Influenza A virus is an important human pathogen causing significant morbidity and mortality every year and threatening the human population with epidemics and pandemics. Therefore, it is important to understand the biology of this virus to develop strategies to control its pathogenicity. Here we demonstrate that live influenza A virus infection causes accumulation of autophagosomes by blocking their fusion with lysosomes. Matrix protein 2 is sufficient and necessary for this inhibition of autophagosome degradation. Macroautophagy inhibition compromises cell survival of influenza virus infected cells, but does not influence viral replication. We propose that influenza A virus, which also encodes pro-apoptotic proteins, is able to determine the death of its host cell by inducing apoptosis and blocking macroautophagy.
Many pathogens that cause human disease infect only humans. To identify the mechanisms of immune protection against these pathogens and also to evaluate promising vaccine candidates, a small animal model would be desirable. We demonstrate that primary T cell responses in mice with reconstituted human immune system components control infection with the oncogenic and persistent Epstein-Barr virus (EBV). These cytotoxic and interferon-γ–producing T cell responses were human leukocyte antigen (HLA) restricted and specific for EBV-derived peptides. In HLA-A2 transgenic animals and similar to human EBV carriers, T cell responses against lytic EBV antigens dominated over recognition of latent EBV antigens. T cell depletion resulted in elevated viral loads and emergence of EBV-associated lymphoproliferative disease. Both loss of CD4+ and CD8+ T cells abolished immune control. Therefore, this mouse model recapitulates features of symptomatic primary EBV infection and generates T cell–mediated immune control that resists oncogenic transformation.
Successful host defense against numerous pulmonary infections depends on bacterial clearance by polymorphonuclear leukocytes (PMNs); however, excessive PMN accumulation can result in life-threatening lung injury. Local expression of CXC chemokines is critical for PMN recruitment. The impact of chemokinedependent PMN recruitment during pulmonary Mycobacterium tuberculosis infection is not fully understood. Here, we analyzed expression of genes encoding CXC chemokines in M. tuberculosis-infected murine lung tissue and found that M. tuberculosis infection promotes upregulation of Cxcr2 and its ligand Cxcl5. To determine the contribution of CXCL5 in pulmonary PMN recruitment, we generated Cxcl5 -/-mice and analyzed their immune response against M. tuberculosis. Both Cxcr2 -/-mice and Cxcl5 -/-mice, which are deficient for only one of numerous CXCR2 ligands, exhibited enhanced survival compared with that of WT mice following high-dose M. tuberculosis infection. The resistance of Cxcl5 -/-mice to M. tuberculosis infection was not due to heightened M. tuberculosis clearance but was the result of impaired PMN recruitment, which reduced pulmonary inflammation. Lung epithelial cells were the main source of CXCL5 upon M. tuberculosis infection, and secretion of CXCL5 was reduced by blocking TLR2 signaling. Together, our data indicate that TLR2-induced epithelial-derived CXCL5 is critical for PMN-driven destructive inflammation in pulmonary tuberculosis.
Cells of the innate immune system act in synergy to provide a first line of defense against pathogens. Here we describe that dendritic cells (DCs), matured with viral products or mimics thereof, including Epstein-Barr virus (EBV), activated natural killer (NK) cells more efficiently than other mature DC preparations. CD56brightCD16− NK cells, which are enriched in human secondary lymphoid tissues, responded primarily to this DC activation. DCs elicited 50-fold stronger interferon-γ (IFN-γ) secretion from tonsilar NK cells than from peripheral blood NK cells, reaching levels that inhibited B cell transformation by EBV. In fact, 100- to 1,000-fold less tonsilar than peripheral blood NK cells were required to achieve the same protection in vitro, indicating that innate immune control of EBV by NK cells is most efficient at this primary site of EBV infection. The high IFN-γ concentrations, produced by tonsilar NK cells, delayed latent EBV antigen expression, resulting in decreased B cell proliferation during the first week after EBV infection in vitro. These results suggest that NK cell activation by DCs can limit primary EBV infection in tonsils until adaptive immunity establishes immune control of this persistent and oncogenic human pathogen.
IntroductionEpstein-Barr virus (EBV) is a ubiquitous human ␥-herpesvirus that latently infects B cells and establishes chronic infection in more than 90% of the adult population. Although infection with EBV during adolescence can lead to infectious mononucleosis (IM), the vast majority of infected people acquires and harbors EBV as a benign lifelong infection, which is controlled by strong T-cell immunity. However, in a small subset of infected individuals, EBV latency programs with different viral antigen expression patterns are associated with malignancies such as Hodgkin and Burkitt lymphomas as well as nasopharyngeal carcinoma (NPC). 1 The nuclear antigen 1 (EBNA1) is the one EBV antigen that is expressed in all of these EBV-associated tumors as well as in EBV-positive proliferating cells in healthy carriers. 2 EBNA1 is crucial for viral persistence, because it initiates viral DNA replication and anchors the circular viral episome to the mitotic chromosomes during cell division, thereby ensuring the survival of the viral genome in proliferating cells. Thus, even in the absence of all other EBV proteins, such as in Burkitt lymphoma, EBNA1 expression must be maintained, and from an immune surveillance point of view, EBNA1 should be a critical target of protective immunity. Indeed, EBNA1 is consistently recognized by Th1-type CD4 ϩ T cells, [3][4][5][6] and can elicit CD8 ϩ T-cell responses 7-9 in healthy EBV carriers. These T cells that recognize mostly epitopes in the C-terminal domain of EBNA1 can target EBV-transformed B cells and prevent their outgrowth in vitro. 10 While EBNA1-specific T-cell responses can also be detected in peripheral blood of NPC patients, 11 they are greatly diminished in patients with EBVassociated non-Hodgkin lymphoma in the context of HIV infection, 12 EBV-associated Hodgkin disease (K. N. Heller, F.A., P. Steinherz, C. Postlook, A. Chadburn, K. Kelly, C.M., manuscript submitted) and endemic Burkitt lymphomas (Ann Moormann, Case Western Reserve University, Cleveland, OH, personal communication April 2008), thus making EBNA1, and specifically its C-terminal domain, a logical target for vaccine development against all EBV-associated malignancies.A promising cell type, to which EBNA1 could be targeted for vaccine design, is dendritic cells (DCs). These sentinels of the immune system have an exceptional T-cell stimulatory capacity, which includes their ability to efficiently process antigens, and present them on both major histocompatibility class (MHC) I and class II molecules in combination with T-cell costimulatory molecules. 13 DCs are also crucial for initiating protective innate and adaptive immune responses against bacterial and viral pathogens in vivo, 14,15 which further supports targeting DCs for therapeutic vaccination. However, many current DC-targeted immunization approaches use individualized culture, antigen loading, and activation of DCs in vitro for adoptive transfer. 16 A more recent strategy that circumvents the analysis of ex vivo DCs is to target antigens to DCs in...
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