Host Resistance In Mice Research Articles

Eosinophils are part of the granulocyte response in tuberculosis and promote host resistance in mice.

Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the activities of multiple leukocyte subsets, yet the roles of the different innate effector cells during tuberculosis are incompletely understood. Here we uncover an unexpected association between eosinophils and Mtb infection. In humans, eosinophils are decreased in the blood but enriched in resected human tuberculosis lung lesions and autopsy granulomas. An influx of eosinophils is also evident in infected zebrafish, mice, and nonhuman primate granulomas, where they are functionally activated and degranulate. Importantly, using complementary genetic models of eosinophil deficiency, we demonstrate that in mice, eosinophils are required for optimal pulmonary bacterial control and host survival after Mtb infection. Collectively, our findings uncover an unexpected recruitment of eosinophils to the infected lung tissue and a protective role for these cells in the control of Mtb infection in mice.

Differential anxiety-like behavior, HPA responsiveness, and host-resistance in mice with different circling preference

Relationships between behavioral sidedness and immune responses in previous studies have differed depending on behavior tests and severity of biological stress in mice. It was necessary to elucidate the psychophysiological mediators that connect behavioral sidedness and immune responses. This study investigated interrelationships among anxiety-like behavior, the HPA axis responsiveness, and host-resistance to bacterial infection. Mice that preferred clockwise circling had lower locomotor activities, higher anxiety-like behavior, and faster activation of the HPA axis than mice that preferred counterclockwise circling. A fast activation of the HPA axis was associated with a higher host-resistance to low dose bacterial infection.

CD62L− memory T cells enhance T-cell regeneration after allogeneic stem cell transplantation by eliminating host resistance in mice

A major challenge in allogeneic hematopoietic cell transplantation is how to transfer T-cell immunity without causing graft-versus-host disease (GVHD). Effector memory T cells (CD62L(-)) are a cell subset that can potentially address this challenge because they do not induce GVHD. Here, we investigated how CD62L(-) T cells contributed to phenotypic and functional T-cell reconstitution after transplantation. On transfer into allogeneic recipients, CD62L(-) T cells were activated and expressed multiple cytokines and cytotoxic molecules. CD62L(-) T cells were able to deplete host radioresistant T cells and facilitate hematopoietic engraftment, resulting in enhanced de novo T-cell regeneration. Enhanced functional immune reconstitution was demonstrated in CD62L(-) T-cell recipients using a tumor and an influenza virus challenge model. Even though CD62L(-) T cells are able to respond to alloantigens and deplete host radioresistant immune cells in GVHD recipients, alloreactive CD62L(-) T cells lost the reactivity over time and were eventually tolerant to alloantigens as a result of prolonged antigen exposure, suggesting a mechanism by which CD62L(-) T cells were able to eliminate host resistance without causing GVHD. These data further highlight the unique characteristics of CD62L(-) T cells and their potential applications in clinical hematopoietic cell transplantation.

Innate Immunity and Inflammation in Sepsis: Mechanisms of Suppressed Host Resistance in Mice Treated with Ethanol in a Binge-Drinking Model

Sepsis is a major cause of mortality worldwide. Acute or chonic ethanol exposure typically suppresses innate immunity and inflammation and increases the risk of mortality in patients with sepsis. The study described here was designed to address the mechanism(s) by which acute ethanol exposure alters the course of sepsis. Ethanol administered to mice shortly before Escherichia coli (injected ip to produce sepsis) decreased production of proinflammatory cytokines and chemokines for several hours. Bacteria in the peritoneal cavity decreased over time in control mice and were mostly cleared by 21 h, but in ethanol-treated mice, bacteria increased over time to more than 2 × 10(8) at 21 h. Killing of bacteria in macrophages and neutrophils was apparently compromised by ethanol, as the percentage of these cells that had cleared phagocytosed bacteria increased over time in control mice but not in ethanol-treated mice. The roles of TLR4, MyD88, and myeloperoxidase (MPO) were evaluated using mutant or knockout mice, and these experiments indicated that mice with hyporesponsive TLR4 survived better than those with normal TLR4. Lack of MyD88 or MPO did not significantly alter survival in the presence or absence of ethanol. Ethanol decreased survival in all groups. This indicates that the antimicrobial activities induced though TLR4 are dispensable for survival but contribute to lethality late in the course of sepsis. Thus, the effects of ethanol responsible for lethal outcome in sepsis are not dependent on inhibition of TLR4 signaling, as we and others had previously suspected.

Interleukin‐1 and Host Control of Pulmonary Histoplasmosis

We found that interleukin (IL)-1beta levels were elevated in the lungs of mice infected with Histoplasma capsulatum. Hence, we examined the influence that IL-1beta and IL-1 signaling has on host defenses against pulmonary histoplasmosis. In IL-1 receptor 1 knockout (IL-1R(-/-)) mice challenged intratracheally, fungal recovery on day 7 after infection exceeded that in wild-type (WT) mice. Antibody neutralization of IL-1beta also exacerbated infection. For both groups of mice, the absence of bioactive cytokine led to a failure to control infection in a high proportion of mice. The absence of signaling had a modest effect on host resistance in mice with secondary histoplasmosis. Several perturbations in host defense mechanisms were detected in the lungs of IL-1R(-/-) mice. The number of CD4+ cells was decreased, and transcription of the gene for inducible nitric oxide synthase was depressed transiently. IL-4 and IL-10 levels were elevated in the lungs of IL-1R(-/-) mice, compared with those in the lungs of WT mice. Conversely, interferon- gamma levels were decreased. Thus, IL-1 contributes to host resistance to infection with H. capsulatum.

Host Resistance Model to an Intracellular Pathogen

This unit describes a model for the determination of host resistance in mice using a Gram-positive intracellular bacterium, Listeria monocytogenes (LM), and discusses its broad use in immunotoxicological studies. The provides detailed procedures for LM infection and sample analysis, including preparation and infection of mice with LM, recording of sickness behaviors in infected mice, and determination of viable LM numbers in the tissues from infected animals. The protocol also describes use of serum and tissue homogenates for assessment of cytokines. Additionally, background information on LM and LM infection is provided for better understanding and utilization of this model. The LM infection model is useful for the initial screening of possible modulation of immune responses, particularly innate immunity and type-1 cell-mediated immunity (CMI), by environmental factors, as well as for further investigation of the underlying mechanisms of environmental factor-induced changes in immunity.

Quantifying the relationship between multiple immunological parameters and host resistance: probing the limits of reductionism.

Although reductionist experimental designs are excellent for identifying cells, molecules, or functions involved in resistance to particular microbes or cancer cells, they do not provide an integrated, quantitative view of immune function. In the present study, mice were treated with either dexamethasone (DEX) or cyclosporin A (CyA), and immune function and host resistance were evaluated. Multivariate statistical methods were used to describe the relative importance of a broad range of immunological parameters for host resistance in mice treated with various dosages of DEX. Multiple regression and logistic regression analysis indicated that changes in 24 immunological parameters explained a substantial portion of the changes in resistance to B16F10 tumor cells or streptococcus group B. However, at least 40% of the change in host resistance remained unexplained. DEX at all dosages substantially suppressed numerous relevant immunological parameters, but significantly decreased resistance to Listeria monocytogenes only at the highest dosage. In contrast, CyA substantially decreased resistance to L. monocytogenes at dosages that caused relatively minor suppression of just a few immunological parameters (unfortunately, CyA data and host resistance data for L. monocytogenes were not suitable for multivariate analysis). These results illustrate that mathematical models can be used to explain changes in host resistance on the basis of changes in immune parameters, and that moderate changes in relevant immunological parameters may not produce the types of changes in host resistance expected on the basis of results from reductionist experimental designs.

Pathogen-specific loss of host resistance in mice lacking the IFN-gamma-inducible gene IGTP.

Interferon-gamma (IFN-gamma) is critical for defense against pathogens, but the molecules that mediate its antimicrobial responses are largely unknown. IGTP is the prototype for a family of IFN-gamma-regulated genes that encode 48-kDa GTP-binding proteins that localize to the endoplasmic reticulum. We have generated IGTP-deficient mice and found that, despite normal immune cell development and normal clearance of Listeria monocytogenes and cytomegalovirus infections, the mice displayed a profound loss of host resistance to acute infections of the protozoan parasite Toxoplasma gondii. By contrast, IFN-gamma receptor-deficient mice have increased susceptibility to all three pathogens. Thus, IGTP defines an IFN-gamma-regulated pathway with a specialized role in antimicrobial resistance.

Role of tumor necrosis factor alpha in the host response of mice to bacteremia caused by pneumolysin-deficient Streptococcus pneumoniae.

Pneumolysin-deficient mutant strains of Streptococcus pneumoniae are known to cause less-severe sepsis than wild-type pneumococcal strains that produce pneumolysin. This difference is associated with greater host resistance in mice infected with the pneumolysin-deficient strains. These studies show that the host resistance developed during the first 1 to 2 days after infection with a pneumolysin-deficient mutant strain is dependent on tumor necrosis factor alpha but is apparently independent of interleukin 1beta (IL-1beta) or IL-6. Survival beyond 5 days appeared to depend on the ability of the mice to produce IL-1beta.

Effects of Cl-949, a novel antiallergy compound, on host resistance in mice

The effect of CI-949, a novel inhibitor of allergic mediator release, on immune function was assessed with holistic mouse models of immunocompetence. Resistance to the bacterial pathogens Listeria monocytogenes and Streptococcus pneumoniae and the B16F10 melanoma cell line was used to evaluate the potential of CI-949 to affect immune function. CI-949 treatment of female B 6C 3F 1 mice increased pulmonary tumor burden at 100 mg/kg/day in the B16F10 melanoma model, with a no effect level of at least 50 mg/kg/day. A correlation was seen between decreased clearance of the B16F10 cells and increased tumor burden. However, CI-949 produced this effect only at the maximum tolerated dose. No effect of the drug was seen in the S. pneumoniae model. Host resistance to L. monocytogenes was increased after CI-949 administration, with the no adverse effect level in this model being at least equivalent to the top dose of 100 mg/kg/day. Therefore, the immune system does not appear to be adversely affected or to be a specific target for CI-949 even at an overtly toxic dose.

Effects of Cl-949, a Novel Antiallergy Compound, on Host Resistance in Mice

Effects of Cl-949, a Novel Antiallergy Compound, on Host Resistance in Mice

Effects of Pyran Copolymer on Host Resistance of Mice to Plasmodium yoelii

Female B6C3F1 mice treated with 25 mg/kg pyran intravenously (i.v.) on days -4 and -3 were more susceptible to nonlethal Plasmodium yoelii 17XNL or lethal Plasmodium berghei ATCC-30090 than untreated mice or mice treated intraperitoneally (i.p.). Female B6C3F1 mice treated with pyran i.p. displayed enhanced resistance to Listeria monocytogenes as compared to untreated mice or mice given pyran i.v. Peritoneal exudate cells (PEC) primed by pyran i.p. possessed enhanced ability to kill Listeria but impaired ability to destroy Plasmodium. Phagocytosis of Covaspheres by PEC was greater for mice given pyran i.p. than those given pyran i.v. Chemiluminescence evoked by zymosan was less for PEC from mice given pyran i.v. than for those from untreated mice or those given pyran i.p. Chemiluminescence was greater for adherent splenocytes from mice treated with pyran i.p. than for those from untreated mice or those from mice treated i.v. Pyran administered i.v. is less effective in modulating the host immune response than pyran administered i.p. Immunomodulatory agents such as pyran have adverse as well as beneficial effects depending upon the route of administration.

Effects of Nitrogen Dioxide on Resistance to Klebsiella pneumoniae in Mice

We studied the effects of nitrogen dioxide (NO2) exposure on host resistance in mice. Mice were exposed continuously in inhalation chambers to 0.5, 1.0, or 1.5 ppm NO2 for 3 months or to 5 ppm NO2 for 3 days. Chamber NO2 concentrations were monitored continuously by a Thermoelectron chemiluminescent analyzer verified by the Saltzman procedure in accordance with Federal Register procedures. After the NO2 exposure, the mice were placed in an infectivity chamber and exposed to aerosolized cultures of Klebsiella pneumoniae for 15 minutes. Chamber clouds contained 55.2 ± 9.3 organisms (1–3 μ in size) per liter of air. The animals were removed from the infectivity chamber and observed for 15 days, after which percent mortalities and relative mean survival times (RMST) were determined. Control mice and mice exposed to 0.5, 1.0, or 1.5 ppm NO2 for 3 months did not differ significantly in mortality or RMST. In mice exposed to 5 ppm NO2 for 3 days, percent mortality was significantly higher and RMST was significantly lower. Lung index (lung weight/body weight) and body weight did not differ significantly after exposure to 0.5, 1.0, and 1.5 ppm NO2 for 3 months or to 5 ppm NO2 for 3 days. These results indicate that inhalation of 5 ppm NO2 for 3 days depresses host resistance to K. pneumoniae, whereas inhalation of 1.5 ppm NO2 for up to 3 months does not.

Influence of steroidal and nonsteroidal sex hormones on host resistance in mice: increased susceptibility to Listeria monocytogenes after exposure to estrogenic hormones.

Subchronic exposure to pharmacological levels of estrogenic compounds, including 17 beta-estradiol, diethylstilbestrol, and alpha-dienestrol, significantly increased the mortality of B6C3F1 female mice after Listeria infection. Compounds with little estrogenic activity, including 5 alpha-dihydrotestosterone, progesterone, zearalenol, and corticosterone, did not alter Listeria-related mortality. Estrogen-induced alterations in resistance were inhibited by both adult thymectomy and the estrogen antagonist tamoxifen. Estrogen exposure depressed the accumulation of monocytes and lymphocytes at infective foci. Significantly elevated numbers of bacteria were observed in infective foci of estrogen-treated mice later in the infection when bacteria were nearly eliminated from untreated animals. These results indicate that estrogen-induced suppression of Listeria immunity is partially mediated by the thymus, probably through receptor events which may ultimately suppress the activation of T cell-dependent defense mechanisms. This may be partially reflected by the inability of estrogen-exposed mice to eliminate Listeria cells or to accumulate mononuclear effector cells at infective foci at the same rate as controls.

Influence of steroidal and nonsteroidal sex hormones on host resistance in mice: increased susceptibility to Listeria monocytogenes after exposure to estrogenic hormones.

Influence of steroidal and nonsteroidal sex hormones on host resistance in mice: increased susceptibility to Listeria monocytogenes after exposure to estrogenic hormones.