Bacterial flagellin is critical to mediate NLRC4 inflammasome-dependent caspase-1 activation. However, Shigella flexneri, a non-flagellated bacterium, and a flagellin (fliC) knockout strain of Pseudomonas aeruginosa (Pa) are known to activate NLRC4 in bone marrow-derived macrophages. Furthermore, the fliC knockout strain of Pa was used in a mouse model of peritonitis to show the requirement of NLRC4. In a model of pulmonary Pa infection, flagellin was shown to be essential for the induction of NLRC4-dependent caspase-1 activation. Moreover, in all Pa studies, IL-1β production was attenuated in NLRC4−/− mice; however, the role of IL-1β in NLRC4-mediated innate immunity in the lungs against a non-flagellated bacterium was not explored. Here, we report that NLRC4 is important for host survival and bacterial clearance as well as neutrophil-mediated inflammation in the lungs following Klebsiella pneumoniae (Kp) infection. NLRC4 is essential for Kp-induced production of IL-1β, IL-17A, and neutrophil chemoattractants (KC, MIP-2, and LIX) in the lungs. NLRC4 signaling in hematopoietic cells contributes to Kp-induced lung inflammation. Furthermore, exogenous IL-1β, but not IL-18 or IL-17A, partially rescued survival, neutrophil accumulation and cytokine/chemokine expression in the lungs of NLRC4−/− mice following infectious challenge. Furthermore, IL-1R1−/− mice displayed a decrease in neutrophilic inflammation in the lungs after infection. Taken together, these findings provide novel insights into the role of NLRC4 in Kp-induced host defense.

Klebsiella pneumoniae causes extensive lung damage. TLR signaling involves adaptors TRIF and MyD88. However, the relative contribution of TRIF and MyD88 signaling in host defense against pulmonary K. pneumoniae infection has not been elucidated. Therefore, we investigated the role of TRIF and MyD88 in K. pneumoniae pneumonia. TRIF−/− mice infected with K. pneumoniae showed impaired survival and reduced bacterial clearance, neutrophil influx, histopathologic evidence of inflammation, and TNF-α, IL-6, KC, MIP-2, but not LIX, expression in the lungs. In addition, K. pneumoniae-induced late NF-κB activation and phosphorylation of MAPKs was attenuated in the lungs of TRIF−/− mice. However, MyD88−/− mice infected with K. pneumoniae showed a much more remarkable phenotype, including impaired survival and reduced bacterial clearance, histopathology, and TNF-α, IL-6, KC, MIP-2, and LIX expression with almost no neutrophil influx in the lungs. In MyD88−/− mice, K. pneumoniae-induced early NF-κB and MAPK activation in the lungs was also reduced. Furthermore, the role of MyD88 is dominant over TRIF because TRIF/MyD88 double knockout mice displayed a more pronounced phenotype than TRIF−/− mice. Moreover, human alveolar macrophages pretreated with MyD88 blocking peptide showed attenuated TNF-α, IL-6, and IL-8 expression. Also, C57BL/6 mice pretreated with MyD88 blocking peptide exhibited attenuation in K. pneumoniae-induced neutrophil influx and enhanced bacterial burden in the lungs and dissemination. Overall, this investigation provides new insights into the TRIF and MyD88 signaling triggered by pulmonary K. pneumoniae infection in the lungs and demonstrate the therapeutic potential of MyD88 in reducing excessive neutrophil influx in human disease during Gram-negative bacterial pneumonia.

Abstract. Exotic Newcastle disease virus (NDV) isolated from chickens during the 2002-2003California outbreak (CA exotic Newcastle disease [END] virus) was inoculated into 4-week-old specificpathogen-free (SPF) White Leghorn chickens, 3-week-old SPF Beltsville White turkeys, 6-week-old commercial Broad Breasted White turkeys, and 10-to 20-week-old racing pigeons, and the clinicopathologic features of disease were compared. Birds were monitored clinically and euthanized sequentially with collection of tissues. Tissues were examined by histopathology, by immunohistochemistry to detect viral nucleoprotein, and by in situ hybridization to detect viral mRNA. Clinically, infected chickens and SPF turkeys showed severe depression, and all died or were euthanized because of severe clinical signs by day 5 postinoculation. In these birds, histologic lesions were widespread and virus was detected in multiple organs. All infected commercial turkeys showed mild depression, and incoordination was observed in some birds. Histologic lesions were mild, and viral distribution was limited. In pigeons, only 1 bird showed overt clinical disease, and histologic lesions and viral distribution were present in limited organs. Consequently, susceptibility to highly virulent NDV was shown to vary among chickens, SPF turkeys, commercial turkeys, and pigeons. Additionally, we have evidence of CA END virus subclinical infections that suggest pigeons could be subclinical carriers of other virulent NDV.

Human metapneumovirus (hMPV) is a respiratory paramyxovirus that is distributed worldwide and induces significant airway morbidity. Despite the relevance of hMPV as a pathogen, many aspects of the immune response to this virus are still largely unknown. In this report, we focus on the antiviral immune response, which is critical for viral clearance and disease resolution. Using in vitro and in vivo systems, we show that hMPV is able to induce expression of lambda interferon 1 (IFN-1), IFN-2

Age, female sex, and 3 genera appeared to be positively associated with the presence of advanced atherosclerotic lesions in psittacine birds. This information may be useful in clinical assessment of the cardiovascular system and patient management. Reproductive diseases were the only potentially modifiable risk factor identified and could be a target for prevention in captive psittacine birds.