TLR2 Promotes Monocyte/Macrophage Recruitment Into the Liver and Microabscess Formation to Limit the Spread of Listeria Monocytogenes.

TLR2 signaling plays a critical protective role against acute Listeria monocytogenes (Lm) infection by up-regulating inflammatory cytokines and promoting macrophage antimicrobial capabilities. However, the underlying mechanism by which TLR2 regulates hepatic macrophage-mediated anti-Lm immune responses remains poorly understood. In this study, we found that both the absolute number and proportion of monocyte/macrophage (Mo/MΦ) in the liver and spleen of Tlr2-/- mice were significantly lower compared to wild type mice. Changes in TLR2 signaling in both hepatocytes and Mo/MΦs were associated with the infiltration of Mo/MΦs in response to Lm-infection. Analyses by proteome profiler array and ELISA revealed that hepatocytes recruited Mo/MΦs via TLR2-dependent secretion of CCL2 and CXCL1, which was confirmed by receptor blocking and exogenous chemokine administration. Importantly, we found that TLR2 contributed to macrophage mobility in the liver through a TLR2/NO/F-actin pathway, facilitating the formation of macrophage-associated hepatic microabscesses. Moreover, TLR2 activation induced the expression of several PRRs on hepatic macrophages associated with the recognition of Lm and augmented macrophage bacterial clearance activity. Our findings provide insight into the intrinsic mechanisms of TLR2-induced Mo/MΦ migration and mobility, as well as the interaction between macrophages and hepatocytes in resistance to Lm infection.

Protective Role of Kupffer Cells and Macrophages in Klebsiella pneumoniae-Induced Liver Abscess Disease.

Klebsiella pneumoniae-induced liver abscess (KLA) is emerging as a leading cause of pyogenic liver abscess worldwide. In recent years, the emergence of hypervirulent K. pneumoniae (hvKp) has been strongly associated with KLA. Unlike classical K. pneumoniae, which generally infects the immunocompromised population, hvKp can cause serious and invasive infections in young and healthy individuals. hvKp isolates are often associated with the K1/K2 capsular types and possess hypermucoviscous capsules. KLA is believed to be caused by K. pneumoniae colonizing the gastrointestinal tract of the host and translocating across the intestinal barrier via the hepatic portal vein into the liver to cause liver abscess. We optimized the isolation of the liver-resident macrophages called Kupffer cells in mice and examined their importance in controlling bacterial loads during hvKp infection in healthy mice. Our study reveals the high capability of Kupffer cells to kill hvKp in vitro despite the presence of the bacterial hypermucoviscous capsule, in contrast to other macrophages, which were unable to phagocytose the bacteria efficiently. Depletion of Kupffer cells and macrophages with liposome-encapsulated clodronate (liposomal clodronate) in both an intraperitoneal and an oral mouse infection model resulted in increased bacterial loads in the livers, spleens, and lungs and increased mortality of the infected mice. Thus, Kupffer cells and macrophages are critical for the control of hvKp infection.

Liver abscess due to Sterigmatomyces halophilus in a boy with acute lymphoblastic leukemia.

We report the first case of liver abscess due to Sterigmatomyces halophilus. Because this pathogen grows poorly in culture medium without added salts, it was identified by sequencing analysis targeting the rRNA gene internal transcribed spacer (ITS) region. This method could be useful for pathogens that cannot be cultured using standard methods.

Hepatic microabscesses during CMV reactivation in a multiple sclerosis patient after alemtuzumab treatment.

The anti-CD52 monoclonal antibody alemtuzumab is a highly active treatment for multiple sclerosis (MS) causing rapid depletion of B and T lymphocytes with nadir one month after last infusion. Opportunistic Cytomegalovirus (CMV) infections have been reported in MS patients treated with this drug. We report one patient who developed a CMV reactivation with hepatic involvement three weeks after the first cycle of alemtuzumab. This patient, promptly diagnosed and treated, achieved a complete recovery with valganciclovir. The possibility of this treatable opportunistic infection should be considered by neurologists in febrile patients with hepatic markers alteration after treatment with alemtuzumab.

Pseudomonas aeruginosa liver abscess as the first manifestation of X-Linked agammaglobulinemia with a novel mutation

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Gastrointestinal and liver infections in children undergoing antineoplastic chemotherapy in the years 2000.

AIM: To review gastrointestinal and liver infections in children undergoing antineoplastic chemotherapy. To look at gut microflora features in oncology children. METHODS: We selected studies published after year 2000, excluding trials on transplanted pediatric patients. We searched English language publications in MEDLINE using the keywords: "gastrointestinal infection AND antineoplastic chemotherapy AND children", "gastrointestinal infection AND oncology AND children", "liver infection AND antineoplastic chemotherapy AND children", "liver abscess AND chemotherapy AND child", "neutropenic enterocolitis AND chemotherapy AND children", "thyphlitis AND chemotherapy AND children", "infectious diarrhea AND children AND oncology", "abdominal pain AND infection AND children AND oncology", "perianal sepsis AND children AND oncology", "colonic pseudo-obstruction AND oncology AND child AND chemotherapy", "microflora AND children AND malignancy", "microbiota AND children AND malignancy", "fungal flora AND children AND malignancy". We also analysed evidence from several articles and book references. RESULTS: Gastrointestinal and liver infections represent a major cause of morbidity and mortality in children undergoing antineoplastic chemotherapy. Antineoplastic drugs cause immunosuppression in addition to direct toxicity, predisposing to infections, although the specific risk is variable according to disease and host features. Common pathogens potentially induce severe diseases whereas opportunistic microorganisms may attack vulnerable hosts. Clinical manifestations can be subtle and not specific. In addition, several conditions are rare and diagnostic process and treatments are not standardized. Diagnosis may be challenging, however early diagnosis is needed for quick and appropriate interventions. Interestingly, the source of infection in those children can be exogenous or endogenous. Indeed, mucosal damage may allow the penetrance of endogenous microbes towards the bowel wall and their translocation into the bloodstream. However, only limited knowledge of intestinal dysbiosis in oncology children is available. CONCLUSION: The diagnostic work-up requires a multimodal approach and should be implemented (also by further studies on new biomarkers) for a prompt and individualized therapy.

[Extraenteric infection caused by Blastocystis spp. in a female patient with liver abscess].

The cases associated with the development of liver abscesses in a 64-year-old female patient after elective surgery for colon polyposis could form an opinion that extraenteric infection caused by Blastocystis spp. might develop in the immunocompromised host. The development of Blastocystis spp. in the presence of disintegrated liver tissue and inflammatory cells was verified by microscopic examination of liver abscess aspirates. The Romanovsky-Giemsa stained specimens exhibited typical amoeboid, vacuolar and, what is particularly important, dividing forms of Blastocystis spp. The patients full recovery after timely combination therapy with broad-spectrum antibiotics and imidazole group preparations also indirectly argues for the etiological role of Blastocystis spp. in the development of liver abscess with the signs of changes in both lungs (the signs of right lung compression and bilateral hydrothorax). Physicians' awareness of the potential clinical significance of Blastocystis spp. in immunodeficient patients is sure to expand the range of differential diagnostic studies of patients infected with Blastocystis spp.. particularly in case of gastrointestinal tract diseases of unknown etiology.

TREM-1 promotes survival during Klebsiella pneumoniae liver abscess in mice.

Klebsiella pneumoniae liver abscess (KPLA) is prevalent in East Asia. Liver abscess can develop after translocation of K. pneumoniae from a patient's bowel into the liver via the portal circulation. TREM-1 (triggering receptor expressed on myeloid cells 1) amplifies inflammatory signaling during infection, but its role in KPLA is poorly understood. We used an animal study to characterize the role of TREM-1 in KPLA. We compared survival rates, bacterial burdens in tissues, inflammatory cytokine levels, and histology findings between wild-type and Trem-1 knockout (KO) mice after oral inoculation of capsular type K1 K. pneumoniae. Translocation of K. pneumoniae to mesenteric lymph nodes and liver was examined, and intestinal permeability, antimicrobial peptide expression, and the clearance of K. pneumoniae in the small intestine were determined. In the absence of TREM-1, KPLA model mice showed increased K. pneumoniae dissemination, enhanced liver and systemic inflammation, and reduced survival. Impaired bacterial clearance in the small intestine causes enhanced K. pneumoniae translocation, which renders Trem-1 KO mice more susceptible to K. pneumoniae oral infection. In conclusion, TREM-1-mediated bacterial clearance in the small intestine is an important immune response against K. pneumoniae. TREM-1 deficiency enhances K. pneumoniae translocation in the small intestine and increases mortality rates in mice with KPLA.

Isolated tuberculous liver abscess in immunocompetent children - report of two cases.

Isolated tuberculous liver abscess (TLA) without active pulmonary or miliary tuberculosis, or other clinical evidence of tuberculosis, is distinctly rare and only few cases have been reported in the literature. We report two cases of isolated TLA in immunocompetent children, treated successfully by percutaneous aspiration followed by systemic antituberculous drugs.

Liver abscess caused by Brevundimonas vesicularis in an immunocompetent patient.

Invasive infections caused by Brevundimonas vesicularis are very rare in humans. We experienced an unusual case of liver abscess due to B. vesicularis in an immunocompetent young male. The patient was successfully treated by liver abscess drainage and with antimicrobial therapy of ceftriaxone followed by ampicillin/sulbactam. The organism found in the aspiration culture of the abscess material was initially reported, by using a VITEK 2 system, as Sphingomonas paucimobilis. However, later, B. vesicularis was confirmed as the true pathogen through 16S rRNA gene sequencing. To our knowledge, this is the first case of liver abscess caused by B. vesicularis.

Increasing opsonizing and killing effect of serum from patients with recurrent K1 Klebsiella pneumoniae liver abscess.

BACKGROUND: Klebsiella pneumoniae liver abscess (KLA) is an emerging infectious disease caused by the virulent K pneumoniae strains of capsular serotype K1 and commonly associated with diabetes mellitus. Recurrent KLA is rarely reported and the mechanism of recurrence is uncertain. In this study we evaluated both phagocytosis by neutrophils and serum killing ability of serum from recurrent K1 KLA patients compared to normal healthy subjects (NHS). METHODS: This prospective study included six cases of recurrent K1 KLA consisting of three male and three female patients with a mean age of 67.2 years (range, 56-88 years). The different serotypes of K pneumoniae were reacted with serum from patients with recurrent KLA and NHS. Subsequent phagocytosis by neutrophils was determined using flow cytometry and serum killing assays were performed. RESULTS: The most common underlying disease in patients with recurrent KLA was diabetes mellitus, occurring in about 83.3% (5/6) of patients. The antibiogram of the strains associated with recurrent KLA remained uniquely resistant to ampicillin. The average percentage derived from the serum killing assays showed serotype K1 and K2 resistance to serum from NHS (1281% and 621%, respectively); however, serum susceptibly was observed in the serum of patients with recurrent K1 KLA (0.3% and 1.1%, respectively). A significant increase in neutrophil phagocytosis of serotype K1 was observed following opsonisation with serum from patients with recurrent KLA compared with serum from NHS (p = 0.008). No significant difference in the phagocytic rate of non-K1/K2 or K2 serotypes was observed between NHS and patients with recurrent KLA (p = 0.76 and p = 0.132, respectively). CONCLUSION: These preliminary results showed possible immunologic protection in patients with recurrent KLA due to increasing opsonization and serum killing.

Tuberculous liver abscess in an immunocompetent adult male--a rare presentation.

A 20 year old young male was admitted to our hospital with complaints of pain in upper abdomen right side, anorexia and loss of weight. Ultrasonography of the upper abdomen revealed a hypoechoic area in the left lobe of liver. Entertaining the possibility of pyogenic or amoebic lesion, the patient was started on ofloxacin and metronidazole. Failing to get any response to the therapeutic intervention, ultrasound guided aspiration was undertaken. The aspirated pus did not grow any organism in pyogenic or fungal culture but showed acid fast bacilli in Z.N. stain. The treatment was shifted to four drugs ATT and there was dramatic improvement in the clinical condition. This case is being reported to emphasize that ruling out tuberculosis may avoid unnecessary delays in the initiation of specific anti-tubercular treatment. Also a greater awareness of this rare clinical condition may prevent unwarranted surgical intervention.

Impact of age on neutrophil phagocytic reaction with different capsular serotypes of Klebsiella pneumoniae.

BACKGROUND: Although the prevalence of K pneumoniae liver abscess is higher in patients older than 55 years, the possible relationship of age with decreased phagocytic function of the patients with Klebsiella pneumoniae liver abscess has not been investigated. Our aim was to determine whether susceptibility to K pneumoniae infection depended on age-related impairment of phagocytic function. METHODS: The study enrolled 42 subjects in three age groups: younger than 40 years (n=10), 40-65 years (n=12), and older than 65 years (n=20). Seventy-five strains of K pneumoniae were investigated, including liver abscess isolates (n=25) and blood isolates from the patients without liver abscesses (n=50). The rate of phagocytosis of K1/K2 (n=36) and non-K1/K2 (n=39) K pneumoniae by neutrophils was determined using flow cytometry and compared among the three age groups. RESULTS: The rate of phagocytosis of serotype K1/K2 isolates was significantly lower in the middle-aged group than that in the younger group (p=0.015) and significantly lower in the older group than those in the middle-aged and younger groups (p=0.025 and p<0.01). In contrast, the rate of phagocytosis of non-K1/K2 isolates was similar in all three age groups at 60 minutes (66.4±1.85%, 65.2±2.0%, and 62.3±1.81%; p=not significant). CONCLUSIONS: Thus, as age increases, the ability of neutrophils to phagocytose virulent K1/K2 K pneumoniae decreases. This finding may account for the higher prevalence of K pneumoniae liver abscesses in older patients.

Immune response and pathophysiological features of Klebsiella pneumoniae liver abscesses in an animal model.

Capsular serotypes K1 and K2, the rmpA gene (a regulator of the mucoid phenotype) and aerobactin from Klebsiella pneumoniae have been identified as the major virulence factors for pyogenic liver abscesses with high morbidity, mortality and severe complications. The pathological mechanisms remain unclear. In this study, we compared liver immune responses and pathological changes in response to different serotypes of K. pneumoniae infections. A mouse model was used to investigate cytokine and chemokine production, histopathology findings, phagocytic uptake and mortality induced by serotypes K1 (magA(+), rmpA(+), aerobactin(+)), K2 (magA(-), rmpA(+), aerobactin(+)), K62 (magA(-), rmpA(-), aerobactin(-)) and an acapsulated isogenic K1 mutant (ΔK1, magA(+), rmpA(+), aerobactin(+)). K. pneumoniae serotypes K1 and K2 showed lower 50% lethal dose values and more phagocytic resistance to neutrophils than K62 and the ΔK1 mutant. In sequential liver samples, viable bacteria counts increased 3 h to 3 days after low-dose inoculation (<10(1) colony-forming unit (cfu)) with K1 and K2, while K62 and ΔK1 cleared rapidly and became undetectable even with high-dose inoculation (∼2.9 × 10(5) cfu). Time-dependent increases in cytokines and chemokines, including tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, IL-10, keratinocyte-derived chemokines and macrophage inflammatory protein-2, were observed in the serum and liver tissue of K1- and K2-infected mice, and severe disease progression manifesting as microabscesses was also identified. K62 and ΔK1 inoculation did not result in similar immune responses and histological changes. These findings illustrate the critical role of phagocytic resistance against innate immunological defense mechanisms as well as its contribution to the development of liver abscesses.

Role of T lymphocytes in liver abscess formation by Bacteroides fragilis in mice.

The underlying mechanisms of liver abscess formation have not been fully elucidated with regard to the interaction between bacterial virulence factors and the immune response. The objective of this study was to determine the role of the host T cells in liver abscess formation caused by Bacteroides fragilis. We developed a liver abscess mouse model with inoculation of B. fragilis through the hepatic portal vein and examined the role of T cells by studying T cell-deficient mice, as well as conducting adoptive T cell transfer experiments. No microabscess was formed in the αß T cell receptor-positive (αßTCR(+)) T cell-depleted mice, in contrast to the results for the control mice. In addition, the αßTCR knockout (KO) mice showed significantly lower numbers of microabscesses, and the abscesses were smaller in size than those in the wild-type mice. Adoptive transfer of T cells purified from the wild-type mice into the αßTCR KO mice resulted in liver abscess formation in those mice. These findings suggest that T cells play an essential role in liver abscess formation caused by B. fragilis in mice.

Liver injury and abscess formation in secondary murine peritonitis.

OBJECTIVE: To investigate liver damage and abscess formation in murine, secondary peritonitis. SUBJECTS: Male C57BL/6 mice. TREATMENT: Intraperitoneal injection with 10(3) CFU Klebsiella pneumoniae and treatment with gentamicin 5 mg/kg/day (BID), subcutaneously. METHODS: Animals were killed at 12, 24, 48 and 72 h after infection. Bacterial burden was determined in the blood and the liver. Liver abscess formation was assessed macroscopically and microscopically. Plasma levels of alkaline phosphatase (ALP) and alanine transaminase (ALT) were measured. Polymorphonuclear leukocyte (PMN) accumulation was assessed via tissue myeloperoxidase (MPO) concentrations. Liver interleukin-10 (IL-10) levels were determined by ELISA. RESULTS: K. pneumoniae was detectable in the blood and the liver at 12 h after infection. Liver abscess formation was visible earliest at 24 h after infection and most pronounced within the right liver lobes. ALP and ALT levels peaked at 12 and 24 h after infection, respectively. MPO was elevated in the right and left liver lobes at 12 h but only in the right lobes at 48 h after infection, compared to tissue levels in naïve mice. Liver IL-10 concentrations were not significantly increased. CONCLUSION: Peritonitis led to liver injury and abscess formation but did not significantly affect tissue concentrations of anti-inflammatory IL-10.

Do neutrophils play a role in establishing liver abscesses and distant metastases caused by Klebsiella pneumoniae?

Serotype K1 Klebsiella pneumoniae is a major cause of liver abscesses and endophthalmitis. This study was designed to identify the role of neutrophils in the development of distant metastatic complications that were caused by serotype K1 K. pneumoniae. An in vitro cellular model was used to assess serum resistance and neutrophil-mediated killing. BALB/c mice were injected with neutrophils containing phagocytosed K. pneumoniae. Serotype K1 K. pneumoniae was significantly more resistant to serum killing, neutrophil-mediated phagocytosis and intra-cellular killing than non-K1 isolates (p<0.01). Electron microscopic examination had similar findings as in the bioassay findings. Intraperitoneal injection of neutrophils containing phagocytosed serotype K1 K. pneumoniae led to abscess formation in multiple sites including the subcutaneous tissue, lung, and liver, whereas no abscess formation was observed in mice injected with non-K1 isolates. The resistance of serotype K1 K. pneumoniae to complement- and neutrophil-mediated intracellular killing results in the dissemination of K. pneumoniae via the bloodstream. Escape from neutrophil intracellular killing may contribute to the dissemination and establishment of distant metastases. Thus, neutrophils play a role as a vehicle for helping K. pneumoniae and contributing to the establishment of liver abscess and distant metastatic complications.