Augmentation of Host Resistance to Listeria Monocytogenes Infection by A Traditional Chinese Medicine, Ren-Shen-Yang-Rong-Tang (Japanese Name: Ninjin-Youei-To)

Ren-shen-yang-rong-tang (Japanese name: Ninjin-youei-to, NIN), a traditional Chinese medicine, is a drug made of spray-dried powder of hot water extract obtained from twelve species of medical plants. An intraperitoneal (ip) injection with NIN 2 days before intravenous (iv) infection with Listeria monocytogenes (L. monocytogenes) accelerated elimination of viable bacteria in the spleen in the early stage of infection (from day 1) and protected mice from the lethal infection. It was suggested that the protective effect of NIN was mediated by the activation of nonimmune macrophages playing a principle role in resistance in the early stage of infection. Two days after ip injection with NIN just before infection, significantly increment in the number of monocytes in the peripheral blood was observed, though macrophage number in the spleen and their intracellular killing activity were unchanged. At 12 hours after infection with L. monocytogenes a significantly enhanced increase of splenic macrophage number was observed in NIN-treated mice, compared to controls. After ip injection of NIN, interleukin-1 (IL-1), IL-6 and granulocyte macrophage-colony stimulating factor (GM-CSF) became detectable in the serum or peritoneal cavity. These results suggested that NIN stimulated macrophage-precursor cells in the bone marrow via the production of IL-1, IL-6, GM-CSF by macrophages, accelerated the supply of peripheral macrophages, and such macrophages accumulated into the site of infection in the very early stage of infection. Similar protective effects of NIN were observed by oral administration for 7 days till 1 day before iv infection with L. monocytogenes.     

Augmentation of Host Resistance to Listeria Monocytogenes Infection by A Traditional Chinese Medicine,Ren-Shen-Yang-Rong-Tang (Japanese Name: Ninjin-Youei-To)

Abstract

Ren-shen-yang-rong-tang (Japanese name: Ninjin-youei-to, NIN), a traditional Chinese medicine, is a drug made of spray-dried powder of hot water extract obtained from twelve species of medical plants. An intraperitoneal (ip) injection with NIN 2 days before intravenous (iv) infection with Listeria monocytogenes (L. monocytogenes) accelerated elimination of viable bacteria in the spleen in the early stage of infection (from day 1) and protected mice from the lethal infection. It was suggested that the protective effect of NIN was mediated by the activation of nonimmune macrophages playing a principle role in resistance in the early stage of infection. Two days after ip injection with NIN just before infection, significantly increment in the number of monocytes in the peripheral blood was observed, though macrophage number in the spleen and their intracellular killing activity were unchanged. At 12 hours after infection with L. monocytogenes a significantly enhanced increase of splenic macrophage number was observed in NIN-treated mice, compared to controls. After ip injection of NIN, interleukin-1 (IL-1), IL-6 and granulocyte macrophage-colony stimulating factor (GM-CSF) became detectable in the serum or peritoneal cavity. These results suggested that NIN stimulated macrophage-precursor cells in the bone marrow via the production of IL-1, IL-6, GM-CSF by macrophages, accelerated the supply of peripheral macrophages, and such macrophages accumulated into the site of infection in the very early stage of infection. Similar protective effects of NIN were observed by oral administration for 7 days till 1 day before iv infection with L. monocytogenes.     

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.     

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 granulocyte-macrophage colony-stimulating factor on the number of leucocytes and course of Listeria monocytogenes infection in naive and leucocytopenic mice.

This study concerns the effect of recombinant murine granulocyte-macrophage colony-stimulating factor (GM-CSF) on the number of circulating leucocytes, activation of peritoneal macrophages and proliferation of Listeria monocytogenes in various organs of naive and leucocytopenic mice. Mice were rendered leucocytopenic by sublethal total body irradiation or cyclophosphamide treatment. GM-CSF treatment enhanced the number of granulocytes and monocytes in peripheral blood during L. monocytogenes infection in naive mice, but not in irradiated or cyclophosphamide-treated mice. In naive mice, irradiated and cyclophosphamide-treated mice, GM-CSF did not affect the course of L. monocytogenes infection in thigh muscle, spleen and liver. However, GM-CSF treatment significantly increased the number of macrophages in the peritoneal cavity of naive mice during infection; these macrophages were more enlarged and showed a higher frequency of binucleated and multinucleated cells relative to non-GM-CSF-treated mice. Together, these results demonstrated that GM-CSF increased the number of circulating granulocytes and monocytes, and the number of peritoneal macrophages during infection with L. monocytogenes in naive mice, but did not affect the course of the infection in thigh muscle, spleen or liver of these mice. In leucocytopenic mice, however, GM-CSF did not affect the number of circulating phagocytes, which explains that this factor had no effect on the proliferation of the bacteria in the various organs.     

Early expression of cytokine mRNA in mice infected with Listeria monocytogenes.

Protective immunity first becomes evident at 3 to 4 days after inoculation of mice with a sublethal dose of Listeria monocytogenes. Recent evidence suggests that production of gamma interferon (IFN-gamma) occurs earlier (within the first 24 h of infection). The purpose of this study was to define better the sequence of cytokine mRNA expression during the early stages of L. monocytogenes infection. Cytokine mRNA expression was detected by polymerase chain reaction-assisted amplification of RNA extracted from the spleen cells of individual mice euthanized at 0.5 to 120 h after L. monocytogenes challenge. By using this method, mRNAs for tumor necrosis factor alpha, interleukin-1 alpha (IL-1 alpha), IL-2, IL-4, IL-5, and IFN-gamma were detected in RNA from the spleen cells of uninfected mice. The intensity of the bands for IFN-gamma, however, was increased greatly at 16 h after intravenous injection of 5 x 10(4) CFU (nearly 1 50% lethal dose) of L. monocytogenes. IL-6 and granulocyte-macrophage colony-stimulating factor mRNAs were not detected in spleen cell RNA from uninfected mice but were induced within 30 and 60 min, respectively, after inoculation with L. monocytogenes. Increased amounts of mRNAs for IFN-gamma, IL-6, and granulocyte-macrophage colony-stimulating factor were detected after injection of viable, but not killed, L. monocytogenes. IL-3 mRNA was not detected at any time in RNA extracted from the spleen cells of uninfected or L. monocytogenes infected mice. These results suggest that infection with L. monocytogenes elicits a detectable cytokine mRNA response within the first few hours of infection.     

Contribution of cytokines to time-dependent augmentation of resistance against Listeria monocytogenes after administration of a traditional Chinese medicine, xiao-chai-hu-tang (Japanese name: shosaiko-to)

The augmentation of resistance against Listeria monocytogenes after an intraperitoneal (ip) administration of shosaiko-to in mice was shown to depend on the time interval between the treatment and the infection. A maximal effect was expressed in mice treated 4 days before ip infection. The time dependent resistance correlated to the accumulation of macrophages in the peritoneal cavity just before the infection, but not to bactericidal activity as judged by the fact that peritoneal macrophages from untreated mice and those from mice treated with shosaiko-to 4 days before showed a high bactericidal activity of the same degree. Resistance to the infection in untreated mice may be attributable to newly accumulating macrophages with a low level of bactericidal activity, but not to resident macrophages with a high level of the activity. After intravenous infection, on the other hand, a maximal effect was expressed in mice treated with shosaiko-to 2 days before. The resistance correlated to accumulation of macrophages and bactericidal activity in the spleen just before the infection. Participation of cytokines in an augmenting effect of shosaiko-to on protection against the infection was examined. Shosaiko-to induced a transient elevation of serum CSF activity that was maximal at 3 hours after the administration in uninfected mice, though it did not augment the CSF activity induced by the infection. The elevation of CSF activity may induce accumulation of macrophages with a high level of bactericidal activity in the spleen 2 days after administration of shosaiko-to and then in the peritoneal cavity 4 days after administration. IFN-gamma and TNF-alpha did not participate in the effect because administration of anti-IFN-gamma or anti-TNF-alpha just before administration of shosaiko-to or just before infection did not abrogate the inhibitory effect of shosaiko-to on the bacterial growth in the early stage of infection. Shosaiko-to also induced an increase of CFUm number in the spleen. The effect may contribute to the augmentation of resistance in the late stage of infection by differentiating to mature macrophages.     

Enhancement of host resistance against Listeria infection by Lactobacillus casei: role of macrophages.

Among the 10 species of the genus Lactobacillus, L. casei showed the strongest protective action against Listeria monocytogenes infection in mice. The activity of L. casei differed with regard to the dose of administration. The anti-L. monocytogenes resistance in mice intravenously administered 5.5 X 10(7), 2.8 X 10(8), or 1.1 X 10(9) L. casei cells was most manifest at ca. 2, 2 and 13, and 3 to 21 days after its administration, respectively. The growth of L. monocytogenes in the liver of mice injected with L. casei (10(7), 10(8), or 10(9) cells) 48 h after infection was suppressed, particularly when 10(8) or 10(9) L. casei cells were given 2 or 13 days before the induced infection, respectively. This suppression of L. monocytogenes growth was overcome by carrageenan treatment or X-ray irradiation. [3H]thymidine incorporation into the liver DNA increased 13 days after administration of L. casei, and augmentation of [3H]thymidine incorporation during 6 to 48 h after infection was dependent on the dose of L. casei. Peritoneal macrophage accumulation observed 1 to 5 days after intraperitoneal injection of UV-killed L. monocytogenes was markedly enhanced when the mice were treated with L. casei cells 13 days before macrophage elicitation. Therefore, the enhanced host resistance by L. casei to L. monocytogenes infection may be mediated by macrophages migrating from the blood stream to the reticuloendothelial system in response to L. casei injection before or after L. monocytogenes infection.     

Contribution of Cytokines to Time-Dependent Augmentation of Resistance Against Listeria Monocytogenes After Administration of a Traditional Chinese Medicine,Xiao-Chai-Hu-Tang (Japanese Name: Shosaiko-To)

Abstract

The augmentation of resistance against Listeria monocytogenes after an intraperitoneal (ip) administration of shosaiko-to in mice was shown to depend on the time interval between the treatment and the infection. A maximal effect was expressed in mice treated 4 days before ip infection. The time dependent resistance correlated to the accumulation of macrophages in the peritoneal cavity just before the infection, but not to bactericidal activity as judged by the fact that peritoneal macrophages from untreated mice and those from mice treated with shosaiko-to 4 days before showed a high bactericidal activity of the same degree. Resistance to the infection in untreated mice may be attributable to newly accumulating macrophages with a low level of bactericidal activity, but not to resident macrophages with a high level of the activity. After intravenous infection, on the other hand, a maximal effect was expressed in mice treated with shosaiko-to 2 days before. The resistance correlated to accumulation of macrophages and bactericidal activity in the spleen just before the infection. Participation of cytokines in an augmenting effect of shosaiko-to on protection against the infection was examined. Shosaiko-to induced a transient elevation of serum CSF activity that was maximal at 3 hours after the administration in uninfected mice, though it did not augment the CSF activity induced by the infection. The elevation of CSF activity may induce accumulation of macrophages with a high level of bactericidal activity in the spleen 2 days after administration of shosaiko-to and then in the peritoneal cavity 4 days after administration. IFN-γ and TNF-α did not participate in the effect because administration of anti-IFN-γ or anti-TNF-α just before administration of shosaiko-to or just before infection did not abrogate the inhibitory effect of shosaiko-to on the bacterial growth in the early stage of infection. Shosaiko-to also induced an increase of CFUm number in the spleen. The effect may contribute to the augmentation of resistance in the late stage of infection by differentiating to mature macrophages.     

Immunomodulation of GvH reaction in mice by Listeria monocytogenes

In the first part of experiments the GvHR activity of the spleen cell suspensions from normal parental donors (Balb/c) or infected with Listeria monocytogenes was compared. GvHR was examined in (Balb/c X AKR) F1 mice. Full suspensions from these donors or depleted of adherent cells or with addition of macrophages were studied. It has been proved that adherent cells population plays a significant role in the GvHR development. The addition of syngeneic macrophages from F1 hybrids results in a greater augmentation of GvH reactivity of parental lymphocytes. However, the addition of macrophages harvested from F1 hybrids immunized with L. monocytogenes 7 days before, brings about a weaker GvH reaction. Spleen cells of parental donors injected with L. monocytogenes 5-6 days earlier induced stronger GvHR as compared with the splenocytes of normal donors. Similarly, F1 hosts treated with L. monocytogenes 3-5 days before injection of normal donor's spleen cells showed increased GvHR, but those infected 7-9 days before injection of spleen cells, developed only very weak GvHR.     

Multiple host defense defects in failure of C57BL/6 ep/ep (pale ear) mice to resolve visceral Leishmania donovani infection.

Euthymic C57BL/L ep/ep (pale ear [PE]) mice halt the visceral replication of intracellular Leishmania donovani but fail to properly resolve infection. A previous study identified an isolated defect in tissue granuloma formation in these mice; CD4+ and CD8+ cell number, gamma interferon (IFN-gamma) production, and macrophage antimicrobial activity in vitro were all intact. New in vivo results reported here suggest a considerably more complex immune defect, with evidence indicating (i) enhanced control over L. donovani after transfer of normal C57BL/6 spleen cells, (ii) a partially suppressive Th2 cell-associated response mediated by interleukin-4 (IL-4) but not reversed by CD4+ cell depletion, (iii) absent responses to endogenous Th1 cell lymphokines (IFN-gamma and IL-2) but preserved responsiveness to endogenous tumor necrosis factor alpha, (iv) absent responses to exogenous treatment with recognized antileishmanial cytokines (IFN-gamma, IL-2, IL-12, and granulocyte-macrophage colony-stimulating factor [GM-CSF]) not corrected by transfer of C57BL/6 spleen cells, and (v) a deficient response to antimony chemotherapy. Defective hepatic granuloma formation was not corrected by transfer of C57BL/6 spleen cells or by anti-IL-4 administration. While treatment with IL-2 and GM-CSF modified the tissue reaction and induced selected effector cells to encase tissue macrophages, no antileishmanial activity resulted. Together, these observations suggest that the failure of PE mice to resolve visceral L. donovani infection likely represents expression of multiple suboptimal immune responses and/or partial defects, probably involving a combination of T-cell dysfunction, a Th2 cell response, and target cell (macrophage) hyporesponsiveness.     

Elimination of resident macrophages from the livers and spleens of immune mice impairs acquired resistance against a secondary Listeria monocytogenes infection.

During a secondary Listeria monocytogenes infection in mice, the bacteria are eliminated more rapidly from the liver and spleen than during a primary infection. This acquired resistance against a secondary infection is dependent on T lymphocytes, which induce enhanced elimination of bacteria via stimulation of effector cells such as neutrophils, resident macrophages, exudate macrophages, and hepatocytes. The aim of the present study was to determine the role of the resident macrophages in acquired resistance against a secondary L. monocytogenes infection in mice. Mice which had recovered from a sublethal primary infection with 0.1 50% lethal dose (LD50) of L. monocytogenes intravenously (i.v.), i.e., immune mice, received a challenge of 1 LD50 of L. monocytogenes i.v. to induce a secondary infection. At 2 days prior to challenge, immune mice were given an i.v. injection of liposomes containing dichloromethylene-diphosphonate (L-Cl2MDP) to selectively eliminate resident macrophages from the liver and spleen. Control immune mice received either phosphate-buffered saline (PBS) or liposomes containing PBS (L-PBS). Treatment of mice with L-Cl2MDP effectively eliminated resident macrophages from the liver and spleen but did not affect the number of granulocytes, monocytes, or lymphocytes in peripheral blood or their migration to a site of inflammation. Phagocytosis and killing of L. monocytogenes by peritoneal exudate cells elicited with heat-killed L. monocytogenes were similar in all groups of immune mice. On day 3 of a secondary infection, the number of L. monocytogenes organisms in the livers and spleens of L-Cl2MDP-treated immune mice was 4 log10 units higher than in immune mice treated with PBS or L-PBS. The concentration of reactive nitrogen intermediates in plasma, a measure of the severity of infection, was 70-fold higher for L-Cl2MDP-treated immune mice than for PBS- or L-PBS-treated immune mice. Treatment with L-Cl2MDP significantly increased the number of inflammatory foci in the liver and spleen, decreased their size, and affected their structure. From these results, we conclude that resident macrophages are required for the expression of acquired resistance against a secondary L. monocytogenes infection in mice.     

Differential chemokine response of murine macrophages stimulated with cytokines and infected with Listeria monocytogenes

During inflammatory processes the infected macrophage is a rich source of chemokines which induce infiltration of leukocytes to the site of infection. We investigated the regulation of chemokine production by murine macrophages in response to infection with the intracellular bacterial pathogen, Listeria monocytogenes. As a source of quiescent macrophages, murine bone marrow-derived macrophages (BMM) cultured under serum-free conditions were used. With RT-PCR, we detected induction of RNA message for the chemokines macrophage inflammatory protein (MIP)-2, KC, MIP-1alpha, MIP-1beta, IFN-gamma-inducible protein- 10 and RANTES in L. monocytogenes-infected macrophages. Accordingly, ELISA-detectable MIP-1alpha, MIP-2 and KC protein was induced by infection with L. monocytogenes. In contrast, L. monocytogenes infection of BMM alone failed to induce considerable expression of monocyte chemoattractant protein (MCP)-1 at the mRNA or protein level, but co-treatment with IFN-gamma was necessary. Release of infection- triggered MIP-2, MIP-1alpha and KC was negatively regulated by IFN- gamma. Similarly, IL-4 stimulated MCP-1 release by infected macrophages but reduced production of MIP-1alpha, MIP-2 and KC. IL-10 turned out to be a general deactivator in terms of macrophage chemokine production. IL-13 had no effect on MIP-1alpha, MIP-2 and KC production by infected BMM, but slightly reduced MCP-1 release. By using IFN-gamma and IL-4 gene deletion mutant mice, in vivo regulation of these chemokines by IL- 4 and IFN-gamma in listeriosis was studied. In summary, our results show that chemokines are produced by macrophages infected with L. monocytogenes, and that chemokine release is differentially regulated by the macrophage modulators IFN-gamma, IL-4, IL-10 and IL-13.      

Interleukin-10 has different effects on proliferation of Listeria monocytogenes in livers and spleens of mice

The aim of this study was to investigate the effect of interleukin-10 (IL-10) on the course of Listeria monocytogenes infection in naive and immune mice. Treatment with IL-10 during the course of a primary infection significantly decreased the number of bacteria in the spleen and did not affect the number in the liver. During a secondary infection in immune mice treated with IL-10, the number of bacteria was significantly lower in the spleen but significantly higher in the liver in comparison to mock-treated immune mice. IL-10 treatment during a primary Listeria infection decreased the concentration of gamma interferon (IFN-gamma) in plasma and the toxoplasmastatic activity of macrophages, whereas it increased the percentage of mildly CD3-positive T cells in the spleen. During a secondary infection, the concentration of IFN-gamma in plasma was decreased on day 1 but remained unaffected during later days of infection. From these results, we conclude that IL-10 has different effects on the proliferation of L. monocytogenes in the spleen and liver during primary and secondary Listeria infections.     

Kinetics of interleukin-1 production by macrophages during infection with Listeria monocytogenes

Production of interleukin-1 (IL-1) by peritoneal macrophages from mice inoculated intravenously with Listeria monocytogenes was measured at increasing intervals of infection. IL-1 activity in the 24 h macrophage supernatants was determined by using the thymocyte PHA co-mitogenesis assay. IL-1 production increased as the infection progressed, reached a peak on the 9th or 10th day and then declined progressively to approach normal values by the 20th day. Our data on the kinetics of IL-1 levels during an acute infection with L.monocytogenes are discussed in relationship to the development of cell-mediated immunity and its regulation by macrophages.     

In vivo IL-1 potentiates both specific and non-specific arms of immune response to infection.

Injection of 10(5) U interleukin-1 (IL-1) 4 hr before intravenous infection with Listeria monocytogenes hastens recovery of mice. This is accompanied not only by early stimulation of colony-forming cells in the spleen to levels higher than those in untreated, infected mice but also by accelerated activation of lymphokine-producing, specific T lymphocytes.     

The role of Kupffer cells and regulation of neutrophil migration into the liver by macrophage inflammatory protein-2 in primary listeriosis in mice

Depletion of mouse Kupffer cells and splenic macrophages following intravenous administration of liposome-entrapped clodronate severely reduced host resistance to primary infection with Listeria monocytogenes. Infection of clodronate-treated mice with a sublethal dose of L. monocytogenes resulted in death of the mice within 3 days. The macrophage depletion resulted in marked increases in bacterial growth in the liver and spleen, but not in other tissues. The proliferation of L. monocytogenes was observed in a large number of hepatocytes that underwent apoptosis. Infiltration of neutrophils in the liver and rapid formation of microabscesses were observed in the control mice after L. monocytogenes infection. However, there was less accumulation of neutrophils in the liver of Kupffer cell-depleted mice than in the control mice. Expression of macrophage inflammatory protein-2 (MIP-2) was enhanced in the livers of both the control and Kupffer cell-depleted mice after L. monocytogenes infection. MIP-2 was also induced in a murine hepatocyte cell line following L. monocytogenes infection. The administration of neutralizing anti-interleukin-8 receptor homolog antibody severely abrogated neutrophil infiltration into the Listeria-infected mouse liver. Anti-MIP-2 antibody moderately reduced neutrophil infiltration and microabscess formation in the liver. These findings indicate that Kupffer cells protect hepatocytes from L. monocytogenes infection and the resultant apoptosis. Moreover, MIP-2 and its related molecules produced by the infected hepatocytes regulate neutrophil infiltration and microabscess formation in primary listeriosis.     

Changes in serum colony-stimulating factor and monocytic progenitor cells during Listeria monocytogenes infection in mice

The capacity of a host to produce and mobilize monocytes is an essential component of host defenses during the early phases of infection caused by Listeria monocytogenes. In this study, the concentrations of colony stimulating factor (CSF) and the numbers of monocyte progenitor cells (CFUm) were measured in mice during infection with L. monocytogenes. The concentration of CSF in serum increased sharply during the first 24 h of infection and remained elevated for the next 7 days. The number of CFUm in the bone marrow, however, decreased during the first 4 days after injection of L. monocytogenes. Thereafter, the number increased slowly, returning to normal on day 14. The decrease in marrow progenitor cells did not appear to result from a reduced sensitivity to CSF. In contrast to bone marrow changes, spleen progenitor cells increased greater than 400%, reaching a peak 7 days after bacterial challenge. These data indicate that monocyte production during L. monocytogenes infection is correlated with a rise in serum CSF concentration, depletion of bone marrow CFUm, and an increase in the number of spleen CFUm.     

Importance of murine Vdelta1gammadelta T cells expressing interferon-gamma and interleukin-17A in innate protection against Listeria monocytogenes infection

Murine gammadelta T cells participate in the innate immune response against infection by an intracellular pathogen Listeria monocytogenes. Vdelta1+gammadelta T cells coexpressing Vgamma6 are a major gammadelta T-cell subpopulation induced at an early stage of L. monocytogenes infection in the livers of infected mice. To investigate the protective role of the Vgamma6/Vdelta1+gammadelta T cells against L. monocytogenes infection, Vdelta1 gene-deficient (Vdelta1-/-) mice were analysed because these mice selectively lacked a Vgamma6/Vdelta1+gammadelta T-cell subpopulation in the L. monocytogenes-infected liver. The Vdelta1-/- mice showed increased bacterial burden in the liver and spleen, and decreased survival rate at an early stage of L. monocytogenes infection when compared to wild-type mice. Histological examination showed abscess-like lesions and unorganized distribution of macrophages in the liver of the Vdelta1-/- mice but not in the wild-type mice after L. monocytogenes infection. The Vgamma6/Vdelta1+gammadelta T cells produced interferon-gamma and interleukin-17A. All the results suggest that murine Vgamma6/Vdelta1+gammadelta T cells control the innate protective response against L. monocytogenes infection through production of the proinflammatory cytokines interferon-gamma and interleukin-17A in the infected liver.