Chronic Infection In Mice Research Articles

Course of primary candidiasis in T cell-depleted mice infected with attenuated variant cells.

Anti-CD4, anti-CD8, or anti-interferon-gamma (IFN-gamma) antibodies or combinations of them were administered in the early stages of chronic infection of mice with a Candida albicans live vaccine strain, and the animals were monitored for course of primary infection, development of delayed-type hypersensitivity, resistance to reinfection, production of interleukin 2 (IL-2) and IFN-gamma in vitro by splenic lymphocytes, and levels of IL-2 and IFN-gamma transcripts in these cells. CD4+ cell and IFN-gamma depletion resulted in the development of fatal candidiasis by the attenuated yeast vaccine. In contrast, either treatment alone modified the course but not the outcome of primary infection, though each prevented the development of resistance to reinfection. Our data thus indicate that both IFN-gamma and CD4+ cells participate in resistance to primary infection with attenuated yeast cells and are critical in the induction of persistent systemic anticandidal immunity.

In vivo effects of anticytokine antibodies on isotype restriction in Mesocestoides corti-infected BALB/c mice

Chronic infection of mice with the cestode Mesocestoides corti results in an antibody response restricted to immunoglobulins M (IgM) and G1 (IgG1). To determine which of the known lymphokines are involved in the restricted isotype response, we treated M. corti-infected mice with a panel of anticytokine monoclonal antibodies against interleukin-4 (IL-4), IL-5, IL-6, and gamma interferon. The effects of anti-IL-4 were of particular importance, since IL-4 is known to enhance IgG1 production and an IgG1 response predominates in infected animals. Interestingly, injection of anti-IL-4 alone had no effect on IgG1 levels at day 7 postinfection and actually enhanced levels at day 10. Decreases in IgM levels were observed in anti-IL-4-treated mice. Administration of anti-IL-5 inhibited IgM production early in infection, but no effects on IgG1 levels were observed. Treatment of infected mice with anti-gamma interferon had no effect on any of the isotypes analyzed. Treatment of infected mice with anti-IL-6 antibody had the most dramatic effects, with inhibition of IgM and IgG1 by day 14 of infection. The transient expression of IgG3, which is sometimes observed very early in the infection process, was also inhibited by anti-IL-6, suggesting that the inhibition observed was not isotype specific. To determine whether cytokines were acting in concert to effect the high IgM and IgG1 levels in infected animals, anticytokine antibodies were also injected in combinations. However, the only combinations that inhibited IgG1 levels contained anti-IL-6, and the extent of inhibition was not greater than that of anti-IL-6 alone. Results are discussed in terms of the effects of cytokines on parasite-induced isotype expression and the potential for IL-4-independent mechanisms of IgG1 production.

Trypanosoma cruzi: Aberrant expression of class II major histocompatibility complex molecules in skeletal and heart muscle cells of chronically infected mice

In isolated skeletal, heart, and smooth muscle cells from BALB/c and C3H/HeJ mice infected with different strains of Trypanosoma cruzi the presence of class II MHC molecules was investigated by immunocytochemical techniques. We employed single muscle fibers instead of conventional cryostat sections to obtain a more accurate antigen localization. Approximately half of the skeletal muscle cells isolated from the reclus femoris expressed Ia antigens on their surface, irrespective of the mouse or parasite strain combination. Ia expression was apparent only at 30 days postinfection and thereafter. The heart muscle cells expressed class II molecules only at 1 and 3 months postinfection. In no case did the smooth muscle cells from infected mice express Ia antigens. Studies of the same molecules in the noninfected animals gave constantly negative results. We conclude that in the course of the chronic infection of mice with T. cruzi, ectopic expression of class II MHC molecules occurs at the surface of skeletal and heart muscle cells, providing a possible mechanism for explaining the anti-striped muscle autoreactivity present in Chagas' disease.

Immunomodulation by Candida albicans: crucial role of organ colonization and chronic infection with an attenuated agerminative strain of C. albicans for establishment of anti-infectious protection.

Intravenous inoculation of an attenuated agerminative strain of Candida albicans (PCA-2) of low virulence, but not of two other species of Candida of low virulence (C. parapsilosis and C. viswanathii) into CD2F1 mice conferred protection against the highly virulent microbes C. albicans CA-6, Staphylococcus aureus and Aspergillus fumigatus. To provide protection, a definite inoculum size (10(6) cells per mouse) resulting in organ colonization and establishment of a long-lasting chronic infection with PCA-2 was needed. An inoculum of 10(5) cells gave rise to transient kidney colonization whereas inocula greater than 10(6) cells led to acute septicaemia and eventual death. Chronic infection of mice following inoculation of 10(6) PCA-2 cells was accompanied by detectable mannoprotein antigen levels in the serum (30-70 ng ml-1) while specific antibodies did not appear until 14 d after inoculation, at which time low antimannan antibody was present (ELISA titre 1:40-1:80). Chronic infection was characterized by the presence in the kidneys of 2-3 x 10(6) c.f.u. of PCA-2 for at least 40 d after inoculation. Pharmacological modulation of the host through administration of either an anti-Candida drug, amphotericin B, or an immunosuppressive agent, cyclophosphamide, strongly supported the premise that the anti-infectious state conferred by PCA-2 'immunization' correlated with the maintenance of a sufficient number of PCA-2 in vivo. Protection was 'switched on' when 2-3 x 10(5) cells were present in the kidneys. It was maximal at a kidney count of 2-3 x 10(6) c.f.u. of PCA-2, and promptly declined when the number of PCA-2 cells in the kidney fell below 2 x 10(5). Mice chronically infected with PCA-2 had splenic macrophages with pronounced candidacidal activity in vitro. Modulation of the growth of PCA-2 in vivo, which determined activation or deactivation of the protective state, was paralleled by a similar modulation in macrophage activation, showing that in all cases resistance to virulent organisms persisted as long as macrophage activation was present. The results demonstrate that a critical in vivo antigenic load is crucial for the occurrence of resistance to infection and suggests that macrophages could be involved in this protection.

Studies of latent cytomegalovirus infection: the macrophage as a virus-harboring cell.

During chronic infection of mice with mouse cytomegalovirus (MCMV), the virus was isolated from various tissues by cocultivation with allogeneic mouse embryonic fibroblasts (MEF). Infectious virus was recovered from over 15% of the pancreases, salivary glands, kidneys, lacrimal glands, and spleens. When activated macrophages were obtained by intraperitoneal injection of peptone into mice infected 3 months earlier, they harbored MCMV. Macrophages or lymphocytes were infected with MCMV in vitro and injected into normal mice intravenously. The peritoneal cavities of these mice were then stimulated by peptone injection 3 months after the transfer, and peritoneal or splenic macrophages and lymphocytes were cocultured with allogeneic MEF. MCMV was recovered from the peritoneal and splenic macrophages and not from the lymphocytes.

Expression of the transferrin receptor in murine peritoneal macrophages is modulated in the different stages of activation.

A specific high affinity binding site for the serum glycoprotein transferrin was identified on murine peritoneal macrophages. The binding reached equilibrium within 60 min and was reversible, saturable, and specific for transferrin. Although the presence of this receptor was detected on the cell surface by studies carried out using intact cells, the majority (70 to 90%) of the binding activity was detectable only in detergent extracts of such cells. This suggests that a substantial portion of the binding activity is localized within the macrophage. The association constant (Ka) for binding to intact cells (6 to 9 X 10(8) M-1) was comparable to values reported for transferrin receptors described on other cell types. The expression of transferrin binding activity was examined in macrophages exhibiting qualitatively and quantitatively different degrees of functional activation. Resident peritoneal macrophages, exudate macrophages primed by elicitation with pyran copolymer, and activated macrophages induced by chronic infection of mice with bacillus Calmette-Guerin (BCG) or elicitation with heat killed Propionibacterium acnes (P. acnes) had low numbers of binding sites (1000 to 5000 total sites/cell). Macrophages elicited by sterile inflammatory agents (thioglycollate broth, fetal bovine serum, or casein) all exhibited a greater number of transferrin receptors (15,000 to 20,000 total sites/cell). This modulation did not appear to result from differential shifts between surface and internal loci. Our results suggest that the expression of the transferrin receptor may be a useful marker of the responsive stage of macrophage functional activation and the membrane changes that accompany activation.

Delayed secondary immune response in mice immunized with toxoplasma antigens and its effect for protection against toxoplasma gondii

Primary immune response by mice immunized with Toxoplasma peritoneal exudate (PE) was produced slowly at a low level. To induce high Toxoplasma antibodies, mice should be boostered after the primary immune response reached the peak in 4 weeks or later. Immunization of mice with PE alone in 4 weeks could suppress the growth of Toxoplasma but could not accomplish protection. Two of 9 mice immunized with PE in complete Freund's adjuvant (CFA), and 16 of 27 mice immunized with PE containing Toxoplasma ( ToxoPE ) in CFA were protected against a challenge of 1 X 10(3) Toxoplasma, RH strain. The mice surviving to the challenge showed complete protection against a rechallenge of higher dose, 1 X 10(6) RH strain. Their ascites were very high in LA titer and would be a great source for obtaining high titer antibodies to Toxoplasma without contamination of host serum components. Biological characters of Toxoplasma, RH strain, in chronic infection of mice are discussed.