Diet-induced obesity prolongs neuroinflammation and recruits CCR2 + monocytes to the brain following herpes simplex virus (HSV)-1 latency in mice

Abstract

Herpes simplex virus (HSV)-1 is a ubiquitous human infection, with increased prevalence in obese populations. Obesity has been linked to increased inflammation, susceptibility to infection, and higher rates of anxiety disorder and cognitive impairment. To determine how obesity alters neuroinflammation and behavior following infection, we infected weanling C57BL/6 or CCR2RFP/+/CX3CR1GFP/+ mice with a very low dose of HSV-1. Following viral latency (14 days post infection (d p.i.)), mice were randomly assigned to remain on the low fat (LF) diet or switched to a 45% high fat (HF) diet. Eight weeks post diet shift, latently infected mice on the HF diet (HSV-HF) had greater microglial activation and infiltration of inflammatory CCR2+ monocytes in the hypothalamus and dentate gyrus, in comparison to both HSV-LF mice and uninfected mice on LF and HF diets. VCAM staining was present in hypothalamus and hippocampus of the HSV-HF mice in the areas of monocyte infiltration. Infiltrating monocytes also produced proinflammatory cytokines demonstrating that, along with activated microglia, monocytes contribute to sustained neuroinflammation in latently infected obese mice. Utilizing a light-dark preference test, we found that HSV-HF mice had increased anxiety-like behavior. In the marble-burying test, HF diet and HSV infection resulted in increased numbers of buried marbles. Together, these mice provide a useful, testable model to study the biobehavioral effects of obesity and latent HSV-1 infection in regards to anxiety and may provide a tool for studying diet intervention programs in the future.

Herpes Simplex Virus Type 1 Infects Enteric Neurons and Triggers Gut Dysfunction via Macrophage Recruitment

“…Indeed, macrophages clear viral particles and apoptotic cells, release pro-inflammatory cytokines and chemokines to attract additional innate immune cells, limit viral replication, process, and present viral antigens to lymphocytes (Kodukula et al, 1999 ). Quite the opposite, infiltrating macrophages producing pro-inflammatory cytokines have been described also during latent HSV-1 infection and correlate with prolonged neuroinflammation in hypothalamus and hippocampus (White et al, 2016 ). Indeed, during chronic HSV-1 infection recruited immune cells impact the integrity of peripheral nerves either directly by damaging neurons harboring the virus or through the secretion of soluble factors that modify gene expression and survival of infected and non-infected cells (Kramer et al, 2003 ; Dosa et al, 2011 ).…”

Mapping of Microglial Brain Region, Sex and Age Heterogeneity in Obesity

“…However, others failed to reproduce this hippocampal microglial activation by an obesogenic diet, reporting no differences in the microglial process length, Iba-1+ immunoreactivity and/or cell number [ 41 , 59 , 60 ]. One group even observed a decrease in the Iba-1+ area fraction in hippocampi from rats fed a hypercaloric diet, compared to control animals [ 61 ].…”

“…Obesity caused robust DG microglial activation with increased microglial cell numbers in the hilar region when compared to controls [ 59 , 65 , 69 ]. This microglial activation persisted in the molecular and granule dentate cell layers when animals were chronically exposed to an obesogenic diet.…”

“…Some studies have also reported the obesity-induced microglial status in other brain regions with no direct involvement in food intake, like the amygdala, cerebellum and corpus callosum. Chronic HFD feeding resulted in increased Iba-1+ immunoreactivity in the amygdala [ 59 ]. However, a short-term diet failed to reproduce these results [ 52 ].…”

Herpes Simplex Virus Type 1 Engages Toll Like Receptor 2 to Recruit Macrophages During Infection of Enteric Neurons

“…Recruitment of macrophages and lymphocytes nearby infected neurons or glial cells represents a key step to limit replication and spread of neurotropic viruses. However, the inflammatory infiltrate potentially damages the neuronal tissue through direct or indirect mechanisms ( Kodukula et al, 1999 ; White et al, 2016 ).…”