A distinct brain pathway links viral RNA exposure to sickness behavior

Abstract

Sickness behaviors and metabolic responses to invading pathogens are common to nearly all types of infection. These responses evolved to provide short-term benefit to the host to ward off infection, but impact on quality of life, and when prolonged lead to neurodegeneration, depression, and cachexia. Among the major infectious agents, viruses most frequently enter the brain, resulting in profound neuroinflammation. We sought to define the unique features of the inflammatory response in the brain to these infections. We demonstrate that the molecular pathway defining the central response to dsRNA is distinct from that found in the periphery. The behavioral and physical response to the dsRNA mimetic poly I:C is dependent on signaling via MyD88 when it is delivered centrally, whereas this response is mediated via the TRIF pathway when delivered peripherally. We also define the likely cellular candidates for this MyD88-dependent step. These findings suggest that symptom management is possible without ameliorating protective antiviral immune responses.

MyD88 signalling is critical in the development of pancreatic cancer cachexia

“…However, our prior work demonstrated that muscle‐specific deletion of MyD88 did not attenuate muscle catabolism in response to acute inflammatory challenges . Among multiple central and systemic signalling pathways, the hypothalamic melanocortin system exerts a powerful role in the regulation of feeding behaviour, metabolic activity, energy homeostasis, and body composition and is known to be altered during acute and chronic inflammation and cachexia . Indeed, mice and humans with defects in central melanocortin signalling have large increases in lean mass, including skeletal muscle, cardiac muscle, and bone .…”

“…Real‐time quantitative PCR was performed as described previously . RNA was extracted from tissues using RNeasy kits (Qiagen Inc., Valencia, CA, USA).…”

“…Real-time quantitative PCR was performed as described previously. 18 RNA was extracted from tissues using RNeasy kits (Qiagen Inc., Valencia, CA, USA). Reverse transcription and quantitative PCR reagents were obtained from Life Technologies (Carlsbad, CA, USA).…”

“…Tumour cells can produce inflammatory cytokines and induce the host's local and systemic inflammatory responses, all of which can trigger many of the metabolic changes associated with cachexia . In this way, the response to PDAC is similar to that observed after exposure to bacterial endotoxin, viral RNA, or cytokines, each of which induces robust inflammation that results in anorexia, body weight loss, fatigue, and muscle wasting . Over the past decade, studies in both humans and rodents implicate a number of pro‐inflammatory cytokines as key mediators of cachexia in PDAC, including tumour necrosis factor alpha, interleukin‐1 beta, interleukin‐6 (IL‐6), and interferon gamma .…”

“…10,[12][13][14][15] In this way, the response to PDAC is similar to that observed after exposure to bacterial endotoxin, viral RNA, or cytokines, each of which induces robust inflammation that results in anorexia, body weight loss, fatigue, and muscle wasting. [16][17][18][19] Over the past decade, studies in both humans and rodents implicate a number of pro-inflammatory cytokines as key mediators of cachexia in PDAC, including tumour necrosis factor alpha, interleukin-1 beta, interleukin-6 (IL-6), and interferon gamma. 12,14,20 This in turn led to efforts at developing anti-cytokine agents (e.g.…”