Gender influences herpes simplex virus type 1 infection in normal and gamma interferon-mutant mice

Gender influences the incidence and severity of some bacterial and viral infections and autoimmune diseases in animal models and humans. To determine a gender-based difference, comparisons were made between male and female mice inoculated with herpes simplex virus type 1 (HSV-1) by the corneal route. Mortality was higher in the male mice of the three strains tested: 129/Sv//Ev wild type, gamma interferon (IFN-gamma) knockout (GKO), and IFN-gamma receptor knockout (RGKO). Similarly, in vivo HSV-1 reactivation occurred more commonly in male mice, but the male-female difference in reactivation was restricted to the two knockout strains and was not seen in the 129/Sv//Ev control. Comparison among male mice of the three strains showed a higher mortality of the RGKO mice and a higher reactivation rate of the GKO and RGKO mice than of the 129/Sv//Ev males. In contrast, female RGKO and GKO mice did not differ from female 129/Sv//Ev controls in either mortality or reactivation. HSV-1 periocular and eyelid disease was also more severe in male and dihydrotestosterone (DHT)-treated female mice than in control female mice. These results show a consistent gender difference in HSV-1 infection, with a worse outcome in male mice. In addition, the results comparing GKO and RGKO mice to controls show differences only in male mice, suggesting that some effects of IFN-gamma, a key immunoregulatory molecule, are gender specific.     

Role for gamma interferon in control of herpes simplex virus type 1 reactivation

Observation of chronic inflammatory cells and associated high-level gamma interferon (IFN-gamma) production in ganglia during herpes simplex type 1 (HSV-1) latent infection in mice (E. M. Cantin, D. R. Hinton, J. Chen, and H. Openshaw, J. Virol. 69:4898-4905, 1995) prompted studies to determine a role of IFN-gamma in maintaining latency. Mice lacking IFN-gamma (GKO mice) or the IFN-gamma receptor (RGKO mice) were inoculated with HSV-1, and the course of the infection was compared with that in IFN-gamma-competent mice with the same genetic background (129/Sv//Ev mice). A time course study showed no significant difference in trigeminal ganglionic viral titers or the timing of establishment of latency. Spontaneous reactivation resulting in infectious virus in the ganglion did not occur during latency in any of the mice. However, 24 h after the application of hyperthermic stress to mice, HSV-1 antigens were detected in multiple neurons in the null mutant mice but in only a single neuron in the 129/Sv//Ev control mice. Mononuclear inflammatory cells clustered tightly around these reactivating neurons, and by 48 h, immunostaining was present in satellite cells as well. The incidence of hyperthermia-induced reactivation as determined by recovery of infectious virus from ganglia was significantly higher in the null mutant than in control mice: 11% in 129/Sv//Ev controls, 50% in GKO mice (P = 0.0002), and 33% in RGKO mice (P = 0.03). We concluded that IFN-gamma is not involved in the induction of reactivation but rather contributes to rapid suppression of HSV once it is reactivated.     

Alpha/beta interferon protects adult mice from fatal Sindbis virus infection and is an important determinant of cell and tissue tropism

Infection of adult 129 Sv/Ev mice with consensus Sindbis virus strain TR339 is subclinical due to an inherent restriction in early virus replication and viremic dissemination. By comparing the pathogenesis of TR339 in 129 Sv/Ev mice and alpha/beta interferon receptor null (IFN-alpha/betaR(-/-)) mice, we have assessed the contribution of IFN-alpha/beta in restricting virus replication and spread and in determining cell and tissue tropism. In adult 129 Sv/Ev mice, subcutaneous inoculation with 100 PFU of TR339 led to extremely low-level virus replication and viremia, with clearance under way by 96 h postinoculation (p.i.). In striking contrast, adult IFN-alpha/betaR(-/-) mice inoculated subcutaneously with 100 PFU of TR339 succumbed to the infection within 84 h. By 24 h p.i. a high-titer serum viremia had seeded infectious virus systemically, coincident with the systemic induction of the proinflammatory cytokines interleukin-12 (IL-12) p40, IFN-gamma, tumor necrosis factor alpha, and IL-6. Replicating virus was located in macrophage-dendritic cell (DC)-like cells at 24 h p.i. in the draining lymph node and in the splenic marginal zone. By 72 h p.i. virus replication was widespread in macrophage-DC-like cells in the spleen, liver, lung, thymus, and kidney and in fibroblast-connective tissue and periosteum, with sporadic neuroinvasion. IFN-alpha/beta-mediated restriction of TR339 infection was mimicked in vitro in peritoneal exudate cells from 129 Sv/Ev versus IFN-alpha/betaR(-/-) mice. Thus, IFN-alpha/beta protects the normal adult host from viral infection by rapidly conferring an antiviral state on otherwise permissive cell types, both locally and systemically. Ablation of the IFN-alpha/beta system alters the apparent cell and tissue tropism of the virus and renders macrophage-DC-lineage cells permissive to infection.     

Gamma interferon impedes the establishment of herpes simplex virus type 1 latent infection but has no impact on its maintenance or reactivation in mice

Murine models of gamma interferon (IFN-gamma) deficiency demonstrate the role of this cytokine in attenuating acute herpes simplex virus (HSV) disease; however, the effect of IFN-gamma on the establishment and maintenance of neuronal latency and viral reactivation is not known. Using the IFN-gamma knockout (GKO) model of IFN-gamma deficiency and sensitive quantitative PCR methods, we show that IFN-gamma significantly reduces the ganglion content of latent HSV-1 in BALB/c mice, which in turn delays viral time to reactivation following UV irradiation. Similar effects were not seen in the C57BL/6 strain. These results indicate that IFN-gamma significantly attenuates latent HSV infection in the mouse model of ocular infection but has no impact on the maintenance of latency or virus reactivation.     

Yellow fever virus encephalitis: properties of the brain-associated T-cell response during virus clearance in normal and gamma interferon-deficient mice and requirement for CD4+ lymphocytes

Viral encephalitis caused by neuroadapted yellow fever 17D virus (PYF) was studied in parental and gamma interferon (IFN-gamma)-deficient (IFN-gamma knockout [GKO]) C57BL/6 mice. The T-cell responses which enter the brain during acute fatal encephalitis of nonimmunized mice, as well as nonfatal encephalitis of immunized mice, were characterized for relative proportions of CD4+ and CD8+ cells, their proliferative responses, and antigen-specific expression of cytokines during stimulation in vitro. Unimmunized mice accumulated only low levels of T cells within the brain during fatal disease, whereas the brains of immunized mice contained higher levels of both T-cell subsets in response to challenge, with CD8+ cells increased relative to the CD4+ subset. The presence of T cells correlated with the time at which virus was cleared from the central nervous system in both parental and GKO mice. Lymphocytes isolated from the brains of challenged immunized mice failed to proliferate in vitro in response to T-cell mitogens or viral antigens; however, IFN-gamma, interleukin 4 (IL-4), and, to a lesser extent, IL-2 were detectable after stimulation. The levels of IFN-gamma, but not IL-2 or IL-4, were augmented in response to viral antigen, and this specificity was detectable in the CD4+ compartment. When tested for the ability to survive both immunization and challenge with PYF virus, GKO and CD8 knockout mice did not differ from parental mice (80 to 85% survival), although GKO mice exhibited a defect in virus clearance. In contrast, CD4 knockout and Igh-6 mice were unable to resist challenge. The data implicate antibody in conjunction with CD4+ lymphocytes bearing a Th1 phenotype as the critical factors involved in virus clearance in this model.     

The in vivo antiviral activity of interleukin-12 is mediated by gamma interferon.

The injection of 20 ng of mouse interleukin-12 (IL-12) protects mice from a lethal infection with encephalomyocarditis virus. In vitro, an anti-gamma interferon (anti-IFN-gamma) monoclonal antibody but not an anti-IL-12 monoclonal antibody neutralizes the antiviral activity present in the supernatants of splenocytes stimulated with IL-12. Finally, IL-12 fails to protect 129 Sv/Ev IFN-gamma R0/0 mice against encephalomyocarditis virus infection. These results demonstrate that IL-12 exerts its antiviral activity through the induction of endogenous IFN-gamma.     

Osteopenia in Sparc (osteonectin)-deficient mice: characterization of phenotypic determinants of femoral strength and changes in gene expression.

Sparc null mutants have been generated independently via targeted mutations in exons 4 and 6. Previous studies have identified low-turnover osteopenia in the 129Sv/C57BL/6 exon 4 knockout. Since both Sparc null mutations result in complete absence of Sparc protein, similar phenotypic outcomes are likely. However, genetic background (strain) and/or linkage disequilibrium effects can influence phenotype. Different inactivating mutations should be tested in various mouse strains; similar phenotypic outcomes can then confidently be assigned to the mutated gene. We have evaluated the bone phenotype in the 129Sv/EvSparc(tm1cam) exon 6 knockout at 4 and 9 mo, using physical measurement, mechanical strength tests, and DXA scanning. We have also quantified bone marrow adiposity and circulating leptin levels to assess adipose tissue metabolism. 129Sv/EvSparc(tm1cam) null mice show decreased bone mineral density and bone mineral content and increased mechanical fragility of bone, in line with previous studies. Differences were also noted. Increased body weight and levels of bone marrow adiposity but decreased circulating leptin concentrations were identified at 4, but not 9 mo, and 129Sv/EvSparc(tm1cam) null mice also had shorter femurs. Molecular phenotyping was carried out using mouse HGMP NIA microarrays with cortical femur samples at various ages, using semiquantitative RT-PCR validation. We identified 429 genes highly expressed in normal bone. Six genes (Sparc, Zfp162, Bysl, E2F4, two ESTs) are differentially regulated in 129Sv/EvSparc(tm1cam) cortical femur vs. 129Sv/Ev controls. We confirm low-turnover osteopenia as a feature of the Sparc null phenotype, identifying the usefulness of this mouse as a model for human osteoporosis.     

Viral Load and a Locus on Chromosome 11 Affect the Late Clinical Disease Caused by Theiler’s Virus

Theiler's virus causes a persistent infection and a demyelinating disease of mice which is a model for multiple sclerosis. Susceptibility to viral persistence maps to several loci, including the interferon gamma locus. Inactivating the gene coding for the interferon gamma receptor makes 129/Sv mice susceptible to persistent infection and clinical disease, whereas inactivating the interferon gamma gene makes C57BL/6 mice susceptible to persistent infection but not to clinical disease. This difference in phenotype is due to the difference in genetic background. Clinical disease depends on high viral load and Tmevd5, a locus on chromosome 11. These results have consequences for the identification of viruses which might be implicated in multiple sclerosis.     

Effect of a combination therapy between IL-12 and soluble IL-4 receptor (sIL-4R) on Candida albicans and herpes simplex virus type I infections in thermally injured mice

The effectiveness of a combination using IL-12 and soluble IL-4 receptor (sIL-4R) to treat severe infections of herpes simplex virus type 1 (HSV-1) and Candida albicans in thermally injured mice was investigated. Although sIL-4R decreased burn-associated type 2 T-cell responses, the effect of sIL-4R was minimal on the morbidity and mortality of thermally injured mice exposed to 250 times LD50 of HSV-1 or 10 times LD50 of C. albicans. Compared with 100% mortality in control mice, mortality for HSV-1 and C. albicans was 40 and 20%, respectively, in thermally injured mice that received IL-12 and sIL-4R in combination. After stimulation with anti-CD3 monoclonal antibody, splenic T cells from thermally injured mice exposed to large amounts of HSV-1 or C. albicans did not produce gamma interferon (IFN-gamma) into their culture fluids. However, IFN-gamma was produced by splenic T cells from thermally injured and infected mice treated with IL-12 and sIL-4R in combination. These results suggest that therapeutic treatment with a combination of IL-12 and sIL-4R may be effective by inducing type 1 T-cell responses in thermally injured mice exposed to large amounts of HSV-1 or C. albicans.     

Ectopic expression of gamma interferon in the eye protects transgenic mice from intraocular herpes simplex virus type 1 infections.

Transgenic (rho gamma) mice provide a model for studying the influence of gamma interferon (IFN-gamma) produced in the eye on ocular and cerebral viral infection. To establish this model, we injected BALB/c- and C57BL/6-derived transgenic and nontransgenic mice of different ages intravitreally with herpes simplex virus type 1 (HSV-1) strain F. Eye and brain tissues of these mice were assessed for pathological and immunocytochemical changes. HSV-1 infection induced severe retinitis of the injected eyes and infection of the brain in all mice. In transgenic mice inoculated with HSV-1, the left, nontreated eyes were protected from retinitis, whereas nontransgenic mice developed bilateral retinitis. Additional intravitreal injection of IFN-gamma with the virus protected the noninoculated eyes of nontransgenic mice. Three-week-old nontransgenic mice died from HSV-1 infection, whereas transgenic mice of the same age and nontransgenic mice intravitreally treated with IFN-gamma survived. Ocular IFN-gamma production increased the extent of inflammation in transgenic mice but did not have a significant influence on the growth of HSV-1 until day 3 after inoculation and did not influence the neuroinvasion of this virus. Thus, the effects of IFN-gamma were not caused by an early block of viral replication. Possible mechanisms of IFN-gamma action include activation of the immune response, alteration of the properties of the virus, and direct protection of neurons.     

A role for IFN-gamma from antigen-specific CD8+ T cells in protective immunity to Listeria monocytogenes

Whether IFN-gamma contributes to the per-cell protective capacity of memory CD8(+) T cells against Listeria monocytogenes (LM) has not been formally tested. In this study, we generated LM Ag-specific memory CD8(+) T cells via immunization of wild-type (WT) and IFN-gamma-deficient (gamma knockout (GKO)) mice with LM peptide-coated dendritic cells and compared them phenotypically and functionally. Immunization of WT and GKO mice resulted in memory CD8(+) T cells that were similar in number, functional avidity, TCR repertoire use, and memory phenotype. The protective capacity of memory CD8(+) T cells from immunized WT and GKO mice was evaluated after adoptive transfer of equal numbers of WT or GKO cells into naive BALB/c mice followed by LM challenge. The adoptively transferred CD8(+) T cells from GKO donors exhibited a decreased ability to reduce bacterial numbers in the organs of recipient mice when compared with an equivalent number of Ag-matched WT CD8(+) T cells. This deficiency was most evident early (day 3) after infection if a relatively low infectious dose was used; however, transferring fewer memory CD8(+) T cells or increasing the LM challenge dose revealed a more pronounced defect in protective immunity mediated by the CD8(+) T cells from GKO mice. Our studies identified a decrease in Ag-specific target cell lysis in vivo by CD8(+) T cells from GKO mice as the mechanism for the decreased protective immunity after LM challenge. Further studies suggest that the lack of IFN-gamma production by the Ag-specific CD8 T cells themselves diminishes target cell sensitivity to cytolysis, thereby reducing the lytic potency of IFN-gamma-deficient LM-specific memory CD8(+) T cells.     

Differential antigen burden modulates the gamma interferon but not the immunoglobulin response in mice that vary in susceptibility to Sendai virus pneumonia.

Sendai virus, a paramyxovirus which causes murine pneumonia, grew to approximately 10-fold higher titers and was cleared less rapidly from the lungs of 129/J (129) than H-2b-compatible C57BL/6J (B6) mice. The more susceptible 129 mice also made higher titers of gamma interferon (IFN-gamma) and immunoglobulin G2a (IgG2a) virus-specific antibody. Analysis with acutely irradiated (950 rads) mice and immunologically reconstituted bone marrow (BM) radiation chimeras indicated that the enhanced virus growth was a function of the radiation-resistant respiratory epithelium. Prolonged exposure to more virus in turn influenced the magnitude of IFN-gamma production, most of which was made by CD4+ T lymphocytes. Somewhat surprisingly, however, the 129 pattern of a higher virus-specific serum Ig response skewed towards IgG2a mapped to the reconstituting BM. Thus, the characteristics of the humoral response are at least partly dissociated from both the antigen load, resulting from viral replication, and the level of IFN-gamma production. Further analysis of double chimeras (B6+129 BM-->B6 recipients) confirmed that the divergent humoral immune response to Sendai virus in B6 and 129 mice is largely determined by the inherent characteristics of the lymphoid cells.     

Role of IL-6 in the induction of hepatic metallothionein in mice after partial hepatectomy

Metallothioneins (MT) are induced upon partial hepatectomy (PH), possibly mediated by various cytokines. In the present study, we studied cytokine-dependent MT synthesis in partially hepatectomized IL-6 gene knock-out (GKO) mice in the remaining lobe of the liver. We focused on IL-6, TNFalpha and IL-1beta, the major cytokines thought to be involved in MT synthesis. The IL-6 GKO mice and B6J129Sv (wild-type control) mice were subjected to 70% PH or laparotomy. We found that MT was significantly decreased in IL-6 GKO mice, although PH induced hepatic MT in both strains of mice. Laparotomy induced MT in the liver of wild-type mice but not in IL-6 GKO mice. Pretreatment of IL-6 GKO mice with rIL-6 (5 microg/mouse) restored hepatic MT synthesis. Serum IL-6 level in wild-type mice was maximal at 6 h after surgery and decreased thereafter. Serum IL-1beta was the same in both strains of mice. Serum TNFalpha basal level in IL-6 GKO mice was higher than in wild-type mice. PH caused an increase in serum TNFalpha level in both strains of mice, and it was two times higher in IL-6 GKO mice than in wild-type mice at 18 h after surgery. We conclude that IL-6 plays a predominant role in hepatic MT synthesis after PH, but that IL-6 GKO mice still reserve the capacity to synthesize MT by an as yet unidentified mechanism.     

Clearance of herpes simplex virus type 2 by CD8+ T cells requires gamma interferon and either perforin- or Fas-mediated cytolytic mechanisms

The T-cell-mediated resolution of herpes simplex virus type 2 (HSV-2) genital infections is not fully understood. In these studies, the mechanisms by which CD8+ T cells clear virus from the genital epithelium were examined. Ovalbumin (OVA)-specific CD8+ T cells from OT-I transgenic mice cleared a thymidine kinase-deficient, ovalbumin-expressing HSV-2 virus (HSV-2 tk- OVA) from the genital epithelium of recipient mice, and clearance was abrogated by in vivo neutralization of gamma interferon (IFN-gamma). Further, CD8+ OT-I T cells deficient in IFN-gamma were unable to clear HSV-2 tk- OVA from the vaginal epithelium. The requirement for cytolytic mechanisms in HSV-2 tk- OVA clearance was tested in radiation chimeras by adoptive transfer of wild-type or perforin-deficient OT-I T cells to irradiated Fas-defective or wild-type recipients. Although a dramatic decrease in viral load was observed early after challenge with HSV-2 tk- OVA, full resolution of the infection was not achieved in recipients lacking both perforin- and Fas-mediated cytolytic pathways. These results suggest that IFN-gamma was responsible for an early rapid decrease in HSV-2 virus titer. However, either perforin- or Fas-mediated cytolytic mechanisms were required to achieve complete clearance of HSV-2 from the genital epithelium.     

The role of IFN-gamma and Toll-like receptors in nephropathy induced by Toxoplasma gondii infection

The pathologic links between Toxoplasma gondii infections and renal diseases have not yet been established. Gamma interferon (IFN-gamma) and Toll-like receptors (TLRs) are involved in the host defense mechanism against T. gondii infection. The role of IFN-gamma and TLRs in renal function of T. gondii -infected mice was studied using wild type (WT), TLR2-deficient and TLR4-deficient mice perorally infected with cysts of an avirulent cyst-forming Fukaya strain of T. gondii. T. gondii was abundant in kidneys in IFN-gamma KO (GKO) mice as determined by a quantitative competitive-polymerase chain reaction (QC-PCR). But, T. gondii was not detected in kidneys in WT, TLR2-deficient and TLR4-deficient mice. Interestingly, renal function of TLR2-deficient and TLR4-deficient mice was damaged as evaluated by serum creatinine, serum blood urea nitrogen (BUN), and urine albumin/creatinine ratio (ACR), whereas renal function of GKO and WT mice was not damaged. Histopathology of TLR2-deficient mice exhibited glomerular and extracellular matrix swelling with advancing glomerular tissue proliferation, thickened Bowman's capsules and vacuolization of tubules. Renal immunofluorescence study of T. gondii -infected TLR2-deficient mice displayed positive staining of the glomerular basement membrane, mesangial areas and peritubular capillaries. The damage of kidney from TLR4-deficient mice was less severe compared to TLR2-deficient mice, and histopathological damage of kidney was not observed in WT and GKO mice. These results indicate that TLR2, but not IFN-gamma, plays a role in the protection of the renal function against T. gondii infection.     

Prolonged exposure to progesterone prevents induction of protective mucosal responses following intravaginal immunization with attenuated herpes simplex virus type 2

Depo-Provera (Depo) is a long-acting progestational formulation that is a popular form of contraception for women. In animal models of sexually transmitted diseases, it is used to facilitate infection. Here we report that treatment with Depo, in a mouse model of genital herpes simplex virus type 2 (HSV-2), altered immune responses depending on the length of time that animals were exposed to Depo prior to immunization. Mice immunized intravaginally (i.vag.) with an attenuated strain (TK(-)) of HSV-2 following longer (15 days) exposure to Depo (Depo 15 group) failed to show protection when challenged with wild-type HSV-2. In contrast, mice that were immunized shortly after Depo treatment (5 days; Depo 5 group) were fully protected and showed no genital pathology after HSV-2 challenge. High viral titers were detected in the vaginal washes of the Depo 15 group up to 6 days postchallenge. In contrast, no viral shedding was observed beyond day 3 postchallenge in the Depo 5 group. Following i.vag. TK(-) immunization, high levels of gamma interferon (IFN-gamma) were detected locally in vaginal washes of the Depo 5 group but not the Depo 15 group. After HSV-2 challenge, an early peak of IFN-gamma in the Depo 5 group coincided with clearance of the virus. In Depo 15 animals IFN-gamma was present throughout the 6 days postinfection. HSV-2-specific T-cell cytokine responses measured in the lymph node cells of Depo 5 TK(-)-immunized mice indicated a significantly higher Th1 response than that of Depo 15 TK(-)-immunized mice. The protection after HSV-2 challenge in the Depo 5 group correlated with increased local HSV-2 glycoprotein B (gB)-specific immunoglobulin G (IgG) and IgA responses seen in the vaginal secretions. The Depo 15 group had poor gB-specific antibody responses in the genital tract after HSV-2 challenge. These results indicate that longer exposure to Depo leads to poor innate and adaptive immune responses to HSV-2 that fail to protect mice from subsequent genital challenges.     

Neutrophils Aid in Protection of the Vaginal Mucosae of Immune Mice against Challenge with Herpes Simplex Virus Type 2

Large numbers of polymorphonuclear leukocytes (PMNs) infiltrated the murine vaginal mucosa within 24 h after intravaginal inoculation with an attenuated strain of herpes simplex virus type 2 (HSV-2). The role of these cells in resolution of a primary genital infection and in protection of HSV-immune animals against challenge with a fully virulent HSV-2 strain was investigated. Depletion of greater than 95% of the PMNs at the vaginal mucosal surface prior to intravaginal inoculation with an attenuated HSV-2 strain resulted in significantly higher virus titers on days 3 to 7 but only slightly delayed resolution of the primary genital infection. These results suggest that neutrophils helped control the infection but that other immune mechanisms ultimately cleared the virus. Interestingly, depletion of PMNs from HSV-immune mice prior to challenge with a fully virulent HSV-2 strain resulted in a rise in virus titers to levels comparable to those of nonimmune mice and a more pronounced diminution of virus clearance from the vaginal mucosa despite the presence of HSV-specific B and T cells. Levels of gamma interferon (IFN-gamma) and HSV-specific antibody were comparable in neutrophil-depleted and control-treated immune mice following HSV-2 challenge, suggesting that RB6-8C5 treatment did not impair T- and B-cell function. Therefore, these results suggest that neutrophils play a role in limiting and clearing HSV-2 vaginal infections and that they are, in association with HSV-specific B and T cells, an important component in immune protection of the vaginal mucosa.     

Role of interleukin-4 (IL-4), IL-12, and gamma interferon in primary and vaccine-primed immune responses to Friend retrovirus infection

The immunological resistance of a host to viral infections may be strongly influenced by cytokines such as interleukin-12 (IL-12) and gamma interferon (IFN-gamma), which promote T helper type 1 responses, and IL-4, which promotes T helper type 2 responses. We studied the role of these cytokines during primary and secondary immune responses against Friend retrovirus infections in mice. IL-4- and IL-12-deficient mice were comparable to wild-type B6 mice in the ability to control acute and persistent Friend virus infections. In contrast, more than one-third of the IFN-gamma-deficient mice were unable to maintain long-term control of Friend virus and developed gross splenomegaly with high virus loads. Immunization with a live attenuated vaccine virus prior to challenge protected all three types of cytokine-deficient mice from viremia and high levels of spleen virus despite the finding that the vaccinated IFN-gamma-deficient mice were unable to class switch from immunoglobulin M (IgM) to IgG virus-neutralizing antibodies. The results indicate that IFN-gamma plays an important role during primary immune responses against Friend virus but is dispensable during vaccine-primed secondary responses.     

Mouse strain differences in autonomic responses to stress

In humans, anxiety disorders are often accompanied by an overactive autonomic nervous system, reflected in increased body temperature (BT) and heart rate (HR). In rodents, comparable effects are found after exposure to stress. These autonomic parameters can give important information on stress and anxiety responses in mice. In the present experiments, stress reactivity of three frequently used mouse strains [129 Sv/Ev, Swiss Webster (SW) and C57 BL/6] was assessed using their autonomic stress responses. BT, HR and activity were telemetrically measured. Undisturbed circadian rhythms already showed clear differences between the mouse strains. Hereafter, autonomic responses to stressors with increasing intensity were measured. Strain differences were found in magnitude and duration of the stress responses, especially after high-intensity stressors. Generally, C57BL/6 mice showed the largest autonomic response, SW the lowest and the 129Sv/Ev the intermediate response. Interestingly, the observed ranking in autonomic stress response does not match the behavioral stress responsivity of these strains. Finally, sensitivity to the anxiolytic diazepam (0, 1, 2, 4 and 8 mg/kg) was tested using the stress-induced hyperthermia paradigm. Pharmacological sensitivity to diazepam differed between the strains with the 129Sv/Ev being most sensitive. These studies show that simultaneous measurement of behavioral and autonomic parameters under stressful conditions contributes considerably to a better interpretation of anxiety and stress levels in mice.