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.

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Arenaviruses

10.1093/med/9780198570028.003.0032 ◽

2011 ◽

Author(s):

Colin R. Howard

Keyword(s):

South America ◽

Lassa Fever ◽

Lymphocytic Choriomeningitis ◽

T Cell Response ◽

Cytotoxic T Cell ◽

Virus Infections ◽

Virus Family ◽

Adult Mice ◽

Persistent Virus ◽

Haemorrhagic Disease

There are few groups of viral zoonoses that have attracted such widespread publicity as the arenaviruses, particularly during the 1960’s and 1970’s when Lassa emerged as a major cause of haemorrhagic disease in West Africa. More than any other zoonoses, members of the family are used extensively for the study of virus-host relationships. Thus the study of this unique group of enveloped, single-stranded RNA viruses has been pursued for two quite separate reasons. First, lymphocytic choriomeningitis virus (LCM) has been used as a model of persistent virus infections for over half a century; its study has contributed, and continues to contribute, a number of cardinal concepts to our present understanding of immunology. LCM virus remains the prototype of the Arenaviridae and is a common infection of laboratory mice, rats and hamsters. Once thought rare in humans there is now increasing evidence of LCM virus being implicated in renal disease and as a complication in organ transplantation. Second, certain arenaviruses cause severe haemorrhagic diseases in man, notably Lassa fever in Africa, Argentine and Bolivian haemorrhagic fevers in South America, Guaranito infection in Venezuela and Chaparé virus in Bolivia. The latter is a prime example for the need of ever-continuing vigilance for the emergence of new viral diseases; over the past few years several new arenaviruses have been reported as implicated with severe human disease and indeed the number of new arenaviruses discovered since the last edition of this book have increased the size of this virus family significantly.In common with LCM, the natural reservoir of these infections is a limited number of rodent species (Howard, 1986). Although the initial isolates from South America were at first erroneously designated as newly defined arboviruses, there is no evidence to implicate arthropod transmission for any arenavirus. However, similar methods of isolation and the necessity of trapping small animals have meant that the majority of arenaviruses have been isolated by workers in the arbovirus field. A good example of this is Guaranito virus that emerged during investigation of a dengue virus outbreak in Venezuela (Salas et al. 1991).There is an interesting spectrum of pathological processes among these viruses. All the evidence so far available suggests that the morbidity of Lassa fever and South American haemorrhagic fevers due to arenavirus infection results from the direct cytopathic action of these agents. This is in sharp contrast to the immunopathological basis of ‘classic’ lymphocytic choriomeningitis disease seen in adult mice infected with LCM virus and the use of this system for elucidating the phenomenon of H2-restriction of the host cytotoxic T cell response (Zinkernagel and Doherty 1979). Despite the utility of this experimental model for dissecting the nature of the immune response to virus infection and the growing interest in arenaviruses of rodents, there remains much to be done to elucidate the pathogenesis of these infections in humans.

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Antiviral cytotoxic T cell response induced by in vivo priming with a free synthetic peptide.

Journal of Experimental Medicine ◽

10.1084/jem.171.5.1815 ◽

1990 ◽

Vol 171 (5) ◽

pp. 1815-1820 ◽

Cited By ~ 132

Author(s):

P Aichele ◽

H Hengartner ◽

R M Zinkernagel ◽

M Schulz

Keyword(s):

T Cell ◽

Cell Response ◽

Lymphocytic Choriomeningitis ◽

Effector T Cells ◽

T Cell Response ◽

Class I ◽

Cytotoxic T Cell ◽

Effector T Cell

Induction in vivo of antiviral cytotoxic T cell response was achieved in a MHC class I-dependent fashion by immunizing mice three times with a free unmodified 15-mer peptide derived from the nucleoprotein of lymphocytic choriomeningitis virus in IFA. The effector T cells are CD8+, restricted to the class I Ld allele of the analyzed mouse strain, and are specific both at the level of secondary restimulation in vitro and at the effector T cell level. These results suggest that cocktails of viral peptides may be used as antiviral T cell vaccines.

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Antivirally protective cytotoxic T cell memory to lymphocytic choriomeningitis virus is governed by persisting antigen.

Journal of Experimental Medicine ◽

10.1084/jem.176.5.1273 ◽

1992 ◽

Vol 176 (5) ◽

pp. 1273-1281 ◽

Cited By ~ 135

Author(s):

S Oehen ◽

H Waldner ◽

T M Kündig ◽

H Hengartner ◽

R M Zinkernagel

Keyword(s):

T Cell ◽

Lymphocytic Choriomeningitis ◽

Lymphocytic Choriomeningitis Virus ◽

T Cell Response ◽

Cytotoxic T Cell ◽

Protective Capacity ◽

Activated T Cells ◽

Recombinant Vaccinia ◽

Activated State

The basis of antiviral protection by memory cytotoxic T lymphocytes (CTL) was investigated in vivo and in vitro using lymphocytic choriomeningitis virus (LCMV) and recombinant vaccinia viruses expressing the LCMV-glycoprotein (vacc-GP) or -nucleoprotein (vacc-NP). The widely replicating LCMV with a tendency to persist induced solid long-term protective memory. The poorly replicating vaccinia recombinant viruses revealed in the vaccinated host that the antiviral capacity of the secondary immune T cell response and the protection against lethal LCM was dependent upon the immunizing antigen and its dose. Protection against lethal choriomeningitis is less sensitive to assess memory because it depends upon high levels of CTL precursors (p) and/or on an activated state of memory CTL. In contrast, antiviral protection measured as the capacity of the primed host to reduce virus titers after challenge infection correlated with elevated CTLp frequencies after immunization with live LCMV or recombinant vaccinia virus-expressing the major LCMV epitope. CTLp frequencies were constantly increased up to 70 d for LCMV immune mice, but rapidly decreased a few weeks after immunization with low dose vaccinia recombinant virus. For example, mice primed with 2 x 10(6) plaque-forming units (PFU) of vacc-NP, or 2 x 10(2) PFU, or 2 x 10(6) PFU of vacc-GP were antivirally protected on day 7 but not after day 30 when CTLp could not be measured any longer in vitro. However, greater priming doses of vacc-NP (10(4) or 2 x 10(6) PFU) as well as LCMV (2 x 10(2) PFU) induced elevated levels of CTLp and antiviral protection for 60 d or longer. Adoptive transfer experiments of immune spleen cells into syngeneic recipients without addition of antigen demonstrated that maintenance of the antiviral protective capacity of the transferred cells depended on the presence of viral antigen. Thus, antiviral protection by memory CTL may be rather short-lived since it is based on activated T cells continuously stimulated by persisting antigen. This is best achieved by high immunizing antigen doses yielded either by widely replicating viruses or high doses of poorly replicating recombinant vaccines.

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Mechanisms of suppression of cytotoxic T-cell responses in murine lymphocytic choriomeningitis virus infection.

Journal of Experimental Medicine ◽

10.1084/jem.145.5.1131 ◽

1977 ◽

Vol 145 (5) ◽

pp. 1131-1143 ◽

Cited By ~ 24

Author(s):

M B Dunlop ◽

R V Blanden

Keyword(s):

T Cells ◽

T Cell ◽

Virus Infection ◽

Lymphocytic Choriomeningitis ◽

T Cell Response ◽

Cytotoxic T Cell ◽

Lymphoid Tissues ◽

High Dose ◽

High Level

The cytotoxic T-cell response to lymphocytic choriomeningitis (LCM) virus infection was suppressed either in vitro or in vivo by addition of a high level of syngeneic virus-infected cells or syngeneic cells from congenital LCM virus carriers to the environment of the responding cells. This effect was not duplicated by formaldehyde-fixed carrier cells, nor could it be accounted for by 'cold' target competition by carrier cells at the level of the cytotoxicity assay. Conversely, suppression was produced in vivo by water-lysed, ultrasonically treated carrier cell suspensions, or by a large dose of LCM virus equivalent to that contained in the carrier cells. Thus a high level of infectious virus was a common factor in all observed examples of suppression. Based upon this, the following hypothesis, a form of 'forbidden clone deletion,' was proposed to account for virus-specific cytotoxic T-cell tolerance in LCM virus congenital carriers, or in high dose suppression. A high level of virus in lymphoid tissues, while not cytopathic per se, may result in infection of all or most T cells; this then may lead to deletion either via 'suicide' of individual, infected, cytotoxic T cells with receptors specific for virus-induced antigenic patterns on their own surface membranes, or by mutual lysis of two adjacent T cells.

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Induction of a primary cytotoxic T cell response to lymphocytic choriomeningitis virus-infected cells in vitro

Cellular Immunology ◽

10.1016/s0008-8749(77)80019-1 ◽

1977 ◽

Vol 28 (1) ◽

pp. 190-197 ◽

Cited By ~ 8

Author(s):

Malcolm B.C. Dunlop ◽

Robert V. Blanden

Keyword(s):

T Cell ◽

Cell Response ◽

Lymphocytic Choriomeningitis ◽

Lymphocytic Choriomeningitis Virus ◽

T Cell Response ◽

Cytotoxic T Cell ◽

Infected Cells

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Molecular and Functional Dissection of the H-2Db-Restricted Subdominant Cytotoxic T-Cell Response to Lymphocytic Choriomeningitis Virus

Journal of Virology ◽

10.1128/jvi.75.5.2468-2471.2001 ◽

2001 ◽

Vol 75 (5) ◽

pp. 2468-2471 ◽

Cited By ~ 4

Author(s):

Denis Hudrisier ◽

Joëlle Riond ◽

Jean Edouard Gairin

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cytotoxic T Lymphocyte ◽

Lymphocytic Choriomeningitis ◽

Lymphocytic Choriomeningitis Virus ◽

T Cell Response ◽

Cytotoxic T Cell ◽

Ctl Response ◽

Histocompatibility Complex

ABSTRACT Infection of H-2 b mice with lymphocytic choriomeningitis virus (LCMV) generates an H-2Db-restricted cytotoxic T-lymphocyte (CTL) response whose subdominant component is directed against the GP92-101 (CSANNSHHYI) epitope. The aim of this study was to identify the functional parameters accounting for this subdominance. We found that the two naturally occurring (genetically encoded and posttranslationally modified) forms of LCMV GP92-101 were immunogenic, did not act as T-cell antagonists, and bound efficiently to but were unable to form stable complexes with H-2Db, a crucial factor for immunodominance. Thus, the H-2Db-restricted subdominant CTL response to LCMV resulted not from altered T-cell activation but from impaired major histocompatibility complex presentation properties.

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Neonatal tolerance of major histocompatibility complex antigens alters Ir gene control of the cytotoxic T cell response to vaccinia virus.

Journal of Experimental Medicine ◽

10.1084/jem.157.4.1324 ◽

1983 ◽

Vol 157 (4) ◽

pp. 1324-1338 ◽

Cited By ~ 25

Author(s):

A Müllbacher ◽

R V Blanden ◽

M Brenan

Keyword(s):

Cell Response ◽

Feedback Inhibition ◽

Lymphocytic Choriomeningitis ◽

T Cell Response ◽

F1 Hybrids ◽

Cytotoxic T Cell ◽

Cell Responses ◽

Self Tolerance ◽

Mixed Chimeras

The K region of H-2 controls the Tc cell response to vaccinia-Db. The Kb, Kd, and Kq alleles allow good Tc cell responses against vaccinia-Db. In contrast, the presence of Kk in H-2 recombinants 2R (Kk,Db) and 4R (Kk,Db) or in F1 hybrids greatly reduces the anti-vaccinia-Db response. The defect does not lie in antigen presentation, as infected 4R cells can stimulate anti-vaccinia-Db Tc cells in vitro. Furthermore, nonresponder animals possess Tc cell precursors for vaccinia-Db, as transfer of F1 nonresponder spleen cells into infected, lethally irradiated responder recipients allowed generation of anti-vaccinia-Db effector Tc cells. Secondary responses to vaccinia-Db can also be obtained in vitro from T cells of 4R animals. Feedback inhibition was excluded in experiments with mixed chimeras in which Kk and Db were expressed on separate cell populations. Neonatal tolerance of B10 animals to Kk suppressed the anti-vaccinia-Db response but did not affect anti-vaccinia-Kb, anti-lymphocytic choriomeningitis virus, or anti-H-2d responses. In cold target competition experiments, H-2k competitors inhibited vaccinia-Db-specific target cell lysis by Tc cells, which suggests that anti-vaccinia-Db and anti-H-2Kk Tc cells may cross-react. Therefore, we propose that the suppressive influence of Kk on anti-vaccinia-Db Tc cell responses is a consequence of self-tolerance and that suppression of anti-Kk Tc cells results in cross-reactive suppression of anti-vaccinia-Db Tc cells.

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An Evaluation of a Plasma Fractionation System

Thrombosis and Haemostasis ◽

10.1055/s-0038-1654486 ◽

1960 ◽

Vol 4 (01) ◽

pp. 031-044

Author(s):

George Y. Shinowara ◽

E. Mary Ruth

Keyword(s):

Biological Activity ◽

Ionic Strength ◽

Plasma Proteins ◽

High Concentration ◽

Significant Evidence ◽

Native Proteins ◽

Mobility Data ◽

Fractionation Procedure ◽

The Individual ◽

Low Ionic Strength

SummaryFour primary fractions comprising at least 97 per cent of the plasma proteins have been critically appraised for evidence of denaturation arising from a low temperature—low ionic strength fractionation system. The results in addition to those referable to the recovery of mass and biological activity include the following: The high solubilities of these fractions at pH 7.3 and low ionic strengths; the compatibility of the electrophoretic and ultracentrifugal data of the individual fractions with those of the original plasma; and the recovery of hemoglobin, not hematin, in fraction III obtained from specimens contaminated with this pigment. However, the most significant evidence for minimum alterations of native proteins was that the S20, w and the electrophoretic mobility data on the physically recombined fractions were identical to those found on whole plasma.The fractionation procedure examined here quantitatively isolates fibrinogen, prothrombin and antithrombin in primary fractions. Results have been obtained demonstrating its significance in other biological systems. These include the following: The finding of 5 S20, w classes in the 4 primary fractions; the occurrence of more than 90 per cent of the plasma gamma globulins in fraction III; the 98 per cent pure albumin in fraction IV; and, finally, the high concentration of beta lipoproteins in fraction II.

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