Target cell tropism of enveloped viruses is regulated by interactions between viral and cellular factors during transmission, dissemination, and replication within the host. Binding of viral envelope glycoproteins to specific cell-surface receptors determines susceptibility to viral entry. However, a number of cell-surface molecules bind viral envelope glycoproteins without mediating entry. Instead, they serve as capture receptors that disseminate viral particles to target organs or susceptible cells. We and others recently demonstrated that the C type lectins L-SIGN and DC-SIGN capture hepatitis C virus (HCV) by specific binding to envelope glycoprotein E2. In this study, we use an entry assay to demonstrate that HCV pseudoviruses captured by L-SIGN؉ or DC-SIGN؉ cells efficiently transinfect adjacent human liver cells. Virus capture and transinfection require internalization of the SIGN-HCV pseudovirus complex. In vivo, L-SIGN is largely expressed on endothelial cells in liver sinusoids, whereas DC-SIGN is expressed on dendritic cells. Capture of circulating HCV particles by these SIGN؉ cells may facilitate virus infection of proximal hepatocytes and lymphocyte subpopulations and may be essential for the establishment of persistent infection.H epatitis C virus (HCV) is the etiologic agent of non-A non-B hepatitis in humans (1, 2). Only Ϸ15% of infected individuals clear the virus, and Ϸ170 million people worldwide are persistently infected with HCV (3, 4). These individuals may remain asymptomatic or may develop chronic hepatitis or cirrhosis, the latter often leading to hepatocellular carcinoma (5). Hepatocytes are the primary target cells for HCV infection (6-8). Virus-like particles have been visualized in liver biopsies of HCVϩ individuals (9-11), and in vitro infection, albeit inefficient, of primary hepatocytes and hepatoma cells has been documented (12)(13)(14). The existence of extrahepatic reservoirs of HCV is suggested by the detection of viral RNA in serum and peripheral blood mononuclear cells of HCVϩ individuals (15)(16)(17). Both B and T lymphocytes appear to be infected in vivo, which is supported by in vitro infection of B and T cell lines (7,8,18). One study, however, shows that replicating forms of HCV RNA are restricted to hepatocytes, whereas only nonreplicating forms are present in B lymphocytes, and none are in T lymphocytes (6).HCV envelope glycoproteins E1 and E2 mediate entry into target cells. We and others recently demonstrated that unmodified E1E2 heterodimers reach the cell surface and are incorporated into retroviral pseudoparticles, which can infect primary hepatocytes and some hepatoma cell lines (19 -22). Use of the soluble E2 ectodomain as a surrogate model for studying HCV interactions with cell-surface molecules has identified several potential HCV entry receptors, including CD81, scavenger receptor class B type 1, low-density lipoprotein receptor, and glycosaminoglycans (22-24). Several groups, including ours, have shown that CD81 is necessary but not sufficient for HCV pseu...

The importance of T cell-mediated immunity for resistance to the disease (cryptococcal disease) caused by Cryptococcus neoformans is incontrovertible, but whether Ab immunity also contributes to resistance remains uncertain. To investigate the role of IgM in resistance to C. neoformans, we compared the survival, fungal burden, lung and brain inflammatory responses, and lung phagocytic response of sIgM−/− mice, which lack secreted IgM, to that of IgM sufficient C57BL6x129Sv (heretofore, control) mice at different times after intranasal infection with C. neoformans (24067). sIgM−/− mice had higher mortality and higher blood and brain CFUs 28 d postinfection, but lung CFUs were comparable. Lungs of control mice manifested exuberant histiocytic inflammation with visible C. neoformans, findings that were not observed in sIgM−/− mice, whereas in brain sections, sIgM−/− mice had marked inflammation with visible C. neoformans that was not observed in control mice. Cytokine responses were significant for higher levels of lung IL-1β and IL-12 24 h postinfection in control mice and higher levels of lung and brain IL-17 28 d postinfection in sIgM−/− mice. Alveolar macrophage phagocytosis was significantly higher for control than for sIgM−/− mice 24 h postinfection; however, phagocytic indices of sIgM−/− mice increased after reconstitution of sIgM−/− mice with polyclonal IgM. These data establish a previously unrecognized role for IgM in resistance to intranasal infection with C. neoformans in mice and suggest that the mechanism by which it mediates a host benefit is by augmenting Th1 polarization, macrophage recruitment and phagocytosis of C. neoformans.

The use of pneumococcal capsular polysaccharide (PPS)-based vaccines has resulted in a substantial reduction in invasive pneumococcal disease. However, much remains to be learned about vaccine-mediated immunity, as seven-valent PPS-protein conjugate vaccine use in children has been associated with nonvaccine serotype replacement and 23-valent vaccine use in adults has not prevented pneumococcal pneumonia. In this report, we demonstrate that certain PPS-specific monoclonal antibodies (MAbs) enhance the transformation frequency of two different Streptococcus pneumoniae serotypes. This phenomenon was mediated by PPS-specific MAbs that agglutinate but do not promote opsonic effector cell killing of the homologous serotype in vitro. Compared to the autoinducer, competence-stimulating peptide (CSP) alone, transcriptional profiling of pneumococcal gene expression after incubation with CSP and one such MAb to the PPS of serotype 3 revealed changes in the expression of competence (com)-related and bacteriocin-like peptide (blp) genes involved in pneumococcal quorum sensing. This MAb was also found to induce a nearly 2-fold increase in CSP2-mediated bacterial killing or fratricide. These observations reveal a novel, direct effect of PPS-binding MAbs on pneumococcal biology that has important implications for antibody immunity to pneumococcus in the pneumococcal vaccine era. Taken together, our data suggest heretofore unsuspected mechanisms by which PPS-specific antibodies could affect genetic exchange and bacterial viability in the absence of host cells.