Dengue virus compartmentalization during antibody-enhanced infection

Abstract

Secondary infection with a heterologous dengue virus (DENV) serotype increases the risk of severe dengue, through a process termed antibody-dependent enhancement (ADE). During ADE, DENV is opsonized with non- or sub-neutralizing antibody levels that augment entry into monocytes and dendritic cells through Fc-gamma receptors (FcγRs). We previously reported that co-ligation of leukocyte immunoglobulin-like receptor-B1 (LILRB1) by antibody-opsonized DENV led to recruitment of SH2 domain-containing phosphatase-1 (SHP-1) to dephosphorylate spleen tyrosine kinase (Syk) and reduce interferon stimulated gene induction. Here, we show that LILRB1 also signals through SHP-1 to attenuate the otherwise rapid acidification for lysosomal enzyme activation following FcγR-mediated uptake of DENV. Reduced or slower trafficking of antibody-opsonized DENV to lytic phagolysosomal compartments, demonstrates how co-ligation of LILRB1 also permits DENV to overcome a cell-autonomous immune response, enhancing intracellular survival of DENV. Our findings provide insights on how antiviral drugs that modify phagosome acidification should be used for viruses such as DENV.

Anti‐chlamydia IgG and IgA are insufficient to prevent endometrial chlamydia infection in women, and increased anti‐chlamydia IgG is associated with enhanced risk for incident infection

“…This contrasts with burden‐independent effects, which, while not significant, abrogated the protective effects of antibody mediated through burden. These findings suggest the possibility for antibody‐mediated enhanced uptake of chlamydia that has been well‐described for non‐neutralizing antibodies in viral infections . Evidence that antibody might promote chlamydial infection directly via transcytosis has been obtained in cell culture and in vivo.…”

“…Despite these protective effects, some antibodies can also mediate enhanced uptake of pathogens. Antibody‐mediated enhancement of infection has been well descried for viruses . In addition, IgG specific to the major outer membrane protein (MOMP) of chlamydia has been shown to enhance chlamydial uptake and transcytosis through polarized genital tract epithelial cells, and increase murine genital tract infection .…”

Structural Influence on the Dominance of Virus-Specific CD4 T Cell Epitopes in Zika Virus Infection

“…Although our results emphasize the importance of protein structure for controlling the immunodominance of CD4 T cell epitopes, additional parameters must be considered that could influence epitope selection. These may include virus-specific factors that antagonize host innate immune responses ( 42 ) or the lysosomal protease activity ( 43 ). In addition, individual-specific factors, such as differences in the naive TCR repertoire or stability of TCR/peptide–MHC interactions ( 11 ) may contribute to the epitope patterns observed.…”

Antibody-Dependent Enhancement of Viral Infections

“…Binding to LILR-B1 recruits Src homology phosphatase-1 (SHP-1) which dephosphorylates and inactivates Syk and prevents ISG expression. SHP-1 signaling also prevents rapid acidification and lysosomal degradation of DENV (Ong et al 2017). On the contrary, at high antibody concentrations, DENV E protein epitopes are completely blocked by the antibody; consequently, LILR-B1 binding is not possible, resulting in neutralization of the FcγR-internalized virus.…”