Effects of Acyclovir and IVIG on Behavioral Outcomes after HSV1 CNS Infection

Abstract

Herpes simplex virus 1 (HSV) encephalitis (HSE) has serious neurological complications, involving behavioral and cognitive impairments that cause significant morbidity and a reduced quality of life. We showed that HSE results from dysregulated central nervous system (CNS) inflammatory responses. We hypothesized that CNS inflammation is casually involved in behavioral abnormalities after HSE and that treatment with ACV and pooled human immunoglobulin (IVIG), an immunomodulatory drug, would improve outcomes compared to mice treated with phosphate buffered saline (PBS) or ACV alone. Anxiety levels were high in HSV-infected PBS and ACV-treated mice compared to mice treated with ACV + IVIG, consistent with reports implicating inflammation in anxiety induced by lipopolysaccharide (LPS) or stress. Female, but not male, PBS-treated mice were cognitively impaired, and unexpectedly, ACV was protective, while the inclusion of IVIG surprisingly antagonized ACV's beneficial effects. Distinct serum proteomic profiles were observed for male and female mice, and the antagonistic effects of ACV and IVIG on behavior were paralleled by similar changes in the serum proteome of ACV- and ACV + IVIG-treated mice. We conclude that inflammation and other factors mediate HSV-induced behavioral impairments and that the effects of ACV and IVIG on behavior involve novel mechanisms.

Herpes Simplex Virus Infection, Acyclovir and IVIG Treatment All Independently Cause Gut Dysbiosis

“…Equal numbers (n=8) of female and male C57BL/6 mice were bilaterally inoculated with virulent HSV1 strain 17+ (1×10 5 PFU/eye) by corneal scarification as previously described [15]. At day 4 post infection (pi), ACV was administered at 1.25 mg / mouse by intraperitoneal injection (ip) daily for 3 days, while IVIG was given as single dose of 25 mg/mouse by ip injection on day 4pi [15]. Fresh fecal pellets (n=1-2/ mouse) were collected on day 7 pi and stored at −80°C until processed for Illumina 16S rRNA gene sequencing to determine the effects of infection and drug treatment on the gut microbiome.…”

“…Though the mechanisms by which ocular HSV infection causes gut dysbiosis are unclear, neuroinflammatory mechanisms and effects on the enteric nervous system via connected brainstem neuronal circuits can be envisaged [15, 42]. Indeed, recent paradigm-shifting reports reveal that peripheral neurons, including nociceptive and sensory neurons, can directly sense and respond to environmental alarms by releasing neuropeptides that can regulate immune responses in target organs including the gut [43, 44].…”

“…Indeed, recent paradigm-shifting reports reveal that peripheral neurons, including nociceptive and sensory neurons, can directly sense and respond to environmental alarms by releasing neuropeptides that can regulate immune responses in target organs including the gut [43, 44]. Persistence of gut dysbiosis was not evaluated here, but results from a behavioral study alluded to earlier suggest long-term effects of infection and drug treatment on gut bacterial ecology should be investigated [15]. Sex biased effects on HSV induced dysbiosis merit further study, as these may involve microglial responses to HSV infection and the microglial compartment is known to be regulated by the microbiota in a sex biased manner [45-47].…”

“…Mice were sedated with ketamine (60 mg/kg) and xylazine (5 mg/kg) prior to HSV inoculation by corneal scarification. B6 mice were bilaterally inoculated with 1× 10 5 PFU per eye and monitored daily as previously described [15, 77].…”

Herpes simplex virus infection, Acyclovir and IVIG treatment all independently cause gut dysbiosis

“…Strikingly, development of learning and memory (LM) deficits that were evident only in female PBS treated mice, were inhibited by ACV treatment and counterintuitively, aggravated by ACV+IVIG treatment. Treatment of infected male mice with ACV+IVIG also impaired LM compared to ACV or PBS alone, revealing that IVIG antagonized the beneficial effects of ACV [ 15 ]. Intriguingly, the differential antagonistic effects of ACV+IVIG on cognitive behavior in HSV infected mice, compared to ACV and PBS treatment alone, were reflected in differential serum proteomic profiles [ 15 ].…”