For the past two years, the global pandemic has made us extremely aware of how our bodies respond to viral infection. Within this pandemic is another pandemic – a level of heightened stress that is affecting our behaviors, mental health and potentially our immune systems. The intersection between immune and stress systems has been studied extensively, but our understanding of how stress-specific brain circuits affect discrete elements of the immune system, and how this could impact the body’s ability to respond to various immune challenges is very limited. A new study by Poller et al.1 published in Nature provides mechanistic insights into how acute stress uses distinct brain circuits to regulate leukocyte dynamics and contribute to differential disease susceptibility in response to either auto-immune challenge or viral infection.

The idea that stress orchestrates the movement of immune cells to peripheral targets has been explored previously2. Although key stress hormones such as norepinephrine and glucocorticoids have been implicated in these processes, a direct link between the brain cells that coordinate the neuroendocrine stress response has remained elusive. Poller et al.1 now provide insights into distinct signaling me-chanisms that control the rapid mobilization of neutrophils into the circulation, followed by a slow movement of monocytes and lymphocytes from peripheral organs to the bone marrow after acute stress1 (Fig. 1). Consistent with previous work2, the slow transit of monocytes and lymphocytes from peripheral organs into the bone mar-row requires the activation of the canonical controllers of the neuroendo-crine response to stress, the cortico-tropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN). These cells release CRH to initiate a cascade of peripheral signals that culminate in an increase in circulating glucocorticoids. Poller et al.1 propose that glucocorticoids act in a leukocyte-autonomous fashion to enhance the function of CXC chemokine receptor 4 (CXCR4). CXCR4 has previously been descri-bed as a key player in the homing of cells to the bone marrow. This increase in leukocyte sequestration into the bone marrow has opposing effects on how the body responds to an autoimmune challenge versus a viral challenge.

By subjecting acutely stressed and unstressed mice to experimental auto-immune encephalomyelitis (EAE), Poller et al.1 show that stressed mice have lower clinical severity scores. These effects, which suggest mice are protected from disease initiation and progression, require the activation of CRH neurons and the actions of circulating corticosterone. Importantly, they showed that mice that lack CRH are more susceptible to EAE. Simply put, acute stress prevents the acquisi-tion of autoimmunity.

The results are quite different when the system is challenged with a virus. Given the pandemic, this is par-ticularly topical, so Poller et al.1 examined the effects of acute stress on viral infections. In comparison to age- and sex-matched controls exposed to SARS-CoV-2, stressed mice exposed to SARS-CoV-2 had higher viral titers. These effects were also dependent on corticosterone. Furthermore, this attenuation of the response to virus is not specific to SARS-CoV-2, as stress also increases viral titers after exposure to influenza A virus. The main lesson is that acute stress during the early phase of virus exposure impairs host adaptive immunity against infections.

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