Lymphopenia and increasing viral load in the first 10 days of severe acute respiratory syndrome (SARS) suggested immune evasion by SARS-coronavirus (CoV). In this study, we focused on dendritic cells (DCs) which play important roles in linking the innate and adaptive immunity. SARS-CoV was shown to infect both immature and mature human monocyte-derived DCs by electron microscopy and immunofluorescence. The detection of negative strands of SARS-CoV RNA in DCs suggested viral replication. However, no increase in viral RNA was ob- IntroductionCoronaviruses (CoVs) comprise a large family of RNA viruses that infect a broad range of vertebrates, from mammalian to avian species. 1 Prior to the emergence of severe acute respiratory syndrome (SARS) in 2002 to 2003, human CoVs were known to be associated mainly with relatively mild upper respiratory diseases such as the common cold. The novel SARS-CoV, however, caused severe, rapidly progressive atypical pneumonia with fever, myalgia, and diarrhea. 2,3 The detection of virus in stool and urine in addition to the respiratory tract of patients with SARS further suggested that SARS is a systemic disease. 4,5 At autopsy, white pulp atrophy was observed in the spleen, and there was lymphoid depletion in lymph nodes. [6][7][8] Together with lymphopenia and increasing viral load in the first 10 days of disease, 3,4,6 these clinical features strongly suggest an evasion of the immune system by SARS-CoV. As with other viral infections, such as measles, this lymphoid depletion may have pathogenic significance.Dendritic cells (DCs) are antigen-presenting cells that play key roles in linking innate and adaptive immunity. 9-11 Immature DCs reside in the respiratory tract for immune surveillance, and they respond dynamically to local tissue inflammation in the airways and the distal lung. 12,13 They express a wide range of receptors, including c-type lectins 14,15 and toll-like receptors, 16,17 for the recognition of conserved pathogen patterns. Dendritic cells signal the presence of danger to cells of the adaptive immune response and modulate their responses via the secretion of proinflammatory and/or antiviral cytokines. 18 In particular, DCs secrete cytokines to polarize T-helper (Th) cells toward the Th1 or Th2 subsets. 10 The migration of DCs from tissues to lymph nodes is essential for antigen presentation and triggering of adaptive immune responses. The trafficking of DCs is regulated by chemokines that can be classified as homeostatic (constitutively expressed) or inflammatory (induced/augmented) according to their immune fuctions. [19][20][21] Acute respiratory viruses commonly induce inflammatory chemokines, such as macrophage inflammatory protein 1␣ (MIP-1␣), regulated upon activation, normal T cell expressed and secreted (RANTES), interferon-inducible protein of 10 kDa (IP-10), and monocyte chemotactic protein 1 (MCP-1), in local tissues. 21 Dendritic cells are also a major source of these chemokines. 20 On the basis of the function of DCs in immune surveillance, priming, a...
Little is known about the innate immune response to severe acute respiratory syndrome (SARS) coronavirus (CoV) infection. Mannose-binding lectin (MBL), a key molecule in innate immunity, functions as an anteantibody before the specific antibody response. Here, we describe a case-control study that included 569 patients with SARS and 1188 control subjects and used in vitro assays to investigate the role that MBL plays in SARS-CoV infection. The distribution of MBL gene polymorphisms was significantly different between patients with SARS and control subjects, with a higher frequency of haplotypes associated with low or deficient serum levels of MBL in patients with SARS than in control subjects. Serum levels of MBL were also significantly lower in patients with SARS than in control subjects. There was, however, no association between MBL genotypes, which are associated with low or deficient serum levels of MBL, and mortality related to SARS. MBL could bind SARS-CoV in a dose-and calcium-dependent and mannan-inhibitable fashion in vitro, suggesting that binding is through the carbohydrate recognition domains of MBL. Furthermore, deposition of complement C4 on SARSCoV was enhanced by MBL. Inhibition of the infectivity of SARS-CoV by MBL in fetal rhesus kidney cells (FRhK-4) was also observed. These results suggest that MBL contributes to the first-line host defense against SARS-CoV and that MBL deficiency is a susceptibility factor for acquisition of SARS.Severe acute respiratory syndrome (SARS), a newly emerged infectious disease of humans, has affected 125 countries, with 8098 cases and 774 deaths reported to the World Health Organization (WHO) during the first half of 2003 [1]. The most affected locations were mainland China, Hong Kong, Taiwan, Singapore, and To-
Cell-free HIV-1 virions are poor stimulators of type I interferon (IFN) production. We examined here how HIV-infected cells are recognized by plasmacytoid dendritic cells (pDCs) and by other cells. We show that infected lymphocytes are more potent inducers of IFN than virions. There are target cell-type differences in the recognition of infected lymphocytes. In primary pDCs and pDC-like cells, recognition occurs in large part through TLR7, as demonstrated by the use of inhibitors and by TLR7 silencing. Donor cells expressing replication-defective viruses, carrying mutated reverse transcriptase, integrase or nucleocapsid proteins induced IFN production by target cells as potently as wild-type virus. In contrast, Env-deleted or fusion defective HIV-1 mutants were less efficient, suggesting that in addition to TLR7, cytoplasmic cellular sensors may also mediate sensing of infected cells. Furthermore, in a model of TLR7-negative cells, we demonstrate that the IRF3 pathway, through a process requiring access of incoming viral material to the cytoplasm, allows sensing of HIV-infected lymphocytes. Therefore, detection of HIV-infected lymphocytes occurs through both endosomal and cytoplasmic pathways. Characterization of the mechanisms of innate recognition of HIV-infected cells allows a better understanding of the pathogenic and exacerbated immunologic events associated with HIV infection.
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