The Human Virome in Children and its Relationship to Febrile Illness

This study investigates the relationship of viruses to febrile illness in children. Subjects are normal children 2-36 months of age with fever along with normal children of the same age without fever, plus immunocompromised children with fever along with immunocompromised children without fever. Specimens obtained include blood, nasopharyngeal secretions, and feces. Specimens are analyzed using a panel of virus-specific PCR assays and also by high throughput sequencing using 454 and Illumina platforms

L-plastin is essential for alveolar macrophage production and control of pulmonary pneumococcal infection

We report that mice deficient for the hematopoietic-specific, actin-bundling protein L-plastin (LPL) succumb rapidly to intratracheal pneumococcal infection. The increased susceptibility of LPL(−/−) mice to pulmonary pneumococcal challenge correlated with reduced numbers of alveolar macrophages, consistent with a critical role for this cell type in the immediate response to pneumococcal infection. LPL(−/−) mice demonstrated a very early clearance defect, with an almost 10-fold-higher bacterial burden in the bronchoalveolar lavage fluid 3 h following infection. Clearance of pneumococci from the alveolar space in LPL(−/−) mice was defective compared to that in Rag1(−/−) mice, which lack all B and T lymphocytes, indicating that innate immunity is defective in LPL(−/−) mice. We did not identify defects in neutrophil or monocyte recruitment or in the production of inflammatory cytokines or chemokines that would explain the early clearance defect. However, efficient alveolar macrophage regeneration following irradiation required LPL. We thus identify LPL as being key to alveolar macrophage development and essential to an effective antipneumococcal response. Further analysis of LPL(−/−) mice will illuminate critical regulators of the generation of alveolar macrophages and, thus, effective pulmonary innate immunity

The actin-bundling protein L-plastin is required for marginal zone B cell development (112.4)

Abstract B cell development is exquisitely sensitive to location within specialized niches in the bone marrow and spleen. Location within these niches is carefully orchestrated through chemotactic and adhesive cues. Here we demonstrate the requirement for the actin-bundling protein L-plastin (LPL) in B cell motility towards the chemokines CXCL12 and CXCL13, chemokines that guide normal B cell development. Impaired motility of B cells in LPL-/- mice correlated with diminished splenic maturation of B cells, with a profound (&amp;gt;80%) loss of marginal zone B cells. Entry of LPL-/- B cells into lymph nodes and bone marrow was also impaired. Furthermore, LPL was required for the integrin-mediated enhancement of transwell migration but was dispensable for integrin-mediated lymphocyte adhesion. These results suggest that LPL participates in signaling that enables lymphocyte transmigration. In support of this hypothesis, the phosphorylation of Pyk-2, a tyrosine kinase that integrates chemotactic and adhesive cues, is diminshed in LPL-/- B cells. Furthermore, a well-characterized role of marginal zone B cells is the generation of a rapid humoral response to polysaccharide antigens. LPL-/- mice exhibited a defective antibody response to Streptococcus pneumoniae, and LPL-/- mice succumb rapidly to intra-tracheal infection with Streptococcus pneumoniae. LPL is thus critical for effective immunity against a significant human pathogen.</jats:p

Fatal pneumococcal infection in mice deficient for the actin-bundling protein L-plastin (117.26)

Abstract L-plastin (LPL) is a leukocyte-specific actin-bundling protein that increases the stability of actin-based structures such as podosomes. Fewer lymphocytes and dendritic cells populate the lungs of LPL-/- mice, presumably due to defective motility of these cell types. To determine whether defective immunity in LPL-/- mice would result in increased susceptibility to infection, we challenged mice intra-tracheally with S. pneumoniae. Less than 20% of LPL-/- mice survived pneumococcal infection, compared to 80% of wild-type mice. Rapid mortality of LPL-/- mice correlated with a 100-fold higher bacterial burden in the blood and bronchoalveolar lavage fluid 24 hours following infection, indicating a significant failure to control and limit bacterial growth in vivo. Defective clearance of pneumococcus was apparent as early as six hours after intra-tracheal challenge, and comparison to Rag1-/- mice indicated defective innate immunity. Preliminary experiments demonstrated defective phagocytosis of pneumococci by LPL-/- alveolar macrophages, providing an explanation for the early clearance defect observed. No requirement for LPL in macrophage function has been previously reported. Delineation of the molecular pathways critical to early innate pulmonary defense against pneumococci through the use of mice deficient for LPL will support research efforts aimed at reducing the global health burden of pneumococcal pneumonia.</jats:p