Role of macrophage activation and interferon in the resistance of alveolar macrophages from infected mice to influenza virus

Lung macrophages from uninfected CD1 mice support the replication of influenza viruses (H1N1 and H0N1), but the cells from influenza-infected mice do not. The possible mechanisms of this resistance were investigated. Murine macrophages were "activated" in vitro with lipopolysaccharide and lymphokines, and in both cases activation was associated with resistance of cells to infection with influenza virus. Exposure of alveolar macrophages in vitro to 500 U of purified type I interferon per ml enhanced cell spreading and Fc receptor-mediated phagocytosis, suggesting macrophage activation, and protected the cells against infection with influenza virus. Alveolar macrophages were also protected by a soluble factor in the bronchoalveolar washings from influenza-infected mice. This effect was not virus specific and was abolished by anti-interferon serum.     

Macrophage activity in resistant and susceptible mouse strains infected with Mycobacterium lepraemurium.

The level of activation of peritoneal macrophages following subcutaneous inoculation of resistant (C57BL) and susceptible (BALB/c) mice was assessed by monitoring superoxide anion and hydrogen peroxide production and also tumour cell cytostasis. The level of systemic macrophage activation appeared to correlate with bacterial load, rather than resistance to infection. It was observed that the more susceptible (BALB/c) strain developed higher and more sustained levels of systemic macrophage activation, whereas the more resistant (C57BL) strain showed only low transient levels of macrophage activation. In contrast, in vivo challenge of subcutaneously infected C57BL mice, via the intra-peritoneal route, with heat-killed Mycobacterium lepraemurium and thioglycollate resulted in a high level of macrophage activation compared with similarly treated uninfected mice. Similar treatment of susceptible BALB/c mice, however, did not result in enhanced macrophage activation. It was also observed that high levels of macrophage activation occurred in T-cell deprived C57BL mice following infection with M. lepraemurium.     

Tumor necrosis factor and macrophage activation are important in clearance of Nocardia brasiliensis from the livers and spleens of mice.

The roles of tumor necrosis factor (TNF) and macrophage activation in clearance of Nocardia brasiliensis from BALB/c mouse livers and spleens were evaluated. TNF activity was detectable in sera from animals at all stages of infection. Treatment of infected mice with an antiserum against TNF significantly enhanced the experimental infection as judged by enumeration of CFU in the spleens and livers of infected mice. In another set of experiments, a population of activated macrophages from the peritoneal cavities of N. brasiliensis-infected mice was studied by using a cytostatic assay. The observed cytotoxic activity of these activated macrophages against L929 cells was mediated by TNF, since this activity was inhibited by anti-TNF antiserum treatment. The level of TNF activity generated in vitro in the presence of lipopolysaccharide (LPS) by peritoneal macrophages from infected mice was higher than that of adherent peritoneal cells obtained from normal mice after challenge with LPS. When the nocardiacidal activity of peritoneal cells from N. brasiliensis-infected mice was estimated in vitro, a significant decrease in the number of CFU recovered was observed. Moreover, nocardiacidal activity of peritoneal cells obtained from N. brasiliensis-infected mice previously treated with anti-TNF antiserum was significantly reduced compared with the activity of cells obtained from infected mice previously treated with normal rabbit serum and that of cells from uninfected mice. These data suggest a role for TNF in resistance to N. brasiliensis infection.     

Antibody-independent protection against Pseudomonas aeruginosa infection in mice after treatment with a homologous strain vaccine

Formalin-killed cells of Pseudomonas aeruginosa strain M-24 elicited an antibody-independent protective effect against P. aeruginosa infection in mice. The effect was observed as early as 6 h after administration and 100% protection was obtained by 48 h. The protective effect could not be attributed to the production of specific antibody. In M-24-treated mice, the bacteria in the peritoneal cavity, blood and liver were eliminated 12 h after P. aeruginosa infection. This suggested that the protective effect was due to enhanced bacterial elimination. The percentage of macrophages in the peritoneal cavity was increased after M-24 administration. Furthermore, the enhanced bacterial elimination was abrogated by treatment of mice with 60Co-irradiation or carrageenan. These findings suggest the involvement of macrophages in the enhanced bacterial elimination observed. The chemiluminescence of peritoneal exudate cells from M-24-treated mice was markedly increased when compared with that of cells from untreated mice. The ability to kill P. aeruginosa in vitro was also greater in macrophages from mice treated with killed M-24 than in cells from proteose-peptone-treated mice. The M-24-treated mice showed enhanced nonspecific protection against infection with lethal doses of P. aeruginosa, Escherichia coli or Listeria monocytogenes. However, susceptibility to LPS in mice was not increased by M-24 treatment. These results suggest that macrophage activation without increasing LPS susceptibility was responsible for the antibody-independent protection induced by killed M-24.     

Susceptibility to Yersinia pseudotuberculosis Infection is Linked to the Pattern of Macrophage Activation

T helper 1 cells play a crucial role in the clearance of Yersinia pseudotuberculosis infection. By producing cytokines and presenting antigens to T cells, activated macrophages can orientate the adaptive immune response. The pathway used by macrophages to metabolize arginine has been employed as an important parameter to discriminate their activation state. In this study, the pattern of macrophage activation in Y. pseudotuberculosis- infected BALB/ c ( Yersinia -susceptible) and C57BL/6 ( Yersinia -resistant) mice and their immunostimulatory capacity were analysed. In the early phase of infection, macrophages obtained from C57BL/6 mice produced higher levels of NO, lower arginase activity, and larger amounts of IL-12 and TNF-α than macrophages from BALB/ c mice. On the other hand, macrophages derived from BALB/ c mice produced higher levels of IL-10 and TGF-β than C57BL/6 mice. The Y. pseudotuberculosis infection leads to a fall in the macrophage immunostimulatory capacity of both strains of mice, with T-cell proliferation significantly reduced 12 h after infection. Moreover, we observed in the supernatant of co-culture of macrophages from infected mice with T lymphocytes from heat-killed Yersinia -immunized mice lower IFN-γ production by cells from BALB/ c mice than by C57BL/6 mice, and IL-4 was produced only by BALB/ c mice on the first- and third-day post-infection. These results suggest that the pattern of macrophage activation is associated with susceptibility and resistance to Y. pseudotuberculosis infection in BALB/ c and C57BL/6 mice.     

Roles of peripheral leukocytes and tissue macrophages in antibacterial resistance induced by free or liposome-encapsulated muramyl tripeptide phosphatidylethanolamide.

Administration of free muramyl tripeptide phosphatidylethanolamide (MTPPE) or liposome-encapsulated MTPPE (LE-MTPPE) in a twofold-lower dose at 24 h before bacterial inoculation resulted in clearance of intravenously inoculated Klebsiella pneumoniae by tissue macrophages, whereas in control mice, bacteria were not effectively cleared from the blood. In addition, MTPPE and LE-MTPPE led to increased numbers of leukocytes in the blood, which could compensate for the leukopenia in mice resulting from infection with K. pneumoniae. In an attempt to elucidate the relative contributions of the activation of tissue macrophages and the recruitment of leukocytes to the antibacterial resistance induced by MTPPE and LE-MTPPE, mice were infected intraperitoneally with K. pneumoniae. In these MTPPE- and LE-MTPPE treated mice, intraperitoneal influx of leukocytes and the phagocytic capacity of leukocytes were not higher than in untreated control mice. However, MTPPE- and LE-MTPPE-treated mice survived much longer; eventually 33% of the LE-MTPPE-treated mice survived, whereas all untreated control mice died as a result of bacterial septicemia. This prevention of early death appeared to be the result of an increased clearance of bacteria from the blood by activated tissue macrophages. It was observed that depletion of these tissue macrophages in liver and spleen abrogates the effect of LE-MTPPE treatment, indicating that tissue macrophages are of major importance in the LE-MTPPE-induced resistance against K. pneumoniae infection.     

Infection stage-dependent modulation of macrophage activation in Trypanosoma congolense-resistant and -susceptible mice

The contribution of cytokines and chemokines to resistance and susceptibility to African trypanosomiasis remains controversial. In the present study, the levels of type I and type II cytokines and of the MCP-1 chemokine were compared during the early and late stages of Trypanosoma congolense infection in susceptible BALB/c and resistant C57BL/6 mice. Moreover, the status of macrophage activation was compared in these animals by analyzing the inducible nitric oxide synthase-arginase balance, tumor necrosis factor secretion, and expression of the FIZZ1 and YM genes. Data show that changing from a predominant type I cytokine environment in the early stage of infection to a predominant type II cytokine environment and an enhanced MCP-1 secretion in the late stage of infection correlates with resistance to T. congolense. Concomitantly, macrophage activation evolves from a classical to a predominant alternative phenotype. We further confirmed that the simultaneous occurrence of type I/type II cytokines in the early stage of infection in susceptible BALB/c mice, reflected by the presence of macrophages exhibiting a mixed classical/alternative activation phenotype, is associated with uncontrolled parasite growth and early death. Interleukin-4 (IL-4) and IL-13 signaling did not influence the susceptibility of BALB/c mice to T. congolense infection and interestingly were not the main trigger to alternative macrophage activation. In T. congolense-resistant C57BL/6 mice, our results corroborated the induction of FIZZ1 and YM gene expressions with the alternative pathway of macrophage activation. In susceptible BALB/c mice, however, YM but not FIZZ1 induction reflected the emergence of alternatively activated macrophages. Hence, the FIZZ1 and YM genes may be useful markers to discriminate between distinct populations of alternatively activated macrophages.     

Role of activated macrophages in resistance of congenitally athymic nude mice to hepatitis induced by herpes simplex virus type 2.

Congenitally athymic nude (nu/nu) mice of a BALB/c genetic background were found considerably more resistant to the induction of focal necrotic hepatitis by herpes simplex virus type 2 (HSV-2) tha, were phenotypically normal littermates (nu/+) or BALB/c mice. The augmented resistance was age dependent, as it was only manifested in mice from 4 to 5 weeks of age. Studies of the course of infection showed that nude mice were able to restrain virus multiplication in the liver far better than normal mice in the early phase of infection. However, they seemed inferior to normal mice in eliminating the infectious process. In vitro investigation of peritoneal macrophages revealed that macrophages from 6-week-old nude mice exhibited accelerated spreading and were three times as restrictive in the replication of HSV-2 as macrophages from normal mice. However, no difference was found in the efficiency of adsorption/phagocytosis between macrophages from nude and normal mice. The increased resistance of nude mice could be abolished by blockade of the microphage function of the mice by silica. Nude mice reconstituted at birth with thymus cells were just as susceptible to infection as normal mice. These data suggest that the increased resistance of nude mice to HSV-2 hepatitis is due to the presence of nonspecifically activated macrophages before infection.     

Effects of stimulated or immunologically activated macrophages on the induction of immune responses to Listeria monocytogenes

The influences of peritoneal macrophages induced by proteose peptone, Corynebacterium parvum (C. parvum) or Bacillus Calmette Guérin (BCG) on the initiation and development of immune responses and protection against Listeria monocytogenes infection were studied in mice. Mice treated intraperitoneally (i.p.) with proteose peptone 4 days previously showed much the same level of protection against an intraperitoneal infection with Listeria as untreated mice. Mice treated i.p. with C. parvum 4 days previously, of which peritoneal macrophages had increased abilities for intracellular killing of Listeria and O2- generation as compared with peptone-elicited macrophages, exhibited an enhanced resistance against the listerial infection. The degree of immune responses, as assessed by delayed footpad reaction (DFR), was rather depressed in these mice because C. parvum-activated macrophages acting as scavenger cells reduced the amount of effective antigenic stimulation. BCG-activated peritoneal macrophages from mice treated i.p. with BCG 14 days previously showed a strong ability for antigen presentation in correlation with increases in the number of Ia-bearing macrophages and in the level of interleukin 1 (IL 1) production. These mice showed an early appearance of DFR response and a markedly enhanced resistance against the listerial infection. These results suggested that the differences in macrophage activities as scavenger cells, cytokine-secreting cells and antigen presenting cells may account for the differences in the responsiveness against listerial infection in peptone-, C. parvum- and BCG-treated mice.     

Effects of RU 41740 aerosol treatment on mouse bronchoalveolar cells, and protection afforded against influenza virus infection

RU 41740, an immunomodulating compound extracted from Klebsiella pneumoniae, was previously shown to enhance mice resistance to bacterial and viral lung infections. To explore lung defense mechanisms, we studied the influence of RU 41740 aerosol treatment on the bronchoalveolar cell populations. Five successive daily RU 41740 aerosol treatments induced a large accumulation of leukocytes in the lungs 4h after the last treatment. Polymorphonuclear leukocytes predominated. The numbers of lymphocytes and monocytes rose significantly. A single RU 41740 aerosol treatment significantly raised the number of polymorphonuclears only. A luminol-dependent chemiluminescence assay was used to test the effect of RU 41740 on the opsonized zymosan induced response of alveolar macrophages. In vitro, addition of RU 41740 enhanced this chemiluminescence. After a single RU 41740 aerosol treatment of mice, the chemiluminescence of purified alveolar macrophages from these mice increased significantly. The protective effect of five daily RU 41740 aerosol treatments against influenza virus infection was believed to be due to the great intensity of the cellular response and the polymorphonuclear influx. The alveolar macrophage activation observed might also explain the enhanced resistance of mice to influenza virus infection.     

Peritoneal macrophage activation indicated by enhanced chemiluminescence.

A number of studies have demonstrated the ability of various bacterial preparations, protozoa, and chemicals to activate macrophages and concomitantly to enhance host resistance to both tumors and infections. Recently, viral infections have been shown to have a similar effect upon macrophage function. To better define the metabolic state of activated macrophages, we have evaluated the ability of peritoneal cells (PC) from vaccinia virus- or murine cytomegalovirus-infected or Corynebacterium parvum-treated mice to emit chemiluminescence (CL) during phagocytosis of zymosan particles or yeasts. PC from C. parvum-treated mice (1,400 microgram intraperitoneally) emitted enhanced CL over controls on days 3, 6, 14, and 21 after treatment, thereby establishing the emission of CL as a correlate of metabolic activation. Previous evidence for activation of PC from vaccinia virus-infected mice (10(8) plaque-forming units) was confirmed by demonstration of enhanced levels of CL on days 3, 6, and 13 after murine infection. Likewise, PC from mice infected with murine cytomegalovirus (10(5) plaque-forming units) 3, 6, or 13 days previously demonstrated augmented levels of CL over controls. Opsonized virus particles (vaccinia virus or murine cytomegalovirus) failed to induce the emission of CL with PC from mice infected with the isologous virus. Our data further demonstrate the immunomodulationinduced by virus infections and suggest that the detection of CL is an easily quantitated correlate of macrophage activation which may be helpful in defining metabolic alterations induced during activation.     

Protective Effect of a Traditional Chinese Medicine, Xiao-Chai-Hu-Tang (Japanese Name: Shosaiko-To), On Listeria Monocytogenes Infection in Mice

Lethal effect of Listeria monocytogenes (L. monocytogenes) in mice was prevented by an intraperitoneal (ip) injection of a traditional Chinese herbal medicine, xiao-chai-hu-tang (Japanese name: shosaiko-to), 4 days before ip bacterial infection. The numbers of bacteria in the peritoneal cavity and liver were smaller in shosaiko-to-treated mice from one day after the infection. Macrophage accumulation in the peritoneal cavity after ip inoculation of L. monocytogenes was observed in both untreated and shosaiko-to-treated mice. Although rates of such increases were almost the same between both groups, the absolute number of macrophages was larger in shosaiko-to-treated than in untreated mice because of a higher level of the macrophage number at 4 days after ip injection of shosaiko-to. In untreated mice, bactericidal activity of peritoneal macrophages decreased from one day to 3 days after ip injection of killed L. monocytogenes. Such an activity was maintained at the same level from 1 to 3 days in shosaiko-to-treated mice. Augmented accumulation of macrophages and maintenance of their bactericidal activity may be main mechanisms of the augmented resistance in shosaiko-to-treated mice. Augmented resistance against bacterial growth in the thigh muscle in ip shosaiko-to-treated mice may be caused by such mechanisms. The effect of shosaiko-to observed at an early stage of infection may be T cell-independent, since such an effect was observed in athymic nude mice and delayed footpad reaction could not be detected at such a timing in euthymic normal mice.     

Effect of acute nutritional deprivation on immune function in mice. I. Macrophages.

This study was designed to explore the effects of acute nutritional deprivation (starvation) on macrophage function in mice. In vivo macrophage activity was increased by starvation, as determined by multiplication of Listeria monocytogenes in both spleens and livers after intravenous injection. Similarly, in vitro studies revealed that the capacity of peritoneal macrophages to kill listeria was enhanced by starvation. This function was increased further by the addition of small concentrations of lipopolysaccharide (LPS; 10-100 ng/ml). The bactericidal activity of macrophages from starved mice, however, did not reach the levels observed with macrophages from BCG-infected mice. Furthermore, LPS did not appear to be an important second signal for macrophage activation in vivo, as LPS-unresponsive mice (C3H/HeJ and A/J) were protected by starvation. In contrast to these results we found that starved mice were not protected against Toxoplasma gondii infection and that macrophages from starved mice were unable to prevent multiplication of toxoplasma trophozoites in vitro. In toto, these experiments suggest that macrophage function is enhanced by starvation, but that this enhancement is not sufficient to fulfill all criteria for macrophage activation.     

Role of macrophages in host resistance to group A streptococci

Macrophages provide the first line of defense against invading pathogens. The aim of this study was to determine the role of macrophages during infection with group A streptococci (Streptococcus pyogenes) in mice. Here, we report that resident macrophages can efficiently take up and kill S. pyogenes during in vivo infection, as demonstrated by immunofluorescence and electron microscopy, as well as colony counts. To evaluate the contribution of macrophages to the resolution of experimental infection with S. pyogenes, we compared the susceptibility of BALB/c mice rendered macrophage deficient by treatment with carrageenan with that of intact mice. The results show that depletion of macrophages enhanced the susceptibility of BALB/c mice to S. pyogenes infection, as evidenced by 100% mortality of macrophage-depleted mice compared to 90% survival of nondepleted control animals. The in vivo depletion of macrophages strongly enhanced bacterial loads in the blood and systemic organs. Resistance to S. pyogenes can be restored in macrophage-depleted mice by adoptive transfer of purified macrophages. The in vivo blocking of the macrophage phagocytic function by treatment with gadolinium III chloride also resulted in enhanced susceptibility to S. pyogenes. Interestingly, depletion of macrophages prior to or during the first 24 h of infection decreased survival dramatically; in contrast, no mortality was observed in infected nondepleted animals or mice depleted after 48 h of infection. These results emphasize the important contribution of macrophages to the early control of S. pyogenes infection.     

Induction of unresponsiveness to gamma interferon in macrophages infected with Mycobacterium leprae.

We have previously demonstrated that Mycobacterium leprae-burdened granuloma macrophages isolated from infected nude mice are refractory to activation by gamma interferon (IFN-gamma). To explore further both the afferent and efferent functional capacity of M. leprae-infected macrophages, we examined the IFN-gamma-mediated activation of resident mouse peritoneal macrophages infected in vitro with live or dead M. leprae. When IFN-gamma was administered within 24 h of M. leprae infection, macrophages were fully activated. However, defective activation was evident at 3 to 5 days postinfection in macrophages that were heavily burdened with viable M. leprae. This defect was evident by four parameters of activation in which IFN-gamma failed to stimulate the enhancement of microbicidal activity, cytotoxicity for tumor target cells, O2- production, and surface Ia antigen expression. The development of defective activation closely followed an increase in macrophage production of prostaglandin E2. Defective activation of M. leprae-burdened macrophages was reversible by indomethacin, and a similar block in IFN-gamma activation was observed in three of these four parameters in normal macrophages treated with exogenous prostaglandin E2. Thus, infection of mouse macrophages with M. leprae appears to restrict IFN-gamma-mediated activation at least in part by induction of inhibitory levels of prostaglandin E2.     

Mycobacterial lipoarabinomannan inhibits gamma interferon-mediated activation of macrophages.

The principal efferent role of the macrophage in acquired resistance to intracellular pathogens depends on activation by T-cell lymphokines, primarily gamma interferon (IFN-gamma). However, mouse macrophages that are heavily burdened with Mycobacterium leprae are refractory to activation by IFN-gamma and are thus severely compromised in their capacity for both enhanced microbicidal and tumoricidal activities. We report here that lipoarabinomannan (LAM), a highly immunogenic lipopolysaccharide that is a prominent component of the cell walls of M. leprae and M. tuberculosis, was a potent inhibitor of IFN-gamma-mediated activation of mouse macrophages in vitro. Inhibition of macrophage activation by LAM required preincubation for approximately 24 h, resulting in uptake of LAM into cytoplasmic vacuoles of macrophages. Intact LAM was necessary to inhibit IFN-gamma-mediated activation, as this property was lost when the acyl side chains were removed from LAM by mild alkaline hydrolysis. In addition, LAM was an abundant constituent of macrophages isolated from lepromatous granulomas of M. leprae-infected nude mice and likely contributed to the defective activation of granuloma macrophages by IFN-gamma.     

Protective Effect of a Traditional Chinese Medicine,Xiao-Chai-Hu-Tang (Japanese Name: Shosaiko-To), On Listeria Monocytogenes Infection in Mice

Abstract

Lethal effect of Listeria monocytogenes (L. monocytogenes) in mice was prevented by an intraperitoneal (ip) injection of a traditional Chinese herbal medicine, xiao-chai-hu-tang (Japanese name: shosaiko-to), 4 days before ip bacterial infection. The numbers of bacteria in the peritoneal cavity and liver were smaller in shosaiko-to-treated mice from one day after the infection. Macrophage accumulation in the peritoneal cavity after ip inoculation of L. monocytogenes was observed in both untreated and shosaiko-to-treated mice. Although rates of such increases were almost the same between both groups, the absolute number of macrophages was larger in shosaiko-to-treated than in untreated mice because of a higher level of the macrophage number at 4 days after ip injection of shosaiko-to. In untreated mice, bactericidal activity of peritoneal macrophages decreased from one day to 3 days after ip injection of killed L. monocytogenes. Such an activity was maintained at the same level from 1 to 3 days in shosaiko-to-treated mice. Augmented accumulation of macrophages and maintenance of their bactericidal activity may be main mechanisms of the augmented resistance in shosaiko-to-treated mice. Augmented resistance against bacterial growth in the thigh muscle in ip shosaiko-to-treated mice may be caused by such mechanisms. The effect of shosaiko-to observed at an early stage of infection may be T cell-independent, since such an effect was observed in athymic nude mice and delayed footpad reaction could not be detected at such a timing in euthymic normal mice.     

Aberrant macrophage and neutrophil population dynamics and impaired Th1 response to Listeria monocytogenes in colony-stimulating factor 1-deficient mice

Listeria monocytogenes, a facultative intracellular bacterium, has been used extensively to study innate immune responses. Macrophages act as hosts for this bacterium as well as a major defense against it. Using mice homozygous for a null mutation (Csf1(op)) in the gene for the mononuclear phagocytic growth factor colony-stimulating factor 1 (CSF-1), we have demonstrated that CSF-1-regulated macrophages were essential to defend against a listerial infection. In the absence of CSF-1, monocytes were not recruited to the sites of infection due to the lack of synthesis of the macrophage chemoattractant chemokine MCP-1. In addition, there was no burst of interleukin-10 (IL-10) synthesis that has been shown to result in the egress of neutrophils from sites of infection. Consequently, neutrophils were not replaced by macrophages, and numerous neutrophil-filled microabscesses developed, followed by tissue destruction and death of the mice. In the CSF-1 nullizygous mice compared to wild-type mice, there was also a very low synthesis of gamma interferon (IFN-gamma), resulting in reduced macrophage activation. However, the concentrations of the IFN-gamma-inducing cytokines IL-12 and IL-18 at this bacterial load were similar in these mutant mice. In contrast, IL-6 concentrations were dramatically reduced. Administration of IL-6 to Csf1(op)/Csf1(op) mice significantly increased the synthesis of IFN-gamma and reduced the bacterial burden to a greater extent than treatment with IFN-gamma alone. These data indicate that IL-6 occupies a central role in the CSF-1-regulated macrophage response to L. monocytogenes.     

Effects of BCG infection on the susceptibility of mouse macrophages to endotoxin.

Mice infected intravenously with Mycobacterium bovis (BCG) are 100 to 1,000 times more sensitive to the lethal effects of bacterial lipopolysaccharides (LPS). Since BCG infection results in macrophage activation and LPS may cause pathophysiological effects through interaction with this cell type, it was of interest to determine whether macrophages from BCG-infected animals were more susceptible to the toxic effects of LPS in vitro. When LPS-susceptible, C57BL/6 mice were infected with BCG, a significant reduction in the 50% lethal dose of LPS was first observed after 7 days and persisted for several weeks. Macrophages from these animals had greatly increased susceptibility to LPS in vitro, which correlated with the development of acquired cellular resistance as determined by their ability to inhibit the growth of Listeria monocytogenes. In contrast, BCG infection of C3H/HeJ mice, a strain resistant to LPS, did not alter the 50% lethal dose of LPS for these animals or increase the sensitivity of their peritoneal macrophages to LPS in vitro. These results indicate that susceptibility of BCG-infected mice to the lethal effects of LPS parallels the susceptibility of their macrophages in vitro; release of vasoactive substances from LPS-susceptible activated macrophages in vivo may be, in part, responsible for lethality.     

The inflammatory macrophage response to murine cytomegalovirus in genetically susceptible mice

Summary Adherent suppressor cells have often been implicated in the depression of immunocompetence following CMV infections. We have reported that high levels of cytostatic macrophages in the peritoneal cavities of infected mice correlate with genetically-based sensitivity to CMV disease, suggesting they may modulate protective immune responses. This study investigates the properties and kinetics of such cells.Genetically-susceptible BALB/c mice infected with MCMV accumulated activated peritoneal macrophages, 7 days post-infection. These cells suppressed³H-thymidine-incorporation and lymphokine production in syngeneic lymphocyte cultures and hence appeared to have depressed accessory cell function, although interleukin-1 production and the capacity to take up colloidal gold were enhanced. The cytostatic activity was located in a low density fraction (1.05 g/ml), which was expanded by MCMV infection. The lowest density cells had higher frequencies of infection but the proportion of cells releasing virus (<0.2%) was below the proportion activated, as shown by the shift in the density profile or enhanced colloidal gold uptake.A comparable accumulation of cytostatic activated peritoneal macrophages occurred in mice treated with cyclosporine A, but nude mice showed macrophage activation without cytostasis, so the role of T cells is not resolved.The spleens of infected mice maintaining high level of virus in this organ atrophied, and the remaining cells were unable to proliferate in culture. In contrast, mice clearing the virus developed splenomegaly and restricted responsiveness, which may be governed by cytostatic cells equivalent to those in the peritoneal cavity. The spread of virus to the lymph nodes was limited and MCMV-primed cells were readily demonstrable.