Abstract
Streptococcus pyogenes sometimes induces invasive streptococcal infection, including streptococcal toxic shock syndrome (STSS). Muscular necrosis is one of the peculiar symptoms of invasive streptococcal infection and STSS. We inoculated S. pyogenes into the muscles of mice. To do so, 5 × 108 bacteria in 0·2 ml phosphate-buffered saline were injected into the right hind thigh. None of the mice injected with the bacteria showed muscular necrosis and none died. Tumour necrosis factor-α (TNF-α) and infiltration of leucocytes were detected in the muscles of infected sites, although the condition of the infected mice did not deteriorate after anti-TNF-α monoclonal antibody treatment. The infected mice treated intraperitoneally with Escherichia coli lipopolysaccharide (LPS) showed augmentation of bacterial growth, muscular necrosis and death. TNF-α was detected in the sera of the infected mice treated with LPS, but not in the muscles of the infected sites. Infiltration of leucocytes into the infected muscle was not observed in the infected mice treated with LPS. Anti-TNF-α monoclonal antibody treatment decreased mortality in the infected mice treated with LPS. Moreover, the infected mice treated with recombinant TNF-α showed augmentation of muscular necrosis and death. These results suggest that systemic production of TNF-α induced by stimulation with LPS inhibits infiltration of leucocytes into the infected site and exacerbates muscular infection, and that TNF-α produced in streptococcal infection is not a defence factor for the host. Invasive streptococcal infection and STSS appear to be induced by both S. pyogenes and the host's immune system.
Introduction
Streptococcus pyogenes sometimes causes invasive infections, including streptococcal toxic shock syndrome (STSS). It is reported that virulence factors, for example, cystein protease and others, are important in causing many of the symptoms in invasive streptococcal infection and STSS.1,2 It is thought that virulence factors of S. pyogenes induce toxic shock syndrome-like symptoms in a host, in which huge amounts of bacteria grow. On the other hand, it is not clear what factor triggers abnormal bacterial growth and invasive streptococcal disease in the early stage of infection. It is reported that a specific serotype of S. pyogenes induces STSS,3 and the antibody levels of patients against M1 bacteria and streptococcal superantigen are lower than in healthy controls.4 On the other hand, strain M1T1 also causes mild S. pyogenes infection in patients with a low antibody response.5 Therefore, it is thought that a low antibody response against S. pyogenes is not a sole factor in causing invasive streptococcal infection. It is recognized that immunocompromised hosts have a tendency to be infected with Gram-negative bacteria. However, obvious immunodeficiency is not observed in STSS patients.6 We previously reported that interferon-γ, which is an important factor in eliminating many micro-organisms, prompted the growth of Staphylococcus aureus.7 We expect that cytokines may help the growth of S. pyogenes in the same way. Both Staphylococcus aureus and S. pyogenes have an immunostimulator, so-called superantigen.8 Therefore, we speculated that the immune system was important in triggering invasive streptococcal infection.
The symptoms of STSS are very similar to those of endotoxin shock induced by lipopolysaccharide (LPS).9 The superantigen of S. pyogenes induces production of tumour necrosis factor (TNF) and other cytokines like LPS.8,10 It is reported that superantigens are important in invasive streptococcal infection.11 However, the superantigens of S. pyogenes have many biological activities besides superantigenic activity.1 Therefore, it is not clear whether the superantigens of S. pyogenes trigger cytokine production, which then causes a deterioration in disease during the early phase of invasive streptococcal infections. It is reported that invasive streptococcal infection is sometimes induced by both S. pyogenes and other infections.12–14 It is also recognized that many infectious diseases induce cytokine production in a host.7,15–17 We speculated that invasive streptococcal infection consists of both systemic TNF production and infection of S. pyogenes. Systemic TNF production triggers augmentation of S. pyogenes growth in the host, and an invasive streptococcal infection is triggered.
Materials and methods
Mice
Female ICR outbred mice, C3H/HeN mice and C3H/HeJ mice (aged 6 weeks; obtained from SLC, Hamamatsu, Shizuoka, Japan) were used.
Bacteria
Streptococcus pyogenes was a clinical isolate from a patient in Hokkaido University Hospital, Sapporo, Japan. The bacteria were type M12/T12. The M and T typing was kindly performed by Dr A. Tamaru (Osaka Prefectural Institution of Public Health, Osaka, Japan). In each experiment, bacteria were cultured on nutrient agar (Nissui Pharmaceutical Co., Tokyo, Japan) containing 10% horse defibrinated blood for 18 hr at 37°, inoculated into Todd Hewitt Broth (Difco Laboratories, Detroit, MI), and incubated for another 15 hr. The organisms were collected by centrifugation and washed three times with 0·85% saline. The concentration of washed cells was adjusted spectrophotometrically at 550 nm. The numbers of viable S. pyogenes cells were established by plating serial 10-fold dilutions of a bacterial solution in 0·01 m phosphate-buffered saline (PBS; pH 7·4) on nutrient agar containing 10% defibrinated horse blood. Colonies were routinely counted 24 hr later.
Infection and LPS treatment
Mice were infected intramuscularly in the right hind thigh with 0·2 ml of a solution containing 5 × 108 colony-forming units (CFU) of viable S. pyogenes in PBS. They were injected intraperitoneally with 0·2 ml of PBS containing 100 mg of Escherichia coli O111:B4 LPS (Sigma, St Louis, MO).
Histological study
Muscles injected with the viable bacteria were evaluated histologically using formalin-fixed paraffin sections stained with haematoxylin and eosin.
In vivo depletion of endogenous TNF-α
Hybridoma cell lines secreting a monoclonal antibody (mAb) against mouse TNF-α (MP6-XT22.11; rat immunoglobulin G1)18 were used. MP6-XT22.11 was kindly provided by J. S. Abrams (DNAX Research Institute of Cellular and Molecular Biology, Palo Alto, CA). The mAb found in the ascites fluid was partially purified by 50% (NH4)2SO4 precipitation. The mice were given a single intravenous injection of the mAb 1 day before infection. Normal rat globulin (NRG) was injected as a control for the mAb. NRG was prepared as described previously.19 All of the in vivo effects of the mAb and NRG described were verified to contain < 0·1 ng per injected dose by use of reagents tested using the Limulus amoebocyte lysate assay.
Administration of recombinant mouse TNF-α (rTNF-α) to the infected mice
The mice were given a single intravenous injection of 10 ng/mouse of rTNF-α (Genzyme Co., Boston, MA) simultaneously with infection. PBS was injected as a control for TNF-α. In all cases, the rTNF-α described was verified to contain < 0·1 ng per injected dose by use of reagents tested by the Limulus amoebocyte lysate assay.
Preparation of organ extracts
The serum or muscle was suspended in RPMI-1640 medium (Gibco Laboratories, Grand Island, NY) containing 1% (wt/vol) 3-[(3-(cholamidopropyl)-dimethylammonio]-1-propanesulphate (CHAPS; Wako Pure Chemicals Co., Osaka, Japan), and 10% (wt/vol) homogenates were prepared with a Dounce grinder and then clarified by centrifugation at 2000 g for 20 min. The organ extracts were stored at −70° until cytokine assays were performed.
TNF assay
The TNF assay was carried out with a double-sandwich enzyme-linked immunosorbent assay (ELISA) as described previously.17 Purified hamster anti-recombinant mouse TNF-α mAb (Genzyme) and rabbit anti-recombinant mouse TNF-α7 were used for the ELISA. All ELISAs were run with recombinant mouse TNF-α (Genzyme).
Statistical evaluation of the data
Data were expressed as means±standard deviations from 10 mice, and the Wilcoxon rank sum test was used to determine the significance of the differences of bacterial counts in the organs or the cytokine titres between the control and experimental groups. The generalized Wilcoxon test was used to determine the significance of differences in the survival rate. Each experiment was repeated at least three times and accepted as valid only when the trials showed similar results.
Results
Mortality, bacterial growth and histological appearance in the mice infected with S. pyogenes intramuscularlly
It is reported that mice receiving 9 × 108−3·5 × 109 CFU S. pyogenes intramuscularly develop localized infection, haemorrhagic cutaneous lesions, extensive muscle destruction and death.20 We also observed the deaths of mice infected with 5 × 109−1 × 1010 CFU S. pyogenes. Injection of 1 × 107−1 × 109 CFU S. pyogenes caused localized infection, but not muscle destruction and death. For the purpose of the present experiment, 5 × 108 CFU was used. No mice infected with 5 × 108 CFU S. pyogenes showed muscular necrosis and death. On the other hand, the mortality rate of the infected mice treated with 100 mg of LPS was 60%. Death of the infected mice treated with LPS was observed during day 2 post-infection. No mice treated with 100 mg of LPS alone died. LPS induced death in the mice when it was administered from 12 hr before infection to 12 hr after infection (data not shown).
The number of bacteria in the muscle tissue of the infected mice decreased. On the other hand, the number of bacterial cells in the muscle tissue of the infected mice treated with LPS significantly increased (Fig. 1).
Figure 1.
Kinetics of bacterial growth within 48 hr after infection. ICR mice were infected in the right hind thigh intramuscularly with 5 × 108 CFU of S. pyogenes. The number of viable S. pyogenes cells in the muscles of mice infected with only bacteria (○) or bacteria plus LPS (•) were determined. Each point represents the mean±standard deviation for a group of 10 mice.
To investigate pathological changes in the muscles of the infected mice, we performed a histological study. The infected mice showed only infiltration of leucocytes into the muscles (Fig. 2a). The infected mice treated with LPS showed necrosis of the muscles without infiltration of leucocytes (Fig. 2b).
Figure 2.
Histological findings of mice infected with 5 × 108 CFU S. pyogenes intramuscularly at 48 hr post-infection. Mice infected with only bacteria (a) showed leucocyte infiltration in the right hind thigh, but not muscular necrosis. The infected mice treated with 100 mg LPS (b) showed muscular necrosis in the right hind thigh, but not leucocyte infiltration.
We examined whether LPS induced deterioration of the symptoms of the infected mice using C3H/HeJ mice, which lack a response to LPS. No C3H/HeJ mice infected with 5 × 108 CFU S. pyogenes died as a result of LPS treatment (data not shown). Augmentation of number of bacterial cells was not detected in the muscle tissue of infected C3H/HeJ mice treated with LPS (data not shown). Necrosis of the muscles was not observed in the infected C3H/HeJ mice treated with LPS (data not shown).
TNF production in serum and muscles of the infected mice, with and without LPS treatment
We investigated TNF production in the serum and muscles of the infected mice. TNF was detected in the serum of the infected mice treated with LPS, but not in that of the infected-only mice (Fig. 3a). The peak of TNF-α in the serum of the infected mice treated with LPS occurrede 30 min post-infection. There was no significant difference in TNF-α production between mice treated with LPS only and mice that were LPS-treated and infected with S. pyogenes (Fig. 3a). On the other hand, TNF-α was not detected in the muscles of the infected mice treated with LPS, although its production was observed in the infected-only mice (Fig. 3b). The peak of TNF-α in the muscle tissue of the infected-only mice occurred at 8 hr post-infection.
Figure 3.
Kinetics of endogenous TNF-α production 8 hr after intramuscular infection of ICR mice in the right hind thigh with 5 × 108 CFU of S. pyogenes. The titres of TNF-α in a serum (a) or muscular tissue (b) of mice infected with only LPS (▴), only bacteria (○), or bacteria plus LPS (•) were determined. Each point represents the mean±standard deviation for a group of 10 mice.
Effects of in vivo administration of mAb against TNF-α on mortality, necrosis and the growth of S. pyogenes in the muscles of the infected mice
To elucidate the role of TNF-α produced in the muscular infection of S. pyogenes, we administered an anti-TNF-α mAb to the infected mice. Mice were injected intravenously with NRG or the anti-TNF-α mAb. Treatment with the mAb or NRG was given 1 day before infection. The infected mice treated with LPS and the anti-TNF-α mAb did not die (data not shown), although 50% of the mice treated with only LPS died (Table 1).
Table 1. Effects of in vivo administration of rTNF-α and anti-TNF-α mAb on rates of mortality and muscular necrosis of the mice infected with 5 × 108 CFU/mouse.
| Death (%) 48 hr p.i. | Death (%) 168 hr p.i. | Muscular necrosis (%) 48 hr p.i. | |
|---|---|---|---|
| Infection only | 0 | 0 | 0 |
| Infection+100 mg LPS | 60 | 60 | 100 |
| Infection+100 mg LPS+″anti-TNF-α mAb | 0 | 0 | 0 |
| Infection+10 ng rTNF-α | 20 | 40 | 100 |
p.i., post-infection.
The infected mice treated with LPS and the anti-TNF-α mAb did not have muscular necrosis, but all of the mice treated with LPS showed muscular necrosis (Table 1).
At 24 hr post-infection, the number of S. pyogenes cells in the muscles of the infected mice treated with LPS and the anti-TNF-α mAb were significantly lower than in the infected mice treated with LPS and NRG (Fig. 4). In the infected-only mice, anti-TNF-α mAb and NRG treatments had no effect on the growth of S. pyogenes (Fig. 4).
Figure 4.
Effect of anti-TNF-α mAb on bacterial growth in muscular tissue at 24 hr post-infection. Each of the mice was infected with 5 × 108 CFU of S. pyogenes. LPS-treated mice were injected with 100 mg of LPS intraperitoneally. NRG or anti-TNF-α mAb-treated mice were injected with 1 mg of globulin per mouse 1 day before infection with 5 × 108 CFU of S. pyogenes. A double asterisk indicates a significant difference for the value between the NRG + LPS- and anti-TNF-α mAb + LPS-treated groups at P < 0·01.
Effects of in vivo administration of rTNF-α on mortality, necrosis and the growth of S. pyogenes in the muscles of the infected mice
It has been reported that LPS induces TNF-α production in vivo, thereafter TNF-α causes endotoxic shock. We investigated whether administration of rTNF-α induced STSS-like LPS. Mice were injected intravenously with PBS or rTNF-α. Treatment with the mAb or NRG was given simultaneously with infection. The mortality rate of the infected mice treated with rTNF-α significantly increased compared to that of the infected-only mice (Table 1). However, death of the infected mice treated with rTNF-α was observed by 7 days post-infection, and their mortality rate was low.
The infected mice treated with rTNF-α had muscular necrosis (Table 1).
At 24 hr post-infection, the number of S. pyogenes cells in the muscles of the infected mice treated with rTNF-α was significantly higher than that in the infected mice treated with PBS (Fig. 5).
Figure 5.
Effect of rTNF-α on bacterial growth in muscular tissue at 24 hr post-infection. Each of the mice was infected with 5 × 108 CFU of S. pyogenes. LPS-treated mice were injected with 100 mg of LPS intraperitoneally. PBS or 10 ng rTNF-α-treated mice were intravenously injected with 0·2 ml of PBS per mouse with 5 × 108 CFU of S. pyogenes simultaneously with infection. A double asterisk indicates a significant difference for the value between the PBS- and rTNF-α-treated groups at P ≤ 0·01.
Discussion
In humans, S. pyogenes mostly causes self-limiting infantile infectious diseases, and streptococcal infection induces resistance against re-infection.11 However, S. pyogenes causes STSS, and most of these patients do not show an apparent immunodeficient state.5 Antibiotic therapy for STSS patients is not very effective, although the bacteria isolated from these patients are not resistant to such drugs.6 This indicates that STSS is not simply a deterioration of streptococcal infection. It is possible that a new type of streptococcus induces STSS; however, such cells have not been observed. It is thought that cytokine production in STSS is important in inducing this disease, because STSS is similar to the toxic shock syndrome (TSS) induced by Staphylococcus aureus, and cytokines produced by the stimulation with TSST-1, which is a toxin of this bacterium and superantigen, are important in TSS.21 It has also been reported that cytokines are produced via stimulation by use of toxins of S. pyogenes.8,10,22 However, it is not clear whether S. pyogenes is able to induce cytokine production in the natural course of infection. In contrast with Gram-negative bacterial infections, there is only one report on cytokine production detected in severe streptococcal infection.23 It is possible that cytokines can be detected in the patients with severe streptococcal infection only in the late phase of the disease, because amount of superantigens increases with bacterial growth. In Japan, it is thought that cytokines, besides interleukin-6, are hard to detect in STSS patients. Our present study showed that intramuscular inoculation of S. pyogenes induced TNF production in the site of the infection, but not in the serum (Fig. 3). Cytokine production in systemic infection through the intravenous route was not detected in mice (data not shown). These studies indicated that the ability to induce systemic cytokine production by S. pyogenes was low, at least in the early phase of infection. On the other hand, it is possible that cytokines are important in the growth of S. pyogenes, as for Staphylococcus aureus,7 and trigger severe streptococcal infection. We speculate that for induction of STSS, not only S. pyogenes but also other agents are necessary. It is well recognized that LPS also induces shock in the host infected with Gram-negative bacteria through systemic cytokine production. Therefore, we tried to investigate whether administration of LPS affected streptococcal infection.
LPS induced systemic TNF production (Fig. 3a), augmentation of bacterial growth (Fig. 1) and mortality. Streptococcus pyogenes infection did not affect the TNF-α production induced by the stimulation with LPS (Fig. 3). Moreover, the period to death of mice treated with LPS and infection was a few days, and was longer than that of endotoxic shock mice. This indicated that the death of the infected mice was caused by S. pyogenes infection, not by LPS. It is unclear why LPS treatment augmented the growth of S. pyogenes. In LPS-treated mice, infiltration of leucocytes into the muscle was not observed (Fig. 2). It is possible that a decrease of phagocytosis by leucocytes was the cause of augmentation of the bacterial growth. This histological appearance is similar to that of human STSS.9 LPS treatment also inhibited production of TNF-α in the infectious lesions (Fig. 3b). However, TNF-α produced in the infectious lesions would not be important in augmenting the bacterial growth, because anti-TNF-α mAb treatment did not affect it (Fig. 4). We speculate that the deficiency of TNF-α production in the infectious lesions of the mice treated with LPS was caused by the inhibition of leucocyte infiltration. It has been reported that systemic treatment with LPS inhibits leucocyte infiltration induced by inflammatogenic agents.24
We confirmed that systemic TNF production caused muscular necrosis and lethal shock in streptococcal infection. The effect of LPS administration was reversed by anti-TNF-α mAb treatment (Table 1 and Fig. 4), and recombinant TNF-α administration caused augmentation of the rates of muscular necrosis and lethal shock (Table 1). The mechanism by which S. pyogenes infection of the mice treated with LPS or recombinant TNF-α induces lethal shock was not elucidated. It is thought that this shock is not endotoxic shock, because the amount of TNF production of the infected mice treated with LPS was not increased by the overlapping S. pyogenes infection (Fig. 3). Toxic agents produced by S. pyogenes are probably important in lethal shock.
It is unclear what mechanism induces exacerbation of S. pyogenes infection by LPS or TNF-α. It is also reported that LPS accelerates the growth of Salmonella in mice.25 We speculate that systemic TNF-α administration induces a favourable environment in the host for S. pyogenes growth, for example augmentation of nutrition for this bacterium in the host serum or muscular tissue. Systemic cytokine production is probably necessary to induce a favourable environment in the host for S. pyogenes.
Glossary
Abbreviations
- STSS
streptococcal toxic shock syndrome
- TNF-α
tumour necrosis factor-α
- mAb
monoclonal antibody
- LPS
lipopolysaccharide
- CFU
colony-forming unit
- NRG
normal rat globulin
References
- 1.Podbielski A, Woischnik M, Kreikemeyer B, Bettenbrock K, (Leonard) Buttaro BA. Cysteine protease SpeB expression in group A streptococci is influenced by the nutritional environment but SpeB does not contribute to obtaining essential nutrients. Med Microbiol Immunol. 1999;188:99–109. doi: 10.1007/s004300050111. 10.1007/s004300050111. [DOI] [PubMed] [Google Scholar]
- 2.Roggiani M, Stoehr JA, Leonard BA, Sclievert PM. Analysis of toxicity of streptococcal pyogenic exotoxin A mutants. Infect Immun. 1997;65:2868–75. doi: 10.1128/iai.65.7.2868-2875.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Talkington DF, Schwartz B, Black CM, Todd JK, Elliott J, Breiman RF, Facklam RR. Association of phenotypic and genotypic characteristics of invasive Streptococcus pyogenes isolates with clinical components of streptococcal toxic shock syndrome. Infect Immun. 1993;61:3369–74. doi: 10.1128/iai.61.8.3369-3374.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Basma H, NorrbyTeglund A, Guedez Y, McGeer A, Low DE, El-Ahmedy O, Schwartz B, Kotb M. Risk factors in the pathogenesis of invasive group A streptococcal infections: role of protective humoral immunity. Infect Immun. 1999;67:1871–7. doi: 10.1128/iai.67.4.1871-1877.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Hoge CW, Schwartz B, Talkington DF, Breiman RF, MacNeill EM, Englender SJ. The changing epidemiology of invasive group A streptococcal infections and the emergence of streptococcal toxic shock-like syndrome. A retrospective population-based study. JAMA. 1993;269:384–9. [PubMed] [Google Scholar]
- 6.Kaplan EL, Johnson DR, Del Rosario MC, Horn DL. Susceptibility of group A beta-hemolytic streptococci to thirteen antibiotics: examination of 301 strains isolated in the United States between 1994 and 1997. Pediatr Infect Dis J. 1999;18:1069–72. doi: 10.1097/00006454-199912000-00008. 10.1097/00006454-199912000-00008. [DOI] [PubMed] [Google Scholar]
- 7.Nakane A, Okamoto M, Asano M, Kohanawa M, Minagawa T. Endogenous gamma interferon, tumor necrosis factor, and interleukin-6 in Staphylococcus aureus infection in mice. Infect Immun. 1995;63:1165–72. doi: 10.1128/iai.63.4.1165-1172.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kotb M, Ohnishi H, Majumdar G, Hackett S, Bryant A, Higgins G, Stevens D. Temporal relationship of cytokine release by peripheral blood mononuclear cells stimulated by the streptococcal superantigen pep M5. Infect Immun. 1993;61:1194–201. doi: 10.1128/iai.61.4.1194-1201.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Ohe K. Invasive group A streptococcal infections, toxic shock-like syndrome. In: Ohe K, editor. Emerging and Re-Emerging Infectious Diseases. Tokyo: Nihon Izi Shinpou Shya; 1997. pp. 66–71. [Google Scholar]
- 10.Muller-Alouf H, Alouf JE, Gerlach D, Fitting C, Cavaillon JM. Cytokine production by murine cells activated by erythrogenic toxin type A superantigen of Streptococcus pyogenes. Immunobiology. 1992;186:435–48. doi: 10.1016/S0171-2985(11)80396-7. [DOI] [PubMed] [Google Scholar]
- 11.Mascini EM, Jansze M, Schellekens JF, et al. Invasive group A streptococcal disease in the Netherlands: evidence for a protective role of anti-exotoxin A antibodies. J Infect Dis. 2000;181:631–8. doi: 10.1086/315222. [DOI] [PubMed] [Google Scholar]
- 12.Laupland KB, Davies HD, Low DE, Schwartz B, Green K, McGeer A. Invasive group A streptococcal disease in children and association with varicella-zoster virus infection. Ontario Group A Streptococcal Study Group. Pediatrics. 2000;105:E60. doi: 10.1542/peds.105.5.e60. [DOI] [PubMed] [Google Scholar]
- 13.Bernald de Quiros JC, Moreno S, Cercenado E, Diaz D, Berenguer J, Miralles P, Catalan P, Bouza E. Group A streptococcal bacteremia. A 10-year prospective study. Medicine (Baltimore) 1992;76:238–48. doi: 10.1097/00005792-199707000-00002. 10.1097/00005792-199707000-00002. [DOI] [PubMed] [Google Scholar]
- 14.Davies HD, Schwartz B. Invasive group A streptococcal infections in children. Adv Pediatr Infect Dis. 1999;14:129–45. [PubMed] [Google Scholar]
- 15.Abe J, Forrester J, Nakahara T, Lafferty JA, Kotzin BL, Leung DY. Selective stimulation of human T cells with streptococcal erythrogenic toxins A and B. J Immunol. 1991;146:3747–50. [PubMed] [Google Scholar]
- 16.Abrams JS, Roncarolo M-G, Yessel H, Anderson U, Gleich GJ, Silver JE. Strategies of anti-cytokine monoclonal antibody development: immunoassay of IL-10 and IL-5 in clinical samples. Immunol Rev. 1992;127:5–24. doi: 10.1111/j.1600-065x.1992.tb01406.x. [DOI] [PubMed] [Google Scholar]
- 17.Nakane A, Minagawa T, Kato K. Endogenous tumor necrosis factor (cachectin) is essential to host resistance against Listeria monocytegenes infection. Infect Immun. 1988;56:2563–9. doi: 10.1128/iai.56.10.2563-2569.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Nakane A, Numata A, Minagawa T. Endogenous tumor necrosis factor, interleukin-6, and gamma interferon levels during Listeria monocytogenes infection in mice. Infect Immun. 1992;60:523–8. doi: 10.1128/iai.60.2.523-528.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Nakane A, Numata A, Chen Y, Minagawa T. Endogenous gamma interferon-independent host resistance against Listeria monocytogenes infection in CD4+ T cell- and asialo GM1+ cell-depleted mice. Infect Immun. 1991;59:3439–45. doi: 10.1128/iai.59.10.3439-3445.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Stevens DL, Gibbons AE, Bergstrom R, Winn V. The eagle effect revisited: efficacy of clindamycin, erythromycin, and penicillin in the treatment of streptococcal myositis. J Infect Dis. 1988;158:23–8. doi: 10.1093/infdis/158.1.23. [DOI] [PubMed] [Google Scholar]
- 21.Bergdoll MS, Crass BA, Reiser RF, Robbins RN, Davis JP. A new staphylococcal enterotoxin, enterotoxin F, associated with toxic-shock-syndrome Staphylococcus aureus isolates. Lancet. 1981;8228:1017–21. doi: 10.1016/s0140-6736(81)92186-3. [DOI] [PubMed] [Google Scholar]
- 22.Norrby-Teglund A, Norgren M, Holm SE, Andersson U, Andersson J. Similar cytokine induction profiles of a novel streptococcal exotoxin, MF, and pyogenic extoxins A and B. Infect Immun. 1994;62:3731–8. doi: 10.1128/iai.62.9.3731-3738.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Norrby-Teglund A, Pauksens K, Norgren M, Holm SE. Correlation between serum TNF alpha and IL6 levels and severity of group A streptococcal infections. Scand J Infect Dis. 1995;27:125–30. doi: 10.3109/00365549509018991. [DOI] [PubMed] [Google Scholar]
- 24.Scleiffenbaum B, Fehr J, Odermatt B, Sperb R. Inhibition of leukocyte emigration induced during the systemic inflammatory reaction in vivo is not due to IL-8. J Immunol. 1998;161:3631–8. [PubMed] [Google Scholar]
- 25.Hormaeche CE. Dead salmonellae or their endotoxin accelerate the early course of a Salmonella in mice. Microb Pathog. 1990;9:213–8. doi: 10.1016/0882-4010(90)90023-j. [DOI] [PubMed] [Google Scholar]