Peripheral viral infection induced microglial sensome genes and enhanced microglial cell activity in the hippocampus of neonatal piglets

Abstract

Although poorly understood, early-life infection is predicted to affect brain microglial cells, making them hypersensitive to subsequent stimuli. To investigate this, we assessed gene expression in hippocampal tissue obtained from a previously published study reporting increased microglial cell activity and reduced hippocampal-dependent learning in neonatal piglets infected with porcine reproductive and respiratory syndrome virus (PRRSV), a virus that induces interstitial pneumonia. Infection altered expression of 455 genes, of which 334 were up-regulated and 121 were down-regulated. Functional annotation revealed that immune function genes were enriched among the up-regulated differentially expressed genes (DEGs), whereas calcium binding and synaptic vesicle genes were enriched among the down-regulated DEGs. Twenty-six genes encoding part of the microglia sensory apparatus (i.e., the sensome) were up-regulated (e.g. IL1R1, TLR2, and TLR4), whereas 15 genes associated with the synaptosome and synaptic receptors (e.g. NPTX2, GABRA2, and SLC5A7) were down-regulated. As the sensome may foretell microglia reactivity, we next inoculated piglets with culture medium or PRRSV at PD 7 and assessed hippocampal microglia morphology and function at PD 28 when signs of infection were waning. Consistent with amplification of the sensome, microglia from PRRSV piglets had enhanced responsiveness to chemoattractants, increased phagocytic activity, and secreted more TNFα in response to lipopolysaccharide and Poly I:C. Immunohistochemical staining indicated PRRSV infection increased microglia soma length and length-to-width ratio. Bipolar rod-like microglia not evident in hippocampus of control piglets, were present in infected piglets. Collectively, this study suggests early-life infection alters the microglia sensome as well as microglial cell morphology and function.

Altered Hippocampal Gene Expression and Morphology in Fetal Piglets following Maternal Respiratory Viral Infection

“…PRRSV infects porcine alveolar macrophages, leading to interstitial pneumonia [39]; the symptoms include anorexia, fever, and sometimes cyanosis [40], similar to what is observed with a human influenza infection [41]. Previous studies in our laboratory have shown that early postnatal PRRSV infection results in reduced neurogenesis and enhanced microglial activity in the neonatal hippocampus [42, 43], and that postnatal PRRSV infection impairs neonatal piglet performance in a hippocampus-dependent learning and memory task [44]. More recent evidence from our porcine MIA model demonstrates that prenatal exposure to maternal PRRSV infection causes altered social behaviors postnatally, while prolonged microglial activation is not evident [45].…”

Traumatic brain injury‐induced neuronal damage in the somatosensory cortex causes formation of rod‐shaped microglia that promote astrogliosis and persistent neuroinflammation

“…Rod‐shaped microglia form as early as 1 dpi, peak in the subacute window, and align linearly in the cortex 7 dpi (Taylor, Morganti‐Kossmann, Lifshitz, & Ziebell, ). This structure is observed in other pathological contexts, including aging and chronic viral infection (Bachstetter et al, ; Ji, Schachtschneider, Schook, Walker, & Johnson, ; Sierra et al, ; Yuan, Liang, Peng, Lin, & So, ). Thus, it may represent a conserved response to neuronal degeneration/damage.…”

Environment matters: microglia function and dysfunction in a changing world

“…Notably, infection at a later stage of development, postnatal day (P)30, does not have the same persistent impact, implicating a critical window [42]. Early-life viral infection of piglets, who demonstrate similar brain growth trajectories and time course as humans, similarly induces a long-term priming effect on microglia [43]. Specifically, microglia collected at P28 from piglets infected with virus at P7, display enhanced phagocytic and migratory activity, increased sensitivity to a second challenge with LPS and Poly I:C, as well as increased soma size compared to controls, closely supporting our findings in rodents [20,44].…”