New research conducted at Penn State has found that differences in herpes virus symptoms could be attributable to variations in the way some strains of herpes simplex (HSV-1) activate gene expression in neurons.
Whereas some individuals with HSV-1 may experience painful lesions, others can have no symptoms at all while still spreading the virus, according to the study. In addition to these recurring problems, researchers have also noted that chronic HSV-1 infection has been linked to the development of some diseases as patients age.
“HSV-1 occurs in more than half the global population,” said Moriah Szpara, PhD, associate professor of biology and biochemistry and molecular biology, in a press release. “Not only does it cause recurrent problems, such as cold sores and genital herpes, but recent research has implicated chronic HSV-1 infection with the development of disease later in life, including neurodegenerative diseases like Alzheimer’s.”
The HSV-1 lifecycle begins upon contact with mucosal surfaces, according to Szpara, where the virus invades skin cells and replicates, which can induce local lesion formation. The virus also enters local nerve endings in the skin and transits into neurons in the nervous system, where the virus can lie dormant until it reactivates on future occasions. The neuronal damage and host immune responses triggered by viral reactivations are believed to contribute to long-term neurodegeneration.
“Since every person carries a subtly different version of HSV-1, this might explain some of the variation in human responses to infection,” Szpara said in the press release. “For example, why people have different triggers for their outbreaks or why some people experience more painful sores.”
To investigate the causes of response variations, Szpara and her investigative team infected human neuronal cells with 1 of 3 HSV-1 strains that are known to differ in their ability to cause disease in the nervous system. Next, they used deep sequencing to identify and quantify the transcriptomes of the neurons during infection by HSV-1.
According to the study, when a neuronal cell is infected with HSV-1, the resulting transcriptome includes the entire collection of mRNAs produced by both the human neuron and the HSV-1 virus. By analyzing the timing and amount of mRNAs expressed during infection, scientists can gain insights on the proteins that will soon be produced. The viral proteins and new viral progeny produced during infection ultimately lead to health problems.
“By simultaneously examining both the viral and neuronal transciptomes in the infected cells, we were able to observe the interplay between the timing of viral mRNA production and protein production, and the ensuing host responses,” Szpara explained in the press release.
The investigators also used immunofluorescence staining of neurons and Western blotting for viral protein cells to observe the outcomes of viral and host gene expression. Additionally, they used scanning electron microscopy to directly observe changes in neuronal morphology during infection.
They found that different genetic variants of HSV-1 induce different patterns of gene expression in human neuronal cells. Specifically, the viral variants expressed their genes at different rates and quantities, which likely contributes to the different timing and severity of symptoms within hosts. For example, they found that 1 variant caused greater changes in expression of genes involved in cell adhesion, which could impact cell-to-cell spread of HSV-1.
“Together, these data demonstrate the importance of studying virus strain- and cell-type-specific factors that may contribute to neurovirulence in vivo,” Szpara said in the press release. “It also highlights the specificity of HSV-1-host interactions. Our study suggests that differences observed between viral variants in cell-based models like neurons can be used to help understand the more complex interactions of viruses with hosts.”
Differences in herpes virus symptoms may relate to variations in strain gene expression [news release]. EurekAlert; March 29, 2021. https://www.eurekalert.org/pub_releases/2021-03/ps-dih032921.php. Accessed April 2, 2021.