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PubMed2004

Association of tuberculin-boosted antibody responses with pathology and cell-mediated immunity in cattle vaccinated with Mycobacterium bovis BCG and infected with M. bovis.

Vaccine development and our understanding of the pathology of bovine tuberculosis in cattle would be greatly facilitated by definition of the immunological correlates of protection and/or pathology. In this study we analyzed humoral immune responses in Mycobacterium bovis BCG-vaccinated and control cattle (in particular, the relationship between the intradermal comparative tuberculin skin test and serum immunoglobulin G [IgG] responses) against a range of mycobacterial antigens (MPB59, MPB64, MPB70, MPB83, ESAT-6, CFP-10, Acr1, and PstS-1) by multiantigen print immunoassay and conventional enzyme-linked immunosorbent assay. Following M. bovis infection, the comparative tuberculin skin test strongly boosted IgG, IgG1, and IgG2 antibody responses, particularly against MPB83 and MPB70, in unvaccinated cattle but failed to boost these responses, or did so only weakly, in BCG-vaccinated calves. In addition, the skin test-induced increases in MPB83-specific IgG responses correlated positively with bacterial loads and ESAT-6-induced in vitro gamma interferon responses. In conclusion, both the negative correlation of skin test-enhanced MPB83-specific antibody responses with BCG-induced protection and their positive correlation with bacterial loads can serve as useful markers for vaccine efficacy after challenge.

Animals↗

PubMed2000

Clarithromycin-resistant mycobacterium avium is still susceptible to treatment with clarithromycin and is virulent in mice.

Resistance to clarithromycin in breakthrough Mycobacterium avium complex (MAC) isolates typically occurs 3 to 4 months after the initiation of monotherapy in bacteremic AIDS patients. It has been suggested that continuation of clarithromycin therapy still results in clinical and microbiological improvement. To study this paradox, C57BL/6 beige mice were infected with a clarithromycin-resistant (MIC, > or =128 microg/ml) strain of MAC 101 (CLA-R MAC 101) and treated with 200 mg of clarithromycin per kg of body weight/day alone or in combination with ethambutol (100 mg/kg/day) for 2 weeks. Mice infected with a clarithromycin-susceptible strain of MAC 101 had bacterial loads reduced by 90% in the liver and 91% in the spleen (P<0.05, compared with the control). Clarithromycin treatment of CLA-R MAC 101 resulted in a 65% reduction of bacterial loads in the liver (P = 0.009) and a 71% reduction in the spleen (P = 0.009), compared with the results for the untreated control. CLA-R MAC 101 and MAC 101 (isogenic strains) had comparable growth rates in murine tissue, ruling out a loss of virulence of CLA-R MAC 101. Strains of MAC currently defined as macrolide resistant may still respond to treatment with an agent such as clarithromycin within infected tissues.

AIDS-Related Opportunistic Infections↗

PubMed2000

Protective effect of DNA immunization against mycobacterial infection is associated with the early emergence of interferon-gamma (IFN-gamma)-secreting lymphocytes.

The development of more effective anti-tuberculosis (TB) vaccines would contribute to the global control of TB. Understanding the activated/memory T cell response to mycobacterial infection and identifying immunological correlates of protective immunity will facilitate the design and assessment of new candidate vaccines. Therefore, we investigated the kinetics of the CD4+ T cell response and IFN-gamma production in an intravenous challenge model of Mycobacterium bovis bacille Calmette-Guérin (BCG) before and after DNA immunization. Activated/memory CD4+ T cells, defined as CD44hiCD45RBlo, expanded following infection, peaking at 3-4 weeks, and decreased as the bacterial load fell. Activated/memory CD4+ T cells were the major source of IFN-gamma and the level of antigen-specific IFN-gamma-secreting lymphocytes, detected by ELISPOT, paralleled the changes in bacterial load. To examine the effects of a DNA vaccine, we immunized mice with a plasmid expressing the mycobacterial secreted antigen 85B (Ag85B). This led to a significant reduction in mycobacteria in the liver, spleen and lung. This protective effect was associated with the rapid emergence of antigen-specific IFN-gamma-secreting lymphocytes which were detected earlier, at day 4, and at higher levels than in infected animals immunized with a control vector. This early and increased response of IFN-gamma-secreting T cells may serve as a correlate of protective immunity for anti-TB vaccines.

Adjuvants, Immunologic↗

PubMed2006

Immunobiology of bovine mammary gland: apoptosis of somatic cells in milk during naturally occurring mastitis.

Mastitis remains a major cause of economic losses in dairy herds. It is believed, that the enhancement of natural defense mechanisms in mammary gland may be helpful in the treatment of bovine mastitis. Our study was designed to assess the apoptosis of leukocytes isolated from bovine milk during subclinical staphylococcal mastitis. Milk samples were collected from cows naturally infected with one pathogen--Staphylococcus aureus and from animals with mastitis caused by several pathogens, including S. aureus. It has been determined that the rate of apoptosis was lower in mastitic milk, as compared with control samples, although varied significantly between groups. High percentage of apoptotic cells was detected in milk with high counts of pathogenic bacteria. In all groups the rate of apoptosis was dependent on the bacterial load, although various correlations were identified. Thus, it is postulated, that the rate of apoptosis of somatic cells in mastitic milk is related to the etiology of infection and is determined by the bacterial load.

Animals↗

PubMed2006

Role of reactive nitrogen species in development of hepatic injury in a C57bl/6 mouse model of human granulocytic anaplasmosis.

Human granulocytic anaplasmosis (HGA), caused by the granulocytic rickettsia-like organism Anaplasma phagocytophilum, is the 3rd most frequent vector-borne infection in North America. To understand the disease mechanisms of HGA, we developed a murine model that lacks clinical disease yet exhibits characteristic histopathologic and immunologic changes. Because the degree of hepatic histopathology is unrelated to high bacterial numbers, tissue injury in HGA is thought to occur due to products of innate immunity, such as nitric oxide (NO) and reactive nitrogen species (RNS) from cytokine-activated macrophages. To test the hypothesis that RNS cause hepatic tissue damage, mice received either water treated with a nonspecific inhibitor of inducible nitric oxide synthase, L-NAME, or untreated water for 7 to 10 d before infection and continuing thereafter. Mice were euthanized for tissue harvest at 0, 7, 14, or 21 d after infection to assess differences in histopathology, hepatic bacterial load, RNS quantity in urine and liver, and serum chemistry values. Overall, L-NAME treatment had a beneficial effect, resulting in lower histopathology scores and RNS levels compared with those of untreated mice. There were no significant differences in hepatic bacterial load among treatment groups of infected mice. The observed increases in serum glucose and alanine aminotransferase levels on day 14 appear to be unexpected side effects of L-NAME administration. HGA is best characterized as an immunopathologic disease rather than one caused by direct bacterial injury to the host. Therefore, human and animal patients with HGA likely would benefit from therapy targeting reduced inflammation to supplement anti-infective modalities.

Anaplasma phagocytophilum↗

PubMed2002

Effective control of dental chair unit waterline biofilm and marked reduction of bacterial contamination of output water using two peroxide-based disinfectants.

Bacterial biofilm in dental unit waterlines (DUWs) is a widespread problem, and poses a potentially significant risk of infection to dental staff and patients, particularly those who are medically compromised or immunocompromised. The purpose of the present study was to investigate the level of bacterial contamination of dental chair unit output water in the Dublin Dental Hospital, and to investigate the efficacy of two hydrogen peroxide-based disinfectants in reducing bacterial loads to < or =200 cfu/mL as recommended by the American Dental Association. The chemical quality of dental chair unit input and output water was well within the limits recommended for potable water. Water supplied to the units yielded an average aerobic heterotrophic bacterial cell density of 184 cfu/mL. However, the corresponding density in output water was considerably higher; the average cell density in water from the three-in-one air/water syringes and cup fillers in 12 chairs was 8200 and 4300 cfu/mL, respectively. Dental unit water obtained from 18 separate reservoir-supplied units in general practices in the Dublin area yielded an average of 66000 cfu/mL. The bacterial species found were predominantly environmental organisms, which were also present at low levels in the input water. Some of the species identified (e.g., Burkholderia cepacia and Pseudomonas fluorescens) are known opportunistic pathogens. The capacity of two disinfectants, Sterilex Ultra and Sanosil, to reduce bacterial contamination to safe levels was compared. In a controlled study, once weekly overnight (15 h) disinfection using either agent reduced the bacterial density to below the American Dental Association recommended level of 200 cfu/mL. However, once disinfection ceased the bacterial loads increased to unacceptably high levels within three weeks. Electron microscopic analysis showed that both disinfectants markedly reduced biofilm in the DUWs, but the biofilm rapidly became extensive again when once weekly disinfection ceased. While both disinfectants were equally effective in lowering the bacterial counts to acceptable levels, Sterilex Ultra was associated with clogging of DUWs in some dental chair units after repeated usage, suggesting that Sanosil is a more suitable agent for routine use.

Biofilms↗

PubMed2004

Cecal ligation and puncture versus colon ascendens stent peritonitis: two distinct animal models for polymicrobial sepsis.

Colon ascendens stent peritonitis (CASP) and cecal ligation and puncture (CLP), two animal models designed to closely mimic the clinical course of intra-abdominal sepsis, were compared. In the past, immunomodulatory therapies developed in animal studies failed to be successful in humans. As a consequence, the established animal sepsis models were criticized. It has been proposed that present models had to be reevaluated, and new, clinically more relevant models should be evolved. CLP procedure was performed puncturing once (CLP[1]) or twice (CLP[2]) the ligated cecum of C57BL/6 mice. In the CASP model, a stent with defined diameter was surgically inserted into the ascending colon. Survival, bacterial load, immunohistochemistry, and serum cytokine levels were analyzed in the groups. Survival after CASP procedure correlated strongly with the stent diameter, whereas the number of punctures in CLP did not significantly change survival rate. Bacterial loads of peritoneal lavage, liver, and lung, as well as serum cytokine levels (tumor necrosis factor, interleukin 1 beta, interleukin 10) steadily increased from 6 to 24 h after the CASP procedure. In contrast, continuously low amounts of bacteria and cytokines were found in CLP mice at any point of time. Twenty-four hours after CLP surgery, the ligated cecum was covered by adhesive small bowel loops, whereas in CASP mice, the intestinal leakage was then still present. The CASP model mimics closely the clinical course of diffuse peritonitis with early and steadily increasing systemic infection and inflammation (systemic inflammatory response syndrome). In contrast, CLP reveals a model of intra-abdominal abscess formation with sustained and minor signs of systemic inflammation.

Abdomen↗

PubMed2006

Cytokine expression profiles of bovine lymph nodes: effects of Mycobacterium bovis infection and bacille Calmette-Guérin vaccination.

Cytokine expression in lymph nodes from cattle inoculated intranasally with Mycobacterium bovis was compared to that of non-infected animals using real-time polymerase chain reaction. The effect of M. bovis infection, 4 months post-challenge, was to suppress the expression of anti-inflammatory cytokines interleukin (IL)-4 and IL-10 as well as the pro-inflammatory cytokines tumour necrosis factor (TNF) and IL-6. Expression of interferon (IFN)-gamma and IL-12 was maintained. Animals vaccinated with bacille Calmette-Guérin responded differently to challenge with M. bovis. In particular, no decrease in expression of IL-4 or IL-6 was observed following challenge of vaccinated animals and decreased IFN-gamma was detected. Also, vaccinated animals had higher levels of IL-4 and IL-10 transcripts compared to unvaccinated animals following challenge. These changes in cytokine expression levels led to a significant shift in the IFN-gamma/IL-4 or IFN-gamma/IL-10 ratio within the lymph node following challenge. Challenged animals generally showed a strong Th1 bias that was not seen in animals vaccinated prior to challenge. An inverse correlation between the level of pathology and bacterial load within the lymph node and the expression of IL-4, IL-10 and TNF was also observed. These results suggest that in the lymph nodes of cattle with established tuberculosis and a persisting bacterial infection, maintenance of the pro-inflammatory response in combination with a suppressed anti-inflammatory response may control the infection but contribute to host-induced tissue damage. Vaccination, which reduces the bacterial load and consequently the IFN-gamma response, may result in less suppression of anti-inflammatory cytokines.

Animals↗

PubMed1996

Effect of rhuIFN-gamma treatment in multibacillary leprosy patients.

Previous studies have shown that when multibacillary leprosy patients were treated with recombinant human interferon gamma (rhuIFN-gamma) for 6-10 months there was an accelerated reduction in the number of acid-fast bacilli in the skin at the site of injection as well as an accelerated bacillary reduction at distal sites. However, this favorable out-come of IFN-gamma treatment was associated with the development of erythema nodosum leprosum (ENL). The present study was undertaken to investigate whether rhuIFN-gamma-induced bacillary clearance could be disassociated from the induction of ENL. rhuIFN-gamma was administered together with thalidomide and conventional multidrug chemotherapy to newly diagnosed leprosy patients. During treatment with this combination of drugs, the mean reduction in bacterial load was the same as the reduction observed with chemotherapy alone. Moreover, the inclusion of thalidomide in the treatment regimen was associated with a low frequency of ENL episodes. A second group of leprosy patients, who had already completed 2 years of chemotherapy, were treated with rhuIFN-gamma only. In those patients who were skin bacilli negative, ENL did not occur during rhuIFN-gamma treatment. In contrast, in bacilli-positive patients the frequency of ENL during rhuIFN-gamma treatment was higher, as was the occurrence of local erythema and induration. However, rhuIFN-gamma treatment without concomitant chemotherapy did not result in a reduction in the bacterial load in the skin of bacilli-positive patients. These findings, taken together, indicate that rhuIFN-gamma does not, by itself, accelerate bacterial clearance, but requires concomitant chemotherapy to achieve the accelerated reduction in bacillary load. Thalidomide reduces the frequency of IFN-gamma-induced ENL, but also eliminates the IFN-gamma-induced bacillary clearance.

Clofazimine↗

PubMed2002

Association of MHC class I and class II gene polymorphisms with vaccine or challenge response to Salmonella enteritidis in young chicks.

Salmonella enteritidis (SE) is a worldwide source of salmonellosis in humans, caused mainly by consumption of contaminated poultry products. The major histocompatibility complex (MHC) class I and class II molecules, which function as antigen-presentation structures, are involved in both macrophage and dendritic cell immune response to Salmonella and may, therefore, play an important role in host resistance to infections. The chicken MHC class I and class II were investigated as candidate genes for immune response to SE. We characterized the complete MHC class I cDNA sequences for an outbred broiler line and four diverse highly inbred lines: two MHC-congenic Leghorn (G-B2 and G-B1), one Egyptian Fayoumi (M15.2), and one Spanish (Sp21.1), to define the allelic sequences within these lines, so that we might study the association between particular MHC polymorphisms and response to SE. The F1 offspring of outbred broiler sires crossed with three inbred lines (G-B1, G-B2, and Fayoumi) were evaluated as young chicks for either bacterial load in spleen and cecum after pathogenic SE inoculation or antibody level after SE vaccination. Alleles defined by a Lys(148)-->Met(148) polymorphism in the MHC class I alpha(2) domain were associated with spleen bacterial load after SE challenge. These results suggest that particular MHC haplotypes may contribute to control of responses to SE, and that particular polymorphisms may serve as markers for genetic resistance to SE in the chicken.

Animals↗

PubMed1998

AFB staining in cytodiagnosis of tuberculosis without classical features: a comparison of Ziehl-Neelsen and fluorescent methods.

Fine needle aspirates (FNA) were obtained from lymph node and other sites in 250 suspected cases of tuberculosis. Twenty-four cases proved to be non-tubercular on FNA smears and served as negative controls. Of the smears obtained from the remaining 226 cases, 233 were classified into five groups based on cytomorphological features, i.e. presence of necrosis and granulomas, necrosis alone or acute inflammatory exudate (AIE) with or without granuloma. Cases with AIE alone formed the largest group (n = 123). Staining for AFB was done by Ziehl-Neelsen (ZN) and fluorescent methods in all 250 cases. A correlation of AFB positivity and its semiquantitative scoring (1+ to 3+) with the cytomorphological spectrum was done. Overall AFB positivity by ZN staining was 33.5% and by fluorescent staining 45.4%. When the two methods were combined, AFB positivity was 58.7%. Fluorescent staining was superior to the ZN stain in the presence of a low bacterial load as seen in smears with diagnostic cytomorphological features of tuberculosis. In problem areas like AIE alone or with occasional granulomas, AFB positivity by ZN staining is nearly as good as the fluorescent method, because the bacterial load is high.

Adolescent↗

PubMed1997

Defects in cell-mediated immunity affect chronic, but not innate, resistance of mice to Mycobacterium avium infection.

To investigate the role of cell-mediated immunity in the control of Mycobacterium avium infection, we studied the effects of targeted gene disruptions in components of the T lymphocyte-dependent, macrophage-mediated response on resistance of mice to this pathogen. Normal mice developed a chronic, asymptomatic infection, with rapid induction of mRNAs for IFN-gamma, IL-12, and TNF-alpha in spleen, liver, and lung. Bacterial loads in gene knockout, scid, and wild-type mice were indistinguishable for the first 4 wk of infection. However, by 8 wk postinfection, scid mice as well as animals with a targeted disruption of the IFN-gamma gene showed enhanced bacterial growth compared with wild-type controls. In contrast, knockout mice lacking the genes for the TNF-alpha p55/p75 receptors or inducible nitric oxide synthase not only developed comparable bacterial loads to wild-type animals, they also failed to display the splenomegaly and profound suppression of mitogen-induced lymphocyte proliferative responses evident in infected wild-type controls. Thus, M. avium is clearly distinct from other intracellular pathogens (e.g., Leishmania monocytogenes, Toxoplasma gondii, and Mycobacterium tuberculosis) whose initial replication in the host is tightly controlled by Th1-dependent effector mechanisms. Instead, the major effect of host cell-mediated immunity is to limit bacterial growth during the chronic phase of infection. Surprisingly, inducible nitric oxide appears to be more important for the immunopathology than for the host resistance induced by this bacterial pathogen.

Animals↗

PubMedDate not supplied

Role of interleukin-8 in community-acquired pneumonia: relation to microbial load and pulmonary function.

In pneumonia local phagocyte activation is crucial for clearing of pathogenic microorganisms. In this context alveolar macrophage interleukin-8 secretion, phagocyte oxidative response and concentrations of lavage proteins were quantified, including interleukin-8, in 31 patients with pneumonia, 13 age matched patients with peripheral lung consolidation and six healthy volunteers; these findings were related to the impairment of gas exchange and the bacterial load in the alveolar space. Increased interleukin-8 levels were found in bronchoalveolar lavage fluid (BALF) and in alveolar macrophage supernatants from patients with pneumonia (214 ng/10(5) AM +/- 121 vs 71 ng/10(5) AM +/- 35 and 66 ng/10(5) AM +/- 30, p < 0.05). Interleukin-8 release from alveolar macrophages correlated with the upregulated spontaneous luminol enhanced oxidative response of pulmonary phagocytes but not with the neutrophil count in BALF. In pneumonia patients a significant difference was found between patients with 10(4) or more colony forming units (CFU)/ml BALF of one pathogen and patients with less CFU or nonspecific microbiological results (261 ng/10(5) AM +/- 89 vs 179 ng/10(5) AM +/- 81 and 7.5 ng/ml BALF +/- 17 vs 0.44 ng/ml BALF +/- 1, p < 0.05). Further, a negative correlation between interleukin-8 release of alveolar macrophages and the arterial pO2 at the time of BALF could be demonstrated (r = -0.47, p < 0.05). The results demonstrate local cellular activation in community-acquired pneumonia, which is related to the bacterial load in the alveolar space and to impairment of gas exchange. This is consistent with the hypothesis that pulmonary phagocytes play a central role in the pathogenesis of bacterial pneumonia, contributing not only to bacterial clearing but also to local tissue damage.

Adult↗

PubMed2006

An alternative regimen for root canal disinfection.

OBJECTIVE: To compare the effect of a combination of 20% citric acid solution and photo-activated disinfection with the use of 20% citric acid and 2.25% sodium hypochlorite solutions on bacterial load on the dentine walls in prepared canals in vivo. SUBJECTS AND METHODS: Sixty-four randomly selected cases were evaluated and allocated to one of two groups. In Group 1, after gaining access to the root canal, bacterial load on the canal walls was sampled using endodontic files. A further sample was taken after apex location and initial widening of the canal had been completed and the photo-activated disinfection process carried out. A final sample was taken after completion of the canal preparation using citric acid and sodium hypochlorite solutions. In Group 2, the initial sample was taken as described previously. A second sample was taken after conventional preparation using 20% citric acid and sodium hypochlorite solutions as co-irrigants. A final sample was then taken after a subsequent PAD treatment. All samples were cultured for facultative anaerobic bacteria. RESULTS: Of the canals treated in Group 1 only two of the 23 canals infected showed culturable bacteria after the use of citric acid and photo-activated disinfection. Of these two canals, one was free of culturable bacteria on completion of conventional treatment but the other still contained culturable bacteria. In Group 2, four canals of the 23 infected initially, remained contaminated after conventional treatment. After subsequent photo-activated disinfection three of these four canals were free of culturable bacteria. CONCLUSION: Results indicate that the use of a chelating agent acting as a cleaner and disrupter of the biofilm and photo-activated disinfection to kill bacteria is an effective alternative to the use of hypochlorite as a root canal cleaning system.

Adolescent↗

PubMed1991

Analysis of the time course of IFN-gamma mRNA and protein production during primary murine listeriosis. The immune phase of bacterial elimination is not temporally linked to IFN production in vivo.

IFN-gamma clearly plays an important role in the murine host response against Listeria monocytogenes, but the time course of its production and its precise role in immunity remain controversial. To address these issues, we sequentially monitored IFN production and bacterial accumulation in vivo in C57B1/6 mice during primary listeriosis. IFN-gamma mRNA levels (measured by Northern blot analysis of freshly isolated splenic RNA) and serum IFN (measured by ELISA) were both maximal on day 1 of infection, decreasing steadily after day 2 to barely detectable levels by days 4 to 6. Significantly, there was no direct relationship between IFN levels and listericidal activity in vivo. Between days 1 and 3, the period of maximal IFN production, host bacterial load (assessed by quantitating live L. monocytogenes/spleen) increased approximately 10- to 50-fold. On the other hand, during the immune phase of infection (between days 5 and 7), a period when both IFN mRNA and protein were barely detectable, the host bacterial load decreased 1,000- to 10,000-fold. The paucity of IFN production in vivo during the immune phase was unexpected in light of previous reports demonstrating abundant in vitro lymphokine release by splenocytes isolated during the same time period. By direct comparisons of IFN production in vivo and in vitro, however, we could show that the late (days 6-7) peak of IFN release observed in Ag-stimulated cultures was an in vitro artifact. By contrast the pattern of spontaneous IFN release (obtained when freshly isolated cells were incubated in the absence of Ag) conformed more closely to that observed in vivo. Because listerial Ag stimulated vigorous lymphokine release in vitro, we sought to determine whether an analogous effect could be observed in vivo. In fact, even the infusion of very large doses of live bacteria (5-20,000,000/mouse) did not stimulate endogenous IFN-gamma production in mice infected for 6 to 7 days. These studies suggest three major conclusions: 1) IFN production in vivo occurs primarily during the early phase of listeriosis; 2) the dramatic decrease in bacterial numbers observed late in infection cannot be directly attributed to increased IFN production by LM-immune T cells; 3) although Ag-driven cultures of freshly isolated cells can provide useful information about the potential lymphokine-producing capabilities of Ag-specific T cells, these results have limited relevance in understanding patterns of T cell lymphokine production in vivo.

Animals↗

PubMed2006

Comparison of eggshell hygiene in two housing systems: standard and furnished cages.

1. The hygienic properties of eggs produced in two designs of furnished cage were investigated and compared to two standard cage designs. 2. At 28, 37, 47 and 58 weeks of age, the proportion of dirty eggs was higher in one of the furnished cage designs while, in the other, it was similar to standard cages. 3. At 27, 33 and 60 weeks, the bacterial load on the eggshell (total aerobic bacteria and enterococci) was higher in furnished cage designs. A seasonal effect was observed with lower counts at 60 weeks (winter) than at 27 weeks (summer). 4. More dirty eggs and a higher bacterial load were observed in eggs laid outside the nests, which suggests egg hygiene in furnished cages could be similar to standard cages if the equipment in furnished cages was improved to enhance nest laying.

Aging↗

PubMed2001

Improved innate immunity of endotoxin-tolerant mice increases resistance to Salmonella enterica serovar typhimurium infection despite attenuated cytokine response.

During infection with gram-negative bacteria, exposure of immune cells to lipopolysaccharide (LPS) from the bacterial cell membrane induces a rapid cytokine response which is essential for the activation of host defenses against the invading pathogens. Administration of LPS to mice induces a state of hyporesponsiveness, or tolerance, characterized by reduced cytokine production upon subsequent LPS challenge. In the model of experimental Salmonella enterica serovar Typhimurium infection of mice, we assessed the question of whether complete LPS tolerance induced by repetitive doses of LPS interfered with cytokine production and host defense against gram-negative bacteria. Although production of various cytokines in response to serovar Typhimurium was attenuated by LPS pretreatment, LPS-tolerant mice showed improved antibacterial activity, evidenced by a prolongation of survival and a continuously lower bacterial load. We attribute this protective effect to three independent mechanisms. (i) Peritoneal accumulation of leukocytes in the course of LPS pretreatment accounted for enhanced defense against serovar Typhimurium during the first 6 h of infection but not for decreased bacterial load in late-stage infection. (ii) LPS-tolerant mice had an increased capacity to recruit neutrophilic granulocytes during infection. (iii) LPS-tolerant mice showed threefold-increased Kupffer cell numbers, enhanced phagocytic activity of the liver, and strongly improved clearance of blood-borne serovar Typhimurium. These results demonstrate that despite attenuated cytokine response, acquired LPS tolerance is associated with enhanced resistance to infections by gram-negative bacteria and that this effect is mainly mediated by improved effector functions of the innate immune system.

Animals↗

PubMed2004

Role of host genetic factors in susceptibility to group A streptococcal infections.

BACKGROUND & OBJECTIVES: Epidemiological evidences indicate that host genetic factors might be critical in determining susceptibility to infection with group A streptococci (GAS). The objective of the present study was to determine the extent to which the genetic background of the mouse strain affected induction and resolution of GAS infection. METHODS: Several inbred mouse strains were intravenously infected with Streptococcus pyogenes strain A20 and the mean survival times of mice was recorded overtime. Bacterial loads were determined in liver and spleen of infected animals at 48 h postinoculation. RESULTS: Different strains of mice exhibited differential susceptibility to GAS infection. After systemic infection with S. pyogenes, inbred mice showed substantial differences in mortality and bacterial loads. INTERPRETATION & CONCLUSION: This study provides further evidences that a genetic component is associated with host susceptibility or resistance to GAS infection.

Animals↗