Lymphocytic Choriomeningitis Infection Research Articles

Chronic Lymphocytic Choriomeningitis Infection Causes Susceptibility to Mousepox and Impairs Natural Killer Cell Maturation and Function.

Chronic viral infections. like those of humans with cytomegalovirus, human immunodeficiency virus (even when under antiretroviral therapy), and hepatitis C virus or those of mice with lymphocytic choriomeningitis virus (LCMV) clone 13 (CL13), result in immune dysfunction that predisposes the host to severe infections with unrelated pathogens. It is known that C57BL/6 (B6) mice are resistant to mousepox, a lethal disease caused by the orthopoxvirus ectromelia virus (ECTV), and that this resistance requires natural killer (NK) cells and other immune cells. We show that most B6 mice chronically infected with CL13 succumb to mousepox but that most of those that recovered from acute infection with the LCMV Armstrong (Arm) strain survive. We also show that B6 mice chronically infected with CL13 and those that recovered from Arm infection have a reduced frequency and a reduced number of NK cells. However, at steady state, NK cells in mice that have recovered from Arm infection mature normally and, in response to ECTV, get activated, become more mature, proliferate, and increase their cytotoxicity in vivo Conversely, in mice chronically infected with CL13, NK cells are immature and residually activated, and following ECTV infection, they do not mature, proliferate, or increase their cytotoxicity. Given the well-established importance of NK cells in resistance to mousepox, these data suggest that the NK cell dysfunction caused by CL13 persistence may contribute to the susceptibility of CL13-infected mice to mousepox. Whether chronic infections similarly affect NK cells in humans should be explored.IMPORTANCE Infection of adult mice with the clone 13 (CL13) strain of lymphocytic choriomeningitis virus (LCMV) is extensively used as a model of chronic infection. In this paper, we show that mice chronically infected with CL13 succumb to challenge with ectromelia virus (ECTV; the agent of mousepox) and that natural killer (NK) cells in CL13-infected mice are reduced in numbers and have an immature and partially activated phenotype but do respond to ECTV. These data may provide additional clues why humans chronically infected with certain pathogens are less resistant to viral diseases.

Effect of IL-7 Therapy on Phospho-Ribosomal Protein S6 and TRAF1 Expression in HIV-Specific CD8 T Cells in Patients Receiving Antiretroviral Therapy.

IL-7 therapy has been evaluated in patients who do not regain normal CD4 T cell counts after virologically successful antiretroviral therapy. IL-7 increases total circulating CD4 and CD8 T cell counts; however, its effect on HIV-specific CD8 T cells has not been fully examined. TRAF1, a prosurvival signaling adaptor required for 4-1BB-mediated costimulation, is lost from chronically stimulated virus-specific CD8 T cells with progression of HIV infection in humans and during chronic lymphocytic choriomeningitis infection in mice. Previous results showed that IL-7 can restore TRAF1 expression in virus-specific CD8 T cells in mice, rendering them sensitive to anti-4-1BB agonist therapy. In this article, we show that IL-7 therapy in humans increases the number of circulating HIV-specific CD8 T cells. For a subset of patients, we also observed an increased frequency of TRAF1+ HIV-specific CD8 T cells 10 wk after completion of IL-7 treatment. IL-7 treatment increased levels of phospho-ribosomal protein S6 in HIV-specific CD8 T cells, suggesting increased activation of the metabolic checkpoint kinase mTORC1. Thus, IL-7 therapy in antiretroviral therapy-treated patients induces sustained changes in the number and phenotype of HIV-specific T cells.

Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells

IL-21 is a type I cytokine essential for immune cell differentiation and function. Although IL-21 can activate several STAT family transcription factors, previous studies focused mainly on the role of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 and show that STAT1 and STAT3 have at least partially opposing roles in IL-21 signaling in CD4(+) T cells. IL-21 induced STAT1 phosphorylation, and this was augmented in Stat3-deficient CD4(+) T cells. RNA-Seq analysis of CD4(+) T cells from Stat1- and Stat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. Expression of some genes, including Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3. Moreover, opposing actions of STAT1 and STAT3 on IFN-γ expression in CD4(+) T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis infection. Finally, IL-21-mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4(+) T cells from patients with autosomal dominant hyper-IgE syndrome, which is caused by STAT3 deficiency, as well as in cells from STAT1 gain-of-function patients. These data indicate an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions.

Immune Complexes: Not Just an Innocent Bystander in Chronic Viral Infection

Understanding of how persistent viral infection impacts humoral immunity is incomplete. In this issue of Immunity, Wieland et al. (2015) and Yamada et al. (2015) find that high amounts of IgG-antigen complexes formed during chronic lymphocytic choriomeningitis infection can interfere with Fcγ-receptor-mediated effector activities, potentially contributing to immune dysfunction.

PS1-116 Role of interferon regulatory factor 7 (IRF7) in the host response to lymphocytic choriomeningitis infection

PS1-116 Role of interferon regulatory factor 7 (IRF7) in the host response to lymphocytic choriomeningitis infection

Lymphocytic choriomeningitis infection of the central nervous system

Viral infection of the central nervous system (CNS) can result in a multitude of responses including pathology, persistence or immune clearance. Lymphocytic choriomeningitis virus (LCMV) is a powerful model system to explore these potential outcomes of CNS infection due to the diversity of responses that can be achieved after viral inoculation. Several factors including tropism, timing, dose and variant of LCMV in combination with the development or suppression of the corresponding immune response dictates whether lethal meningitis, chronic infection or clearance of LCMV in the CNS will occur. Importantly, the functionality and positioning of the LCMV-specific CD8+ T cell response are critical in directing the subsequent outcome of CNS LCMV infection. Although a basic understanding of LCMV and immune interactions in the brain exists, the molecular machinery that shapes the balance between pathogenesis and clearance in the LCMV-infected CNS remains to be elucidated. This review covers the various outcomes of LCMV infection in the CNS and what is currently known about the impact of the virus itself versus the immune response in the development of disease or clearance.

Transforming growth factor-beta fails to inhibit allograft rejection or virus-induced autoimmune diabetes in transgenic mice.

Transgenic mice whose pancreata express transforming growth factor-beta (TGF-beta) directed by an insulin promoter (Ins-TGF-beta mice) were used to assess the effect of local TGF-beta1 on allograft rejection and on autoimmune diabetes occurring as a cross-reaction to viral antigens. Pancreatic TGF-beta1 did not delay allograft rejection, nor did it inhibit autoimmune diabetes after lymphocytic choriomeningitis infection of double transgenic mice (LCMV/TGF-beta1 mice). These results suggest that local TGF-beta1 does not serve as an immunosuppressive agent for allograft rejection or virus-mediated autoimmune diabetes.

Lymphocytic choriomeningitis virus killer T cells are lethal only in weakly disseminated murine infections.

Two types of lymphocytic choriomeningitis (LCM) viruses were studied which, upon intracerebral injection into adult C3H mice, provoked either (a) acute fatal central nervous system (CNS) disease or (b) life-long persistent infection. Both virus types, (a) aggressive and (b) docile, had been found to induce LCM-specific lymphocytes with comparable in vitro lytic activity (11). Because the requirement for T cells in the development of adult LCM disease has been extensively documented, we sought other reasons for the lack of acute disease in mice infected with docile virus. A striking correlation was found between the outcome of the infection and spread of virus to visceral organs. Adoptive transfer experiments showed that a 300-plaque forming unit inoculum of docile virus induced a population of T cells in donor mice fully capable of causing CNS disease in identically infected recipients. This disease causing ability was lost if the interaction was delayed beyond 3 d after infection of the recipients, but could be preserved by lowering the size of the viral inoculum in the recipients. Furthermore, without adoptive transfer, very low intracerebral doses of docile virus (which mimicked the normally slow spread of aggressive virus) were lethal. On the other hand, very high doses of aggressive virus, which mimicked the normally rapid spread of docile virus, did not induce fatal CNS disease. The results suggest that rapid dissemination of the LCM infection creates multiple target organs which divert the focused lethal T cell attack on the brain.

Interferon induction by lymphocytic choriomeningitis viruses correlates with maximum virulence.

Lymphocytic choriomeningitis (LCM) viruses isolated from the blood of persistently infected mice, could be clearly divided into two categories by observing the disease patterns they produced after intracerebral (i.c.) injection in a number of adult inbred and outbred mice. One type (aggressive) caused the classic pattern of convulsive death in 100% of the mice 7 to 9 days after infection, while the other (docile) caused a protracted disease with deaths occurring, if at all, 2 to 4 weeks after infection. Interferon could be detected in the serum of adult mice on the 3rd and 4th day after infection with several independently cloned aggressive, but not docile, viruses. The inability of docile virus to induce interferon was not due to poor or delayed virus replication in the brain. The aggressive pattern of disease could be provoked easily in docile virus-infected mice with the interferon inducers poly(rI) . poly(rC), tilorone hydrochloride or Newcastle disease virus. The amount of interferon produced had little effect on the mean day of death. Mice that differed over 10-fold in their serum interferon levels after LCM infection, either by genetic predisposition or by stimulation with increasing amounts of poly(rI) . poly(rC), presented almost identical patterns of mortality.

Lymphomas associated with a tolerant lymphocytic choriomeningitis virus infection in mice.

On each of 2 occasions when a tolerant lymphocytic choriomeningitis (LCM) virus infection was introduced experimentally by a natural route into breeding stock of the Pirbright P(SD) mouse strain, and a comparison made with genetically identical controls, where was in successive generations an overall 15-fold increase in the incidence of lymphomas. Most of these were recognized clinically after the age of 16 months. The same observation was made in mice of the P(H) strain from which the P(SD) strain had been surgically derived. The finding is interpreted as the activation of an endogenous viral oncogene by the LCM infection. It was concurrently observed that the incidence of mammary tumours in the P(H) strain mice before the age of 16 months was markedly lower in the animals infected with LCM.

Viral antibody in the cerebrospinal fluid of patients with acute central nervous system infections

Cerebrospinal fluid (CSF) and sera from 129 patients of a study population of 139 were tested for antibody to herpes simplex, measles,and mumps viruses. Herpes simplex virus antibody was found in three of five patients with laboratory-confirmed herpes simplex infection and in eight patients without serological or virological evidence of current infection with this or other common neurotropic visuses. Eleven of the 139 patients were studied for antibody to lymphocytic choriomeningitis (LCM) virus. Eight of these had laboratory-confirmed LCM infection, and antibody was detected in the CSF of five of them. In one of these five, complement-fixing antibody appeared earlier in the CSF than in the blood. Assay of LCM virus antibody in the CSF may thus indicate infection with LCM virus more rapidly than serological and virological studies. The diagnostic and the possible prognostic significance of herpes simplex visus antibody in CSF remains to be ascertained.

Lysis mediated by T cells and restricted by H-2 antigen of target cells infected with vaccinia virus.

VARIOUS virus infections lead to the formation of cytotoxic lymphocytes (CL), which are capable of killing virus-infected target cells1−4. Specific lysis of target cells infected with 51Cr-labelled vaccinia virus could be observed when investigating the cell-mediated cytotoxic reaction to vaccinia virus5; the CL could be characterised as a T cell. The sensitised lymphocytes from C3H mice could only kill syngeneic L929 cells infected with vaccinia virus, whereas lysis by sensitised lymphocytes derived from DBA/2 mice was restricted to the syngeneic infected mastocytoma P815X2 cells. In the lymphocytic choriomeningitis infection the target cell lysis was shown to be restricted by H-2 antigen6. We report here experiments with primary fibroblasts of the mouse strains C3H, DBA/2 and the (C3H DBA/2)F1 generation were designed to affirm that the effector phase of virus-specific lysis of target cells mediated by T cells is restricted by H-2 antigen even in the vaccinia virus infection. Further experiments with H-2 alloantisera were performed to indicate the close local relationship between H-2 antigens and viral surface antigens.

Immunopathogenesis of acute central nervous system disease produced by lymphocytic choriomeningitis virus. II. Adoptive immunization of virus carriers.

Lymphocytic choriomeningitis (LCM) virus carriers were established by intracerebral inoculation of adult BALB/c mice followed by a single dose of cyclophosphamide (CY) (150 mg/kg) 3 days after infection, and by intracerebral injection within 24 hr of birth. These carriers were then adoptively immunized with spleen cells or serum from immune or normal BALB/c donors. Transfer of immune spleen cells into drug-induced carriers consistently resulted in acutely fatal choriomeningitis, histologically strikingly similar to classical LCM. Normal spleen cells or immune serum failed to produce either central nervous system (CNS) pathology or illness with any regularity. In addition, focal necrosis of the cerebellum was seen after adoptive immunization of drug-induced carriers but only when mice received cells at least 3 wk after inoculation, which is probably explained by the gradual spread of infection from membranes to the neural parenchyma during the first month after establishment of the carrier state in adult mice. Immune spleen cells, when transferred to neonatal carriers, led to a decrease in virus titers in blood and brains and to development of antibody without acute CNS disease. It appears that the production of fatal choriomeningitis after LCM infection is determined in part by the distribution of viral antigen, and this is markedly different in neonatal and drug-induced carriers at the time of cell transfer. Another factor of potential importance is the much higher level of circulating viral antigen in the plasma of neonatal than in that of drug-induced LCM carriers. Classical LCM disease can only be transferred by immune lymphoid cells and not by antiserum. Furthermore, little or no complement-fixing (CF) antibody was found in the plasma of mice dying of acute choroiditis. These observations strongly suggest that acute choroiditis is dependent upon the cell-mediated immune response.

Effect of murine strain and viral strain on the pathogenesis of lymphocytic choriomeningitis infection and a study of footpad responses.

investigated. Further studies of the footpad response to LCM virus infection [6], which depends on immunologic mechanisms, are reported. No antigenic differences have been demonstrated between strains of LCM virus, but the passage history has been shown to be of great importance in determining the behavior of the virus in animals [7, 8]. With the use of the WE3 and Armstrong strains of LCM virus, possible reasons for the difference in their behavior have

Interaction of graft-versus-host reaction and lymphocytic choriomeningitis infection in mice: histopathological changes.

Comme conséquence de l'interaction de la maladie homologue produite dans des souris F1 hybrides adultes et de l'infection avec le virus de la chorioméningite lymphocytique, les signes histologiques de la maladie homologue étaient aggravés. D'autre part, une action protectrice inversement proportionnelle à la gravité des altérations histologiques attribuables à la maladie homologue vis-à-vis des manifestations neurologiques de l'infection avec ce virus était évidente.

Meningitis Due to Lymphocytic Choriomeningitis Virus Endemic in a Hamster Colony

Meningitis due to lymphocytic-choriomeningitis (LCM) virus occurred in a 36-year-old man after brief contact with infected hamsters. To our knowledge, this is the second instance of an LCM infection developing in a man exposed to hamsters used for experimental tumor investigation.

Meningitis due to lymphocytic choriomeningitis virus endemic in a hamster colony

Meningitis due to lymphocytic-choriomeningitis (LCM) virus occurred in a 36-year-old man after brief contact with infected hamsters. To our knowledge, this is the second instance of an LCM infection developing in a man exposed to hamsters used for experimental tumor investigation.

Further Studies of Antiviral Activity of Natural Products on Lymphocytic Choriomeningitis Infection

Further Studies of Antiviral Activity of Natural Products on Lymphocytic Choriomeningitis Infection

Antiviral activity of higher plants and propionin on lymphocytic choriomeningitis infection.

SummaryFurther studies of 2 higher plants (Narcissus tazetta L and Magnolia kobus DC) with antiviral action against lymphocytic choriomeningitis infection in mice have been reported, and the activity of a third substance, propionin, added. The anti-LCM activities of the 3 natural products have been compared with methotrexate.The authors are indebted to Dr. H. A. Chirigos, Nat. Inst. of Health, for supplying methotrexate and to Dr. Ralph F. Anderson, International Minerals & Chemical Corp., for supplying crudes containing propionin.

Interference between lymphocytic choriomeningitis and Rauscher leukemia in mice.

In a series of 10 independent experiments, performed on 314 adult and 105 newborn BALB/c mice, preinoculation with lymphocytic choriomeningitis (LCM) virus induced a significant protection against the leukemic disease due to infection with Rauscher virus. This protection was evidenced by lower incidence of leukemia, marked prolongation of incubation period, and delayed mortality. A significant proportion of LCM-pretreated animals remained free of leukemia symptoms for their lifespan. The protection was effective in adult mice when LCM virus was inoculated 1 to 5 days before Rauscher virus, being most effective when done 1 or 2 days in advance. In newborn mice the shielding effect of LCM infection persisted longer. It is concluded that concomitant infection with LCM and Rauscher viruses represents a working model demonstrating an efficient and sparing interference by a nonlethal and even asymptomatic viral infection with the development of usually fatal malignancy induced by an oncogenic virus.