and normal clearance of viral RNA and antigens. Rather than impairing cytotoxicity, excess IL-18 acted on T lymphocytes to amplify their inflammatory responses. Surprisingly, combined perforin deficiency and transgenic IL-18 production caused spontaneous hyperinflammation specifically characterized by CD8 T-cell expansion and improved by IFNg blockade. Even Il18tg;Prf1-haplosufficient mice demonstrated hyperinflammatory features. Thus, excess IL-18 promotes hyperinflammation via an autoinflammatory mechanism distinct from, and synergistic with, cytotoxic impairment. These data establish IL-18 as a potent, independent, and modifiable driver of life-threatening innate and adaptive hyperinflammation and support the rationale for an IL-18–driven subclass of hyperinflammation.

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