Congenital lymphocytic choriomeningitis virus: A review.

INTRODUCTION: Lymphocytic choriomeningitis virus (LCMV) uses rodents such as mice and hamsters as its principal reservoir. When women acquire LCMV during pregnancy because of contact with rodents, it can lead to congenital LCMV infection, which is associated with high mortality and morbidity. Although the number of cases reported in the literature is increasing, LCMV is rarely mentioned because a history of exposure to rodents is uncommon and mostly unknown. OBJECTIVES: The main objective of this article was to summarize all morphological, antenatal, and postnatal abnormalities that may suggest a congenital LCMV infection. METHODS: We reviewed PubMed case reports and case series where an antenatal and/or a postnatal description of at least one case of congenital LCMV infection was documented. RESULTS: We found 70 cases of congenital LCMV infection, 68 of which had antenatal or postnatal brain abnormalities, which were mainly chorioretinitis (59/70), hydrocephaly (37/70), microcephaly (22/70), ventriculomegaly (11/70) and periventricular calcifications (11/70). Antenatal and postnatal extracerebral abnormalities were mainly small for gestational age, ascites, cardiomegaly or anemia. Other organ damage was rare, but could include skin abnormalities, hydrops or hepatosplenomegaly. Seventy percent (49/70) of cases had major cerebral abnormalities that could have been detected by antenatal ultrasound examination. Congenital LCMV infection is associated with a significant mortality rate (30%) and survivors often have severe neurologic sequelae. CONCLUSION: LCMV is a rare congenital infection, but awareness of the various prenatal ultrasound morphological abnormalities should be improved, and LCMV should be considered when first-line etiological explorations are negative, especially when the mother's medical history indicates exposure to rodents.

Lymphocytic Choriomeningitis Virus Alters the Expression of Male Mouse Scent Proteins.

Mature male mice produce a particularly high concentration of major urinary proteins (MUPs) in their scent marks that provide identity and status information to conspecifics. Darcin (MUP20) is inherently attractive to females and, by inducing rapid associative learning, leads to specific attraction to the individual male's odour and location. Other polymorphic central MUPs, produced at much higher abundance, bind volatile ligands that are slowly released from a male's scent marks, forming the male's individual odour that females learn. Here, we show that infection of C57BL/6 males with LCMV WE variants (v2.2 or v54) alters MUP expression according to a male's infection status and ability to clear the virus. MUP output is substantially reduced during acute adult infection with LCMV WE v2.2 and when males are persistently infected with LCMV WE v2.2 or v54. Infection differentially alters expression of darcin and, particularly, suppresses expression of a male's central MUP signature. However, following clearance of acute v2.2 infection through a robust virus-specific CD8 cytotoxic T cell response that leads to immunity to the virus, males regain their normal mature male MUP pattern and exhibit enhanced MUP output by 30 days post-infection relative to uninfected controls. We discuss the likely impact of these changes in male MUP signals on female attraction and mate selection. As LCMV infection during pregnancy can substantially reduce embryo survival and lead to lifelong infection in surviving offspring, we speculate that females use LCMV-induced changes in MUP expression both to avoid direct infection from a male and to select mates able to develop immunity to local variants that will be inherited by their offspring.

JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation.

Cytokine storm syndromes (CSS) are severe hyperinflammatory conditions characterized by excessive immune system activation leading to organ damage and death. Hemophagocytic lymphohistiocytosis (HLH), a disease often associated with inherited defects in cell-mediated cytotoxicity, serves as a prototypical CSS for which the 5-year survival is only 60%. Frontline therapy for HLH consists of the glucocorticoid dexamethasone (DEX) and the chemotherapeutic agent etoposide. Many patients, however, are refractory to this treatment or relapse after an initial response. Notably, many cytokines that are elevated in HLH activate the JAK/STAT pathway, and the JAK1/2 inhibitor ruxolitinib (RUX) has shown efficacy in murine HLH models and humans with refractory disease. We recently reported that cytokine-induced JAK/STAT signaling mediates DEX resistance in T cell acute lymphoblastic leukemia (T-ALL) cells, and that this could be effectively reversed by RUX. On the basis of these findings, we hypothesized that cytokine-mediated JAK/STAT signaling might similarly contribute to DEX resistance in HLH, and that RUX treatment would overcome this phenomenon. Using ex vivo assays, a murine model of HLH, and primary patient samples, we demonstrate that the hypercytokinemia of HLH reduces the apoptotic potential of CD8 T cells leading to relative DEX resistance. Upon exposure to RUX, this apoptotic potential is restored, thereby sensitizing CD8 T cells to DEX-induced apoptosis in vitro and significantly reducing tissue immunopathology and HLH disease manifestations in vivo. Our findings provide rationale for combining DEX and RUX to enhance the lymphotoxic effects of DEX and thus improve the outcomes for patients with HLH and related CSS.

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

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.

Mouse Models of Virus-Induced Type 1 Diabetes.

Virus infections have been linked to the induction of autoimmunity and disease development in human type 1 diabetes. Experimental models have been instrumental in deciphering processes leading to break of immunological tolerance and type 1 diabetes development. Animal models have also been useful for proof-of-concept studies and for preclinical testing of new therapeutic interventions. This chapter describes two robust and clinically relevant mouse models for virus-induced type 1 diabetes; acceleration of disease onset in prediabetic nonobese diabetic (NOD) mice following Coxsackievirus infection and diabetes induction by lymphocytic choriomeningitis virus (LCMV) infection of transgenic mice expressing viral neo-antigens under control of the rat insulin promoter (RIP).

Endogenous n-3 Polyunsaturated Fatty Acids Are Beneficial to Dampen CD8+ T Cell-Mediated Inflammatory Response upon the Viral Infection in Mice.

Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) have been known to exert anti-inflammatory effects on various disease states. However, its effect on CD8+ T cell-mediated immunopathology upon viral infection has not been well elucidated yet. In this study, we investigated the possible implication of n-3 PUFAs in CD8+ T cell responses against an acute viral infection. Infection of FAT-1 transgenic mice that are capable of synthesizing n-3 PUFAs from n-6 PUFAs with lymphocytic choriomeningitis virus (LCMV) resulted in significant reduction of anti-viral CD8+ T cell responses. Interestingly, expansion of adoptively transferred wild-type (WT) LCMV-specific T cell receptor (TCR) transgenic CD8+ (P14) T cells into FAT-1 mice was significantly decreased. Also, activation of anti-viral CD4+ helper T cells was reduced in FAT-1 mice. Importantly, P14 cells carrying the fat-1 gene that were adoptively transferred into WT mice exhibited a substantially decreased ability to proliferate and produce cytokines against LCMV infection. Together, n-3 PUFAs attenuated anti-viral CD8+ T cell responses against an acute viral infection and thus could be used to alleviate immunopathology mediated by the viral infection.

Neuroinvasion and cognitive impairment in comorbid alcohol dependence and chronic viral infection: An initial investigation.

Viruses that invade the central nervous system (CNS) can cause neuropsychiatric impairments. Similarly, chronic alcohol exposure can induce inflammatory responses that alter brain function. However, the effects of a chronic viral infection and comorbid alcohol use on neuroinflammation and behavior are not well-defined. We investigated the role of heavy alcohol intake in regulating inflammatory responses and behavioral signs of cognitive impairments in mice infected with lymphocytic choriomeningitis virus (LCMV) clone 13. LCMV-infected mice exposed to alcohol had increased peripheral inflammation and impaired cognitive function (as indicated by performance on the novel object recognition test). Initial findings suggest that brain region-specific dysregulation of microglial response to viral infection may contribute to cognitive impairments in the context of heavy alcohol use.

Identification of a Locus in Mice that Regulates the Collateral Damage and Lethality of Virus Infection.

Arenaviruses can cause severe hemorrhagic disease in humans, which can progress to organ failure and death. The underlying mechanisms causing lethality and person-to-person variation in outcome remain incompletely explained. Herein, we characterize a mouse model that recapitulates many features of pathogenesis observed in humans with arenavirus-induced hemorrhagic disease, including thrombocytopenia, severe vascular leakage, lung edema, and lethality. The susceptibility of congenic B6.PL mice to lymphocytic choriomeningitis virus (LCMV) infection is associated with increased antiviral T cell responses in B6.PL mice compared with C57BL/6 mice and is T cell dependent. Pathogenesis imparted by the causative locus is inherited in a semi-dominant manner in F1 crosses. The locus includes PL-derived sequence variants in both poorly annotated genes and genes known to contribute to immune responses. This model can be used to further interrogate how limited genetic differences in the host can remarkably alter the disease course of viral infection.

IL-33 induces immunosuppressive neutrophils via a type 2 innate lymphoid cell/IL-13/STAT6 axis and protects the liver against injury in LCMV infection-induced viral hepatitis.

Viral hepatitis is still a public health problem affecting several million people around the world. Neutrophils are polymorphonuclear cells that have a critical role in antibacterial infection. However, the role of neutrophils in viral infection is not fully understood. By using a mouse model of lymphocytic choriomeningitis virus infection-induced viral hepatitis, we observed increased neutrophil recruitment in the liver accompanied by enhanced CD8+ T-cell responses. Liver neutrophils expressed high levels of immunomodulatory cytokines, such as C-X-C chemokine ligand 2, arginase-1, inducible nitric oxide synthase and interleukin (IL)-10, demonstrating immunosuppressive properties. Depletion of neutrophils in vivo by a neutralizing antibody resulted in the exacerbation of liver injury and the promotion of T-cell responses at the immune contraction stage. IL-33 significantly induced neutrophil recruitment in the liver and attenuated liver injury by limiting effector T-cell accumulation. Mechanistically, we found that IL-33 promoted the expression of arginase-1 in neutrophils through the type 2 innate lymphoid cell (ILC2)-derived IL-13. Additionally, IL-13 increased the inhibitory effect of neutrophils on CD8+ T-cell proliferation in vitro, partially through arginase-1. Finally, we found that IL-13 induced arginase-1 expression, depending on signal transducer and activator of transcription factor 6 (STAT6) signaling. Therefore, IL-33 induced immunosuppressive neutrophils via an ILC2/IL-13/STAT6 axis. Collectively, our findings shed new light on the mechanisms associated with IL-33-triggered neutrophils in the liver and suggest potential targets for therapeutic investigation in viral hepatitis.

Congenital lymphocytic choriomeningitis virus-an underdiagnosed fetal teratogen.

Congenital lymphocytic choriomeningitis virus (LCMV) infection is associated with high mortality and morbidity. Although the number of cases reported in the literature has been increasing, it might still be clinically an underdiagnosed human fetal teratogen. We report 2 more cases of serologically proven congenital LCMV infection. One case presented with Aicardi-like syndrome features. Since congenital LCMV infection may mimic Aicardi syndrome, serologic testing should be considered in the workup of patients with Aicardi syndrome to rule out LCMV infection.

Lymphocytic choriomeningitis, Ljungan and orthopoxvirus seroconversions in patients hospitalized due to acute Puumala hantavirus infection.

BACKGROUND: The emergence and re-emergence of zoonotic and vector-borne diseases are increasing in Europe. Prominent rodent-borne zoonotic viruses include Puumala hantavirus (PUUV; the causative agent of nephropathia epidemica, NE), lymphocytic choriomeningitis virus (LCMV), and orthopoxviruses (OPV). In addition, Ljungan virus (LV) is considered a potentially zoonotic virus. OBJECTIVE: The aim of this study was to compare clinical picture between acute PUUV patients with and without additional rodent-borne viral infections, to investigate if concurrent infections influence disease severity. STUDY DESIGN: We evaluated seroprevalence of and seroconversions to LCMV, LV and OPV in 116 patients hospitalized for NE. Clinical and laboratory variables were closely monitored during hospital care. RESULTS: A total of five LCMV, 15 LV, and one OPV seroconversions occurred. NE patients with LCMV seroconversions were younger, and had lower plasma creatinine concentrations and platelet counts than patients without LCMV seroconversions. No differences occurred in clinical or laboratory findings between patients with and without seroconversions to LV and OPV. We report, for the first time, LCMV seroprevalence in Finland, with 8.5% of NE patients seropositive for this virus. Seroprevalences for LV and OPV were 47.8% and 32.4%, respectively. CONCLUSION: Cases with LCMV seroconversions were statistically younger, had milder acute kidney injury and more severe thrombocytopenia than patients without LCMV. However, the low number of seroconversion cases precludes firm conclusions. Concurrent LV or OPV infections do not appear to influence clinical picture for NE patients.

ST2 contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice.

Cytokine storm syndromes, such as familial hemophagocytic lymphohistiocytosis (FHL), are lethal disorders caused by uncontrolled, systemic immune activation. In the murine model of FHL, in which perforin-deficient (Prf1(-/-)) mice are infected with lymphocytic choriomeningitis virus (LCMV), disease is driven by overabundant interferon (IFN)γ-producing LCMV-specific CD8(+) T cells thought to arise from excessive antigen stimulation through the T-cell receptor. However, this paradigm is insufficient to explain several fundamental aspects of FHL, namely, the inability of many pathogenic antigens to induce hyperinflammation, and the previously identified role of MyD88 in the disease. We now show a novel role for the MyD88-dependent interleukin-33 (IL-33) receptor, ST2, in FHL. Expression of IL-33 and ST2 is upregulated in LCMV-infected Prf1(-/-) mice. Blockade of ST2 markedly improves survival of LCMV-infected Prf1(-/-) mice and reduces the severity of multiple disease parameters, including serum levels of IFNγ. This decrease in IFNγ corresponds to a reduction in both the frequency of IFNγ(+) LCMV-specific CD8(+) and CD4(+) T cells and the magnitude of IFNγ expression in these cells. These findings demonstrate that disruption of ST2 signaling in the murine model of FHL reduces T cell-mediated production of IFNγ and suggest a revised paradigm in which danger signals such as IL-33 are crucial amplifiers of immune dysregulation in FHL. Furthermore, this study provides evidence to support blockade of ST2 as a novel therapeutic strategy for FHL.

Maternal onset de novo SH2D1A mutation and lymphocytic choriomeningitis virus infection in a patient with X­linked lymphoproliferative disease type 1: a case report.

X­linked lymphoproliferative disease type 1 (XLP1) is a rare genetic immunodeficiency disease, which occurs due to germline mutations in the SH2D1A gene. This gene has been reported to encode the adaptor molecule signaling lymphocytic activation molecule­associated protein XLP1 is generally triggered by the Epstein­Barr virus (EBV) infection. The present study reported the case of a 4­year­old male who presented with a high fever, hypogammaglobulinemia, diffuse lung disease and encephalitis. The patient was infected with the lymphocytic choriomeningitis virus (LCMV), not EBV or any other human herpes virus. The patient was found to carry a SH2D1A c.7G>T/p.A3S mutation, which was inherited from the mother and maternal grandfather, as well as a SH2D1A c.228T>A/p.Y76X mutation, which was identified to be a maternal­onset de novo mutation at the time of germline development of the patient's mother. To the best of our knowledge, the present study is the first reported case of maternal­onset XLP1 with a de novo SH2D1A mutation and LCMV infection.

Regulatory T cells control diabetes without compromising acute anti-viral defense.

While previous reports have demonstrated the efficacy of regulatory T cell therapy in the prevention of diabetes, systemic immunocompromise and Treg instability remain key safety concerns. Here we examined the influence of induced Treg (iTreg) cell therapy on anti-viral host defense and autoimmune T cell responses during acute viral infection in a murine model of autoimmune diabetes. Protective transfers of iTregs maintained IL-10 expression, expanded in vivo and controlled diabetes, despite losing FoxP3 expression. Adoptive transfer of iTregs affected neither the primary anti-viral CD8 T cell response nor viral clearance, although a significant and sustained suppression of CD4 T cell responses was observed. Following acute viral clearance, iTregs transferred early suppressed both CD4 and CD8 T cell responses, which resulted in the reversion of diabetes. These observations indicate that iTregs suppress local autoimmune processes while preserving the immunocompetent host's ability to combat acute viral infection.

Sustained and incomplete recovery of naive CD8+ T cell precursors after sepsis contributes to impaired CD8+ T cell responses to infection.

Patients who survive severe sepsis often display compromised immune function with impairment in innate and adaptive immune responses. These septic patients are highly susceptible to "secondary" infections with intracellular pathogens that are usually controlled by CD8(+) T cells. It is not known when and if this observed immunoparalysis of CD8(+) T cell immunity recovers, and the long-term consequences of sepsis on the ability of naive CD8(+) T cells to respond to subsequent infections are poorly understood. In this study, using the cecal-ligation and puncture mouse model of sepsis, we show that sepsis induces a rapid loss of naive CD8(+) T cells. However, IL-15-dependent numerical recovery is observed a month after initial septic insult. Numerical recovery is accompanied by IL-15-dependent phenotypic changes where a substantial proportion of naive (Ag-inexperienced) CD8(+) T cells display a "memory-like" phenotype (CD44(hi)/CD11a(hi)). Importantly, the impairment of naive CD8(+) T cells to respond to viral and bacterial infection was sustained for month(s) after sepsis induction. Incomplete recovery of naive CD8(+) T cell precursors was observed in septic mice, suggesting that the availability of naive precursors contributes to the sustained impairment in primary CD8(+) T cell responses. Thus, sepsis can result in substantial and long-lasting changes in the available CD8(+) T cell repertoire affecting the capacity of the host to respond to new infections.

CD8+ T cell-derived IFN-γ prevents infection by a second heterologous virus.

Persistent viral infection is often associated with dysfunctional immune responses against unrelated pathogens. Lymphocytic choriomeningitis virus (LCMV) can establish acute or chronic infections in mice and is widely used as a model for persistent virus infections in humans. Mice infected with LCMV develop a transient defect in Ag-specific immunity against heterologous viral infection. Although it has been proposed that LCMV infection induces an immunosuppressed state within the host, our data show that infected mice successfully clear vaccinia virus through a mechanism that involves CD8(+) T cell-derived IFN-γ. This observation demonstrates that chronic LCMV infection does not impair protective immunity against heterologous viral challenge. Rather, a natural sterilizing immunity is induced following a primary infection that prevents a secondary infection. Our findings suggest a need to re-evaluate current thoughts about the immune suppression that might occur during a persistent infection.

Aberrant CD8+ T-cell responses and memory differentiation upon viral infection of an ataxia-telangiectasia mouse model driven by hyper-activated Akt and mTORC1 signaling.

Immune system-related pathology is common in ataxia-telangiectasia (A-T) patients and mice that lack the protein kinase, A-T mutated (ATM). However, it has not been studied how ATM influences immune responses to a viral infection. Using the lymphocytic choriomeningitis virus (LCMV) infection model, we show that ATM(-/-) mice, despite having fewer naïve CD8⁺ T cells, effectively clear the virus. However, aberrant CD8⁺ T-cell responses are observed, including defective expansion and contraction, effector-to-memory differentiation, and a switch in viral-epitope immunodominance. T-cell receptor-activated, but not naïve, ATM(-/-) splenic CD8⁺ T cells have increased ribosomal protein S6 and Akt phosphorylation and do not proliferate well in response to IL-15, a cytokine important for memory T-cell development. Accordingly, pharmacological Akt or mammalian target of rapamycin complex 1 (mTORC1) inhibition during T-cell receptor activation alone rescues the IL-15 proliferation defect. Finally, rapamycin treatment during LCMV infection in vivo increases the number of memory T cells in ATM(-/-) mice. Altogether, these results show that CD8⁺T cells lacking ATM have hyperactive Akt and mTORC1 signaling in response to T-cell receptor activation, which results in aberrant cytokine responses and memory T-cell development. We speculate that similar signaling defects contribute to the immune system pathology of A-T, and that inhibition of Akt and/or mTORC1 may be of therapeutic value.

Viruses and cytotoxic T lymphocytes in type 1 diabetes.

Histopathological studies on pancreas tissues from individuals with recent-onset type 1 diabetes (T1D) consistently find that CD8 T cells substantially contribute to the formation of islet lesions. CD8 T cells reactive against islet-associated antigens can also be found in blood samples from T1D patients. Mechanistic studies on the pathogenic role of this T cell subset have mostly focused on two animal models, i.e., the non-obese diabetic mouse and the virally induced rat insulin promoter-lymphocytic choriomeningitis virus model. Data were obtained in support of a role for viral infection in expanding a population of diabetogenic cytotoxic T lymphocytes. In view of the theorized association of viral infection with initiation of islet autoimmunity and progression to clinically overt disease, CD8 T cells thus represent an attractive target for immunotherapy. We will review here arguments in favor of a pivotal role for CD8 T cells in driving T1D development and speculate on etiologic agents that may provoke their aberrant activation.

[Lymphocytic choriomeningitis virus and fetal anomalies]. / Infection par le virus de la chorioméningite lymphocytaire et fœtopathies.

OBJECTIVE: Lymphocytic choriomeningitis virus (LCMV), a rodent-borne arenavirus, is an uncommonly recognized cause of severe congenital viral infection. The incidence of this infection during pregnancy is still unknown. Our study aimed to evaluate LCMV infection frequency in pregnancy with fetal neurological abnormalities of unknown etiology. MATERIAL AND METHODS: Samples obtained during three years from 160 pregnant women were retrospectively analysed: 155 maternal sera, 150 amniotic fluids (AF) and 12 fetal sera (FS). Congenital neurological anomalies were diagnosed but TORCH and culture investigations were negatives. Serological analysis was performed with L929 cells infected with the Armstrong strain of LCMV. IgG and IgM antibodies against CMLV were researched by immunofluorescence assay using these infected cells. Interferon alpha was also assayed for AF and FS. RESULTS: No positive serology was found in any of the 317 samples investigated even when interferon alpha was detected. CONCLUSION: This result confirms the rarity of LCMV infection in France. Nevertheless, at the light of the recent literature, this teratogenic pathogen should be considered in pregnancy with unexplained congenital malformation, especially after rodent exposure.