Comparative effects of carbapenems on bacterial load and host immune response in a Klebsiella pneumoniae murine pneumonia model

Doripenem is a carbapenem with potent broad-spectrum activity against Gram-negative pathogens, including antibiotic-resistant Enterobacteriaceae. As the incidence of extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacilli is increasing, it was of interest to examine the in vivo comparative efficacy of doripenem, imipenem, and meropenem against a Klebsiella pneumoniae isolate expressing the TEM-26 ESBL enzyme. In a murine lethal lower respiratory infection model, doripenem reduced the Klebsiella lung burden by 2 log(10) CFU/g lung tissue over the first 48 h of the infection. Treatment of mice with meropenem or imipenem yielded reductions of approximately 1.5 log(10) CFU/g during this time period. Seven days postinfection, Klebsiella titers in the lungs of treated mice decreased an additional 2 log(10) CFU/g relative to those in the lungs of untreated control animals. Lipopolysaccharide (LPS) endotoxin release assays indicated that 6 h postinfection, meropenem- and imipenem-treated animals had 10-fold more endotoxin in lung homogenates and sera than doripenem-treated mice. Following doripenem treatment, the maximum endotoxin release postinfection (6 h) was 53,000 endotoxin units (EU)/ml, which was 2.7- and 6-fold lower than imipenem or meropenem-treated animals, respectively. While the levels of several proinflammatory cytokines increased in both the lungs and sera following intranasal K. pneumoniae inoculation, doripenem treatment, but not meropenem or imipenem treatment, resulted in significantly increased interleukin 6 levels in lung homogenates relative to those in lung homogenates of untreated controls, which may contribute to enhanced neutrophil killing of bacteria in the lung. Histological examination of tissue sections indicated less overall inflammation and tissue damage in doripenem-treated mice, consistent with improved antibacterial efficacy, reduced LPS endotoxin release, and the observed cytokine induction profile.     

Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae

Interleukin (IL)-23 is a heterodimeric cytokine that shares the identical p40 subunit as IL-12 but exhibits a unique p19 subunit similar to IL-12 p35. IL-12/23 p40, interferon gamma (IFN-gamma), and IL-17 are critical for host defense against Klebsiella pneumoniae. In vitro, K. pneumoniae-pulsed dendritic cell culture supernatants elicit T cell IL-17 production in a IL-23-dependent manner. However, the importance of IL-23 during in vivo pulmonary challenge is unknown. We show that IL-12/23 p40-deficient mice are exquisitely sensitive to intrapulmonary K. pneumoniae inoculation and that IL-23 p19-/-, IL-17R-/-, and IL-12 p35-/- mice also show increased susceptibility to infection. p40-/- mice fail to generate pulmonary IFN-gamma, IL-17, or IL-17F responses to infection, whereas p35-/- mice show normal IL-17 and IL-17F induction but reduced IFN-gamma. Lung IL-17 and IL-17F production in p19-/- mice was dramatically reduced, and this strain showed substantial mortality from a sublethal dose of bacteria (10(3) CFU), despite normal IFN-gamma induction. Administration of IL-17 restored bacterial control in p19-/- mice and to a lesser degree in p40-/- mice, suggesting an additional host defense requirement for IFN-gamma in this strain. Together, these data demonstrate independent requirements for IL-12 and IL-23 in pulmonary host defense against K. pneumoniae, the former of which is required for IFN-gamma expression and the latter of which is required for IL-17 production.     

Comparative efficacy of different beta-lactam antibiotics and gentamicin in Klebsiella pneumoniae septicaemia in neutropenic mice

The in-vivo activity of ceftazidime, cefotetan, imipenem/cilastatin, piperacillin and gentamicin against two strains of Klebsiella pneumoniae was evaluated in a model of experimental septicaemia in neuropenic mice. Single agent therapy with the aminoglycoside was highly effective against both strains. Among the beta-lactams, ceftazidime and cefotetan were nearly as active as gentamicin, whereas imipenem/cilastatin was slightly less effective, and the results achieved with piperacillin were markedly inferior.     

Effect of porins and plasmid-mediated AmpC beta-lactamases on the efficacy of beta-lactams in rat pneumonia caused by Klebsiella pneumoniae

The in vivo activities of imipenem, meropenem, and cefepime were studied in a model of rat pneumonia caused by a plasmid-mediated AmpC beta-lactamase ACT-1-producing Klebsiella pneumoniae strain (K. pneumoniae strain 12) and a derivative porin-deficient mutant (K. pneumoniae strain 12dp). No differences between these activities were seen with K. pneumoniae 12. Only meropenem showed an activity slightly better than that of imipenem with K. pneumoniae 12dp.     

Prevalence and mechanisms of decreased susceptibility to carbapenems in Klebsiella pneumoniae isolates

In this study, we examined the prevalence of and mechanisms of decreased susceptibility to either imipenem or meropenem in Klebsiella pneumoniae isolates. A total of 230 clinical isolates of K. pneumoniae were collected from 13 clinical laboratories from a nationwide distribution. The MICs of imipenem and meropenem were determined by the agar dilution method. To characterize the isolates with decreased susceptibility to carbapenems (MICs of >2 microg/mL), we performed polymerase chain reaction amplification of a variety of beta-lactamase genes, isoelectric focusing, and outer membrane profile analysis using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and mass spectrometry. Three isolates (BD6, BD8, and KN16) exhibited decreased susceptibility to carbapenems with imipenem MICs of 1, 4, and 8 microg/mL and meropenem MICs of 4, 8, and 4, respectively. Isolate BD6 produced bla(TEM-1), bla(SHV-12), and bla(OXA-17); isolate BD8 produced bla(GES-3), bla(SHV-12), and bla(OXA-17); and isolate KN16 produced bla(TEM-11), bla(SHV-12), and bla(DHA-1). In all the 3 isolates, OmpK35 porin was not expressed, and in 1 isolate (KN16), OmpK36 was not expressed either. The prevalence of decreased susceptibility to carbapenems was low (1.3%), and none of them showed overt resistance to carbapenems. Decreased susceptibility to carbapenems can occur in K. pneumoniae when bla(GES-3), bla(TEM-11), bla(SHV-12), bla(OXA-17), and/or bla(DHA-1) are produced in combination with porin loss. In addition, to our knowledge, this is the 1st report of bla(OXA-17) in Enterobacteriaceae.     

Therapeutic effects of cefotiam and cefazolin on experimental pneumonia caused by Klebsiella pneumoniae DT-S in mice.

The efficacies of several dosage schedules, productive of plasma levels of cefotiam and cefazolin of short and long duration and starting at three levels of cefotiam and cefazolin of short and long duration and starting at three different times (3, 18, and 30h) after infection, were examined in experimental pneumonia caused by Klebsiella pneumoniae DT-S in mice. With each of the multiday regimens there was a large segment of the day when plasma levels fell below assayable concentrations. In all cases, cefotiam proved about eight times as active as cefazolin, indicating that the potent in vitro antibacterial activity of cefotiam was well reflected in the therapeutic effect in this model infection. As judged by the total dose administered, the regimen of cefotiam producing a low but sustained plasma level gave better therapeutic effects than that exhibiting a high but transient plasma level. The cefotiam levels in the plasma of mice that received the regimen effective when initiated at 18 h after infection were less than the expected levels in humans after intravenous infusion of the usual clinical dose.     

Antibiotic susceptibility in relation to genotype of Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma pneumoniae responsible for community-acquired pneumonia in children

Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma pneumoniae are the main pathogens causing community-acquired pneumonia (CAP). We identified S. pneumoniae (n = 241), H. influenzae (n = 123), and M. pneumoniae (n = 54) as causative pathogens from clinical findings and blood tests from pediatric CAP patients (n = 903) between April 2008 and April 2009. Identification of genes mediating antimicrobial resistance by real-time PCR was performed for all isolates of these three pathogens, as was antibiotic susceptibility testing using an agar dilution method or broth microdilution method. The genotypic (g) resistance rate was 47.7 % for penicillin-resistant S. pneumoniae (gPRSP) possessing abnormal pbp1a, pbp2x, and pbp2b genes, 62.6 % for β-lactamase-nonproducing, ampicillin-resistant (gBLNAR) H. influenzae possessing the amino acid substitutions Ser385Thr and Asn526Lys, and 44.4 % for macrolide-resistant M. pneumoniae (gMRMP) possessing a mutation of A2063G, A2064G, or C2617A. Serotype 6B (20.3 %) predominated in S. pneumoniae, followed by 19F (15.4 %), 14 (14.5 %), 23F (12.0 %), 19A (6.2 %), and 6C (5.4 %). Coverage for the isolates by heptavalent pneumococcal conjugate vaccine (PCV7) and PCV13, respectively, was calculated as 68.5 and 80.9 %. A small number of H. influenzae were identified as type b (6.5 %), type e (0.8 %), or type f (0.8 %); all others were nontypeable. Proper use of antibiotics based on information about resistance in CAP pathogens is required to control rapid increases in resistance. Epidemiological surveillance of pediatric patients also is needed to assess the effectiveness of PCV7 and Hib vaccines after their introduction in Japan.     

Improved efficacy of ciprofloxacin administered in polyethylene glycol-coated liposomes for treatment of Klebsiella pneumoniae pneumonia in rats

Animal and clinical data show that high ratios of the area under the concentration-time curve and the peak concentration in blood to the MIC of fluoroquinolones for a given pathogen are associated with a favorable outcome. The present study investigated whether improvement of the therapeutic potential of ciprofloxacin could be achieved by encapsulation in polyethylene glycol (PEG)-coated long-circulating sustained-release liposomes. In a rat model of unilateral Klebsiella pneumoniae pneumonia (MIC = 0.1 microg/ml), antibiotic was administered at 12- or 24-h intervals at twofold-increasing doses. A treatment period of 3 days was started 24 h after inoculation of the left lung, when the bacterial count had increased 1,000-fold and some rats had positive blood cultures. The infection was fatal within 5 days in untreated rats. Administration of ciprofloxacin in the liposomal form resulted in delayed ciprofloxacin clearance and increased and prolonged ciprofloxacin concentrations in blood and tissues. The ED(50) (dosage that results in 50% survival) of liposomal ciprofloxacin was 3.3 mg/kg of body weight/day given once daily, and that of free ciprofloxacin was 18.9 mg/kg/day once daily or 5.1 mg/kg/day twice daily. The ED(90) of liposomal ciprofloxacin was 15.0 mg/kg/day once daily compared with 36.0 mg/kg/day twice daily for free ciprofloxacin; 90% survival could not be achieved with free ciprofloxacin given once daily. In summary, the therapeutic efficacy of liposomal ciprofloxacin was superior to that of ciprofloxacin in the free form. PEG-coated liposomal ciprofloxacin was well tolerated in relatively high doses, permitting once daily administration with relatively low ciprofloxacin clearance and without compromising therapeutic efficacy.     

Therapeutic activities of cefazolin, cefotaxime, and ceftazidime against experimentally induced Klebsiella pneumoniae pneumonia in rats.

The efficacies of several dosage schedules of cefazolin, cefotaxime, and ceftazidime, started 12 or 36 h after infection, were examined in experimental pneumonia caused by Klebsiella pneumoniae in rats. The therapeutic activities of the cephalosporins were compared with the antibacterial activities in vitro and the serum concentration curves. The course of experimental pneumonia was rapid and characterized by tissue necrosis. Response to antimicrobial treatment was evaluated with respect to mortality and numbers of bacteria in lung (left lobe), blood, and pleural fluid. When antibiotic treatment was started early, i.e., 12 h after bacterial inoculation, cefotaxime and ceftazidime were equally effective and superior to cefazolin. Eleven doses of 10 mg of cefotaxime or ceftazidime per kg or 11 doses of 60 mg of cefazolin per kg were required to improve the survival rate. With a delay in administration to 36 h after inoculation, the efficacy of the cephalosporins decreased markedly. In the three dosages tested, cefazolin was ineffective. Survival improved with the administration of nine doses of 60 mg of cefotaxime per kg or nine doses of 10 mg of ceftazidime per kg. These results are not in accordance with the ratio of in vitro activities of cefotaxime and ceftazidime or the serum concentration curves.     

Treatment of Klebsiella pneumoniae septicemia in normal and leukopenic mice by liposome-encapsulated muramyl tripeptide phosphatidylethanolamide.

The effect of free muramyl tripeptide phosphatidylethanolamide (MTPPE) and liposome-encapsulated MTPPE (LE-MTPPE) on Klebsiella pneumoniae septicemia resulting from intraperitoneal bacterial inoculation was investigated in mice. When administering a single prophylactic dose at 24 h before bacterial inoculation, the percentage survival was 55% (MTPPE) or 40% (LE-MTPPE), whereas untreated control mice died. Only repeated prophylactic treatment with LE-MTPPE could further increase survival up to 85%.     

Influence of dosage interval on the therapeutic response to gentamicin in mice infected with Klebsiella pneumoniae

Without treatment all mice died after receiving 10(3) Klebsiella pneumoniae by intraperitoneal injection. Nevertheless, it was possible to delay treatment for 12 h and still observe a therapeutic response from im gentamicin (5 mg/kg). This gave initial serum concentrations comparable to clinical levels, which fell rapidly (t 1/2 = 15 min) to reach the limit of detection by 90 min. Courses were given of 3 or 6 doses spaced at different intervals. Irrespective of dosage interval there was a marked fall in bacteraemia with each of the first two doses. Between doses separated by 8 or even 12 h there was no evidence of bacterial multiplication but this was obvious by 24 h. Both the bacteraemic responses and the lengths of survival were best with the 12-hour dosage interval. These results are consistent with other reports of the persistence of antibiotic effects despite undetectable serum concentrations and the compatibility of a substantial dosage interval with a successful therapeutic outcome.     

Pharmacokinetics and in vivo activity of liposome-encapsulated gentamicin.

Gentamicin sulfate was encapsulated in liposomes composed solely of egg phosphatidylcholine and administered via intravenous injection to rats and mice. The total gentamicin activity (regardless of whether it was free or liposome associated) in serum and selected tissues was determined for 24 h (serum) or up to 15 weeks (tissues) by using a microbiological assay. The mean half-lives in serum of a single 20-mg/kg dose of free (nonencapsulated) gentamicin in mice and rats were estimated to be 1.0 and 0.6 h, respectively, whereas a similar dose of encapsulated drug had apparent mean half-lives of 3.8 h in mice and 4.0 h in rats. In both species, the apparent half-life in serum of the liposomal formulation increased as the dose increased. Liposome encapsulation resulted in higher and more prolonged activity in organs rich in reticuloendothelial cells (especially spleen and liver). In acute septicemia infections in mice, the liposomal formulation showed enhanced prophylactic activity (as determined by calculation of the 50% protective dose). In a model of murine salmonellosis, liposomal gentamicin greatly enhanced survival when given as a single dose (10 mg/kg) at 1 or 2 days after infection as well as up to 7 days before infection.     

小儿肺炎克雷伯菌临床感染及耐药性分析

目的分析住院患儿肺炎克雷伯菌的临床分布及耐药性,以指导临床合理用药。方法对2009年10月至2010年12月儿科送检标本分离出的肺炎克雷伯菌的临床分布特点及耐药情况进行总结分析。结果共分离出肺炎克雷伯菌172株,其中产超广谱β-内酰胺酶(ESBLs)菌41株,占23.84%;主要来源于咽拭子、血液和痰液等,分别占70.93%、9.88%和8.14%;肺炎克雷伯菌对亚胺培南、厄它培南、丁氨卡那霉素和哌拉西林/他唑巴坦敏感性高。结论小儿肺炎克雷伯菌主要引起下呼吸道感染;对氨苄西林、氨苄西林/舒巴坦及头孢类抗菌药物耐药率高,哌拉西林/他唑巴坦和亚胺培南可作为治疗儿童产ESBLs肺炎克雷伯菌感染或非产ESBLs菌严重感染的首选用药。     

Therapeutic efficacy of cefadroxil and cephalexin for pneumonia in a rat test model.

The therapeutic efficacies of cefadroxil and cephalexin were compared in a Streptococcus pyogenes-induced lung infection in rats. Although MICs, rates of in vitro killing in rat serum, and antibiotic serum levels after oral administration were similar for both drugs, cefadroxil was about eight times more effective than cephalexin in reducing the number of viable streptococci at the site of infection. This excellent in vivo bactericidal activity of cefadroxil in lung tissue and bronchial secretions was reflected in the 50% protective dose (PD50) after single or multiple oral treatments. A single treatment given 24 h after infection resulted in a PD50 of 2.8 mg of cefadroxil per kg, compared with 21 mg of cephalexin per kg. When treatment was administered three times, at 24, 27, and 30 h postinfection, the PD50s of cefadroxil and cephalexin were 0.7 and 8.0 mg/kg, respectively. In infected animals, treated 24 h postinfection, the area under the lung tissue concentration versus time curve for cefadroxil was significantly greater than that of cephalexin. This difference in pharmacokinetic behavior may account, at least in part, for the superior therapeutic results obtained with cefadroxil in this experimental pulmonary infection.     

鲍曼不动杆菌及肺炎克雷伯菌对替加环素体外药敏试验方法评价

摘要：目的：评价3种体外药敏试验检测鲍曼不动杆菌和肺炎克雷伯菌对替加环素敏感性的准确性。 方法：用Vitek 2 Compact系统、纸片扩散法及MIC Test Strip(MTS)检测临床分离的47株碳青霉烯类耐药鲍曼不动杆菌及46株肺炎克雷伯菌对替加环素的敏感性,并将Vitek 2 Compact系统和纸片扩散法的结果与MTS进行比较。 结果：Vitek 2、纸片扩散法和MTS检测47株鲍曼不动杆菌对替加环素敏感率分别为70.2%、78.7%和91.5%,检测46株肺炎克雷伯菌对替加环素敏感率分别为89.1%、58.7%和91.3%。以MTS法结果为标准,除Vitek 2法检测鲍曼不动杆菌时重要误差率为2.3%外,未产生极重要误差和其他重要误差;Vitek 2法检测肺炎克雷伯菌结果与MTS法的一致率（87.0%）高于纸片扩散法（60.9%）,而检测鲍曼不动杆菌结果的一致率（72.3%）低于纸片扩散法（80.9%）。 结论：替加环素对碳青霉烯类耐药鲍曼不动杆菌和肺炎克雷伯菌均有较好的抗菌活性,但不同方法之间敏感率有所不同。对于肺炎克雷伯菌,Vitek 2检测结果优于纸片扩散法;对于鲍曼不动杆菌,纸片扩散法优于Vitek 2方法。     

Effect of glucan on murine lupus evolution and on host resistance to Klebsiella pneumoniae

Glucan is a polysaccharide from the yeast Saccharomyces cerevisiae that stimulates the mononuclear phagocytic system (MPS). NZB/NZW F1 mice were divided into two groups: one group received a subcutaneous injection of 0.5 mg glucan/animal for 1 week, and the other received the same dose for 3 months. No changes were observed in those animals submitted to short-term glucan treatment, whereas animals with active lupus and submitted to long-term glucan administration presented early death, with significant differences in accumulated mortality rates over 33–37 weeks, when compared to controls. No deaths were observed in lupus mice treated with glucan 24 hours before the induction of septic shock by Klebsiella pneumoniae, in contrast to mortality of 95.3% in the control group during the follow-up period of 12 days. We conclude that although glucan is able to exacerbate lupus activity, it enhances resistance to infection in lupus mice. J. Clin. Lab. Anal. 11:175–178, 1997. © 1997 Wiley-Liss, Inc.     

Leptin and host defense against Gram-positive and Gram-negative pneumonia in mice

Leptin is a pleiotrophic protein mainly produced by adipocytes that has been implicated as a link between nutritional status and immune function. Severe bacterial infection is associated with elevated plasma levels of leptin. To determine the role of leptin in the host response to bacterial pneumonia leptin deficient ob/ob mice and normal wild-type (WT) mice were intranasally infected with different doses of the Gram-positive pathogen Streptococcus (S.) pneumoniae or the Gram-negative bacterium Klebsiella (K.) pneumoniae. After infection with lower doses of either pathogen ob/ob mice displayed lower pulmonary levels of proinflammatory cytokines, in particular tumor necrosis factor-alpha and chemokines. However, after infection with a higher dose of S. pneumoniae or K. pneumoniae the lung concentrations of these inflammatory mediators did not differ between ob/ob and WT mice. In addition, the extent and severity of lung inflammation, as assessed by semi-quantitative histopathology scores, were similar in both mouse strains. Finally, leptin deficiency did not impact on the bacterial outgrowth in the lungs during either Gram-positive or Gram-negative pneumonia irrespective of the infective dose. These data suggest that although leptin may play a modest role in the regulation of inflammation during bacterial pneumonia, it does not contribute to host defense mechanisms that act to limit the outgrowth of S. pneumoniae or K. pneumoniae in the lower airways.     

产生物膜的肺炎克雷伯菌的体外药敏试验探讨

目的探讨产生物膜的肺炎克雷伯菌体外药敏试验的不同,为临床治疗提供准确的药敏参考。方法对临床分离筛选的16株产生物膜的肺炎克雷伯菌用K-B纸片扩散法进行药敏试验,记录24、48、72h这几个时间段的结果。然后将菌株传种数代至其不产生物膜,再行上述操作。最后对两次的药敏结果进行对比分析。结果产生物膜的肺炎克雷伯菌24h抑菌圈的毫米数与48、72h结果比较差异有统计学意义(P0.05)。结论产生物膜的肺炎克雷伯菌用K-B纸片扩散法进行体外药敏试验时,结果宜在48h后报告,这对于该菌的预防具有一定参考价值。     

Cross-resistance patterns among clinical isolates of Klebsiella pneumoniae with decreased susceptibility to cefuroxime

The frequency of decreased susceptibility to cefuroxime and quinolones and the correlation between these drug resistance traits was investigated in clinical isolates of Klebsiella pneumoniae from two Danish counties. Eighty-three randomly selected clinical isolates of K. pneumoniae with decreased susceptibility to cefuroxime were examined for cross-resistance patterns and the production of beta-lactamases. The frequency of resistance to cefuroxime and ciprofloxacin has increased from <5% in 1990 to 15% and 7% in 1998, respectively. Two of the 83 isolates were multiply resistant and seemed to produce extended-spectrum beta-lactamases. However, cross-resistance to ciprofloxacin and other classes of drug in 68% of the remaining isolates indicates that other resistance mechanisms, such as penetration barriers, had probably been selected in these Danish isolates. The susceptibility to ciprofloxacin decreased successively with decreasing susceptibility to cefuroxime for K. pneumoniae. This did not occur in cefuroxime-resistant Escherichia coli.     

Exaggerated inflammation,impaired host defense,and neuropathology in progranulin-deficient mice

Progranulin (PGRN) is a widely expressed protein involved in diverse biological processes. Haploinsufficiency of PGRN in the human causes tau-negative, ubiquitin-positive frontotemporal dementia (FTD). However, the mechanisms are unknown. To explore the role of PGRN in vivo, we generated PGRN-deficient mice. Macrophages from these mice released less interleukin-10 and more inflammatory cytokines than wild type (WT) when exposed to bacterial lipopolysaccharide. PGRN-deficient mice failed to clear Listeria monocytogenes infection as quickly as WT and allowed bacteria to proliferate in the brain, with correspondingly greater inflammation than in WT. PGRN-deficient macrophages and microglia were cytotoxic to hippocampal cells in vitro, and PGRN-deficient hippocampal slices were hypersusceptible to deprivation of oxygen and glucose. With age, brains of PGRN-deficient mice displayed greater activation of microglia and astrocytes than WT, and their hippocampal and thalamic neurons accumulated cytosolic phosphorylated transactivation response element DNA binding protein–43. Thus, PGRN is a key regulator of inflammation and plays critical roles in both host defense and neuronal integrity. FTD associated with PGRN insufficiency may result from many years of reduced neutrotrophic support together with cumulative damage in association with dysregulated inflammation.Progranulin (PGRN), also known as proepithelin, acrogranin, or prostate cancer cell–derived growth factor (He and Bateman, 2003), is a secreted protein that undergoes proteolysis to generate seven mutually homologous 6-kD peptides, called GRNs or epithelins. Cysteine comprises 88 of PGRN’s 593 residues and forms six intramolecular disulfide bridges in each of the GRNs, giving them a compact globular structure (Tolkatchev et al., 2008). PGRN is expressed by epithelial cells, macrophages, and neurons. Expression analyses and experiments with the native or recombinant protein have implicated PGRN in embryonic development, tumorigenesis, and wound healing (Daniel et al., 2000; Zhu et al., 2002; He and Bateman, 2003). A prominent role of PGRN in the regulation of inflammation was suggested by our discovery that neutrophil elastase and macrophage-derived secretory leukocyte protease inhibitor (SLPI) promote and prevent, respectively, the conversion of PGRN to GRNs, and that recombinant PGRN inhibits neutrophil activation, whereas GRNs promote epithelial cell generation of neutrophil chemoattractants (Zhu et al., 2002).Mutations in the PGRN gene were recently found to cause frontotemporal dementia (FTD), the second most common dementia in people under the age of 65 (Neary et al., 1998). FTD patients experience gradual and progressive changes in behavior and personality, followed by a cognitive decline, prominent language disorders, and sometimes Parkinsonism, in association with progressive cortical atrophy, neuronal loss, astrocytic gliosis, and microglial activation (Neary et al., 1998). At least 66 different pathogenic mutations in the PGRN gene have been documented in FTD patients, all of which resulted in functional null alleles and haploinsufficiency. These were associated with ubiqitinopathies, characterized by the deposit of ubiquitin-positive but tau-negative immunoreactivity in neuronal cytoplasmic and neuronal intranuclear inclusions (Mackenzie et al., 2006; Cairns et al., 2007; Josephs et al., 2007). One component of neuronal inclusions from PGRN-linked FTD patients was identified as transactivation response element DNA binding protein–43 (TDP-43; Neumann et al., 2006). Recent studies have linked pathological redistribution of TDP-43 from nuclei to cytoplasm to its phosphorylation and degradation (Cook et al., 2008; Hasegawa et al., 2008).In this paper, we report that PGRN-deficient mice responded to infection with exaggerated inflammation. In vitro, their macrophages responded to microbial products by expressing enhanced levels of proinflammatory mediators and reduced antiinflammatory IL-10. Ex vivo, PGRN-deficient hippocampal neurons were more vulnerable than WT to metabolic stress. Finally, we detected microgliosis, astrocytosis, and cytoplasmic localization and phosphorylation of TDP-43 in the hippocampus and thalamus in aged PGRN-deficient mice but not in their WT counterparts. Thus, PGRN has a nonredundant role in modulating inflammatory responses. Our studies raise the possibility that FTD may result in part from brain damage arising from the combination of dysregulated inflammation and heightened neuronal vulnerability.