title: 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.
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 138669, Singapore.|Program in Emerging Infectious Diseases, Duke-NUS Medical School, 169857, Singapore.
authors.forename: Eugenia Z
authors.initials: EZ
authors.lastname: Ong
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Medical School, 169857, Singapore.
authors.forename: Summer L
authors.initials: SL
authors.lastname: Zhang
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Medical School, 169857, Singapore.
authors.forename: Hwee Cheng
authors.initials: HC
authors.lastname: Tan
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Medical School, 169857, Singapore.
authors.forename: Esther S
authors.initials: ES
authors.lastname: Gan
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Medical School, 169857, Singapore.
authors.forename: Kuan Rong
authors.initials: KR
authors.lastname: Chan
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Medical School, 169857, Singapore.|Department of Microbiology and Immunology, National University of Singapore, 8 Medical Drive, Block MD4, 117545, Singapore.|Saw Swee Hock School of Public Health, National University of Singapore, 12 Science Drive 2, 117597, Singapore.|Singapore MIT Alliance Research and Technology, Infectious Diseases Interdisciplinary Research Group, CREATE Campus, 138602, Singapore.
authors.forename: Eng Eong
authors.initials: EE
authors.lastname: Ooi
mesh_terms: D019067:Antibody-Dependent Enhancement; D015703:Antigens, CD / Q000378:metabolism; D045744:Cell Line, Tumor; D003715:Dengue / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology* / Q000502:physiology; D006801:Humans; D000075362:Leukocyte Immunoglobulin-like Receptor B1 / Q000378:metabolism; D010588:Phagosomes / Q000276:immunology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D015703:Antigens, CD; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6