Biology subjects

Gebo, C.

Publications and source records attributed to Gebo, C..

3 recordsLinked to original sources

bioRxiv2026

Molecular and biophysical requirements for B cell receptor dependent enhancement of dengue virus infection

Dengue virus (DENV) is the causative agent of dengue, a mosquito-borne disease that represents a significant and growing public health burden around the world. A unique pathophysiological feature of dengue is immune-mediated enhancement, wherein preexisting immunity elicited by a primary infection can enhance the severity of a subsequent infection by a heterologous DENV serotype. A leading mechanistic explanation for this phenomenon is antibody dependent enhancement (ADE), where sub-neutralizing concentrations of DENV-specific IgG antibodies facilitate entry of DENV into Fc{gamma}R expressing cells. Accordingly, this model posits that phagocytic mononuclear cells are the primary reservoir of DENV. However, multiple independent groups have shown that B cells are the largest reservoir of virally infected cells in circulation during acute dengue, representing a disconnect in our understanding of immune-mediated DENV tropism. In response to this persistent knowledge gap, our team has previously identified a novel mechanism of immune-mediated enhancement we have termed BCR-dependent enhancement (BDE) of DENV infection. In this study, we show that DENV infection of DENV-reactive B cells is highly sensitive to BCR/DENV envelope (E) protein interactions. DENV entry into this subset of B cells is dynamin-mediated and requires proximal BCR signaling. Finally, we show that DENV-reactive B cells are productively infected by live DENV, capable of supporting active viral replication and dissemination. We propose that BDE provides an additional layer of pathogen-specific immune-mediated infection risk that complements existing models of ADE and offers additional insight into potential mechanisms of DENV immunopathogenesis.

immunology↗

bioRxiv2024

B cell receptor dependent enhancement of dengue virus infection

Dengue virus (DENV) is the causative agent of dengue, a mosquito-borne disease that represents a significant and growing public health burden around the world. A unique pathophysiological feature of dengue is immune-mediated enhancement, wherein preexisting immunity elicited by a primary infection can enhance the severity of a subsequent infection by a heterologous DENV serotype. A leading mechanistic explanation for this phenomenon is antibody dependent enhancement (ADE), where sub-neutralizing concentrations of DENV-specific IgG antibodies facilitate entry of DENV into Fc{gamma}R expressing cells such as monocytes, macrophages, and dendritic cells. Accordingly, this model posits that phagocytic mononuclear cells are the primary reservoir of DENV. However, analysis of samples from individuals experiencing acute DENV infection reveals that B cells are the largest reservoir of infected circulating cells, representing a disconnect in our understanding of immune-mediated DENV tropism. In this study, we demonstrate that the expression of a DENV-specific B cell receptor (BCR) renders cells highly susceptible to DENV infection, with the infection-enhancing activity of the membrane-restricted BCR correlating with the ADE potential of the IgG version of the antibody. In addition, we observed that the frequency of DENV-infectable B cells increases in previously flavivirus-naive volunteers after a primary DENV infection. These findings suggest that BCR-dependent infection of B cells is a novel mechanism immune-mediated enhancement of DENV-infection.

immunology↗

bioRxiv2022

Evolution of inflammation and immunity in a dengue virus 1 human infection model

Dengue virus (DENV) infections are significant sources of morbidity and mortality throughout the tropics and subtropics. Over 400 million infections are estimated to occur every year, resulting in nearly 100 million symptomatic infections and over 20,000 deaths. Early immune response kinetics to infection remain unclear, in large part due to the variable incubation period exhibited by the DENVs after introduction into a susceptible host. To fill this knowledge gap, we performed a comprehensive virologic and immunologic analysis of individuals experimentally infected with the under-attenuated DENV-1 strain 45AZ5. This analysis captured both the kinetics and composition of the innate, humoral, and cellular immune responses elicited by experimental DENV-1 infection, as well as virologic and clinical features. Revealed in this analysis was a robust DENV-specific IgA antibody response that manifested between the appearance of DENV-specific IgM and IgG in all challenged individuals, as well as the presence of a non-neutralizing/NS1-specific antibody response that was delayed relative to the appearance of DENV-virion specific humoral immunity. RNAseq analysis also revealed several distinct and temporally-restricted gene modules that allowed for the identification and differentiation of the innate and adaptive immune response to DENV-infection. Our analysis provides a detailed description, in time and space, of the evolving matrix of DENV-elicited human inflammation and immunity and reveals several previously unappreciated immunological aspects of primary DENV-1 infection that can inform countermeasure development and evaluation.

immunology↗