Bacterial Lipopolysaccharide Inhibits Dengue Virus Infection of Primary Human Monocytes/Macrophages by Blockade of Virus Entry via a CD14-Dependent Mechanism

Abstract

Monocytes/macrophages (MO/Mφ) are the major target cells for both dengue virus (DV) and bacterial lipopolysaccharide (LPS), and the aim of this study was to define their interactions. We had found that LPS markedly suppressed DV infection of primary human MO/Mφ when it was added to cultures prior to or together with, but not after, viral adsorption. The inhibitory effect of LPS was direct and specific and was not mediated by LPS-induced secretion of cytokines and chemokines such as tumor necrosis factor alpha, interleukin-1β (IL-1β), IL-6, IL-8, IL-12, alpha interferon, MIP-1α, and RANTES. In fact, productive DV infection was not blocked but was just postponed by LPS, with a time lag equal to one viral replication cycle. Time course studies demonstrated that LPS was only effective in suppressing DV infection of MO/Mφ that had not been previously exposed to the virus. At various time points after viral adsorption, the level of unbound viruses that remained free in the culture supernatants of LPS-pretreated cultures was much higher than that of untreated controls. These observations suggest that the LPS-induced suppression of DV replication was at the level of virus attachment and/or entry. Blockade of the major LPS receptor, CD14, with monoclonal antibodies MY4 or MoS39 failed to inhibit DV infection but could totally abrogate the inhibitory effect of LPS. Moreover, human serum could significantly enhance the LPS-induced DV suppression in a CD14-dependent manner, indicating that the “binding” of LPS to CD14 was critical for the induction of virus inhibition. Taken together, our results suggest that LPS blocked DV entry into human MO/Mφ via its receptor CD14 and that a CD14-associated cell surface structure may be essential for the initiation of a DV infection.

Analysis of the Steps Involved in Dengue Virus Entry into Host Cells

“…The mechanism of this enhancement is not clear, particularly since there was no significant effect on plaque formation by this concentration of Con A. Chen et al (1999) found that bacterial lipopolysaccharide inhibits dengue virus infection of primary human monocytes/ macrophages by blocking for virus entry via a CD14dependent mechanism. Therefore, future studies should examine the entry events of dengue virus and the effects of various lectins on human monocytes/macrophages.…”

Lectin Switching During Dengue Virus Infection

“…Recent reports have identified monocytes as a major cell target of viral replication, and heparin sulfates, DC-SIGN, mannose receptor, and other glycoproteins have been proposed as cellular receptors for DENV [7][8][9][10][11][12][13][14][15][16][17][18]. DC-SIGN polymorphism has been shown to be associated with the disease severity [19].…”

RNA Association, RNA Interference, and microRNA Pathways in Dengue Fever Virus-Host Interaction

“…In mosquito cells, different independent groups have reported many potential DENV receptors like heat shock protein 70 (HSP), R80, R60, and 45 kDa protein [33]. In human beings, heparan sulfate [34], Hsp90 [35], CD14 [36], GRP78/BiP [37], and a 37/67-kDa high-affinity laminin receptor have been reported [38]. DENV particles interact with human myeloid cells by C-type lectin receptors (CLR) including DC-specific intracellular adhesion molecule 3 (ICAM-3)-grabbing no integrin (DC-SIGN, CD209) [39,40], mannose receptor (MR), and C-type lectin domain family 5, member A (CLEC5, MDL-1) [41].…”