Volatile Organic Compound Gamma-Butyrolactone Released upon Herpes Simplex Virus Type -1 Acute Infection Modulated Membrane Potential and Repressed Viral Infection in Human Neuron-Like Cells

Abstract

Herpes Simplex Virus Type -1 (HSV-1) infections can cause serious complications such as keratitis and encephalitis. The goal of this study was to identify any changes in the concentrations of volatile organic compounds (VOCs) produced during HSV-1 infection of epithelial cells that could potentially be used as an indicator of a response to stress. An additional objective was to study if any VOCs released from acute epithelial infection may influence subsequent neuronal infection to facilitate latency. To investigate these hypotheses, Vero cells were infected with HSV-1 and the emission of VOCs was analyzed using two-dimensional gas chromatograph/mass spectrometry (2D GC/MS). It was observed that the concentrations of gamma-butyrolactone (GBL) in particular changed significantly after a 24-hour infection. Since HSV-1 may establish latency in neurons after the acute infection, GBL was tested to determine if it exerts neuronal regulation of infection. The results indicated that GBL altered the resting membrane potential of differentiated LNCaP cells and promoted a non-permissive state of HSV-1 infection by repressing viral replication. These observations may provide useful clues towards understanding the complex signaling pathways that occur during the HSV-1 primary infection and establishment of viral latency.

Volatile fingerprinting of human respiratory viruses from cell culture

“…Five compounds (i.e., acetone, 2-propanol, o-xylene, benzaldehyde, and benzonitrile) have previously been reported in the headspace of cell cultures infected with viruses (three of which in cells infected with IAV, namely 2-propanol, o-xylene, and benzaldehyde) [31,33,34], while forty have been reported in the headspace of cell cultures more generally (mostly cancer cell cultures) (table 1) [33,34,[46][47][48][49][50][51][52][53][54][55][56][57][58]. The relatively minimal overlap between our study and prior studies that have considered in vitro cells infected with viruses is likely related to a number of factors, such as: the low signal generated by this kind of sample, the different MOIs applied, differences in the cell lines used and viral infection performed, as well as growth conditions and media used, different SPME fiber phase composition which affects the selectivity of the extracted compounds, differences in the analytical techniques utilized, as well as the difficulty in assigning precise identifications to alkylated hydrocarbons, which are generally the most abundant chemical class.…”

“…To-date, few studies have focused on the identification of volatile metabolites produced by cell cultures infected with virus (i.e., influenza, RSV, human rhinovirus, adenovirus, and herpes simplex) [31][32][33][34][35]. These studies involved basic characterization of the headspace of infected cell culture versus uninfected cell culture, but did not evaluate the discrimination capability of the volatile metabolites produced during infection.…”

Early Events after Herpes Simplex Virus-Type 1 Entry Are Necessary for the Release of Gamma-Hydroxybutyrate upon Acute Infection

“…Our previous reports showed that a VOC GBL was released upon acute HSV-1 infection of Vero cells [ 20 ]. We also reported that the spiked GBL production is due to an enhanced production of gamma-hydroxybutyrate (GHB).…”