fig1

Figure 1. Respiratory centers of the brainstem and methods of viral entry into the nervous system. A: The brainstem contains the respiratory centers which integrate signals from the cortex through the limbic system and regulate breathing. Motor efferents from the brain stem innervate the diaphragm, airways, and abdominal muscles which create the movements necessary for inhalation and exhalation; B: olfactory neurons are susceptible to infection by viral particles in the nasal cavity (Route 1). These sensory neurons cross the cribiform plate and project through the olfactory tract into areas of the cortex and limbic system; C: alveoli in the lung are innervated by sensory neurons projecting up the spinal cord to the brainstem. The sensory neurons that innervate the lungs directly gather chemo- and mechano-signals from their dendrites in the lung and project them to pre-synapses in the brainstem. These neurons detect changes in oxygen and CO₂, mechanical stretch, and irritants that may be inhaled into the lung. Viral particles may enter these neurons and be transported anterogradely to the respiratory centers of the brainstem (Route 2). They may also enter the bloodstream and be subsequently introduced to the brain parenchyma through the blood–brain barrier (BBB) (Routes 3 and 4); D: a viral infection in the bloodstream may cross the BBB by active transport via receptors on the surface of endothelial cells (Route 3) or by passive diffusion through a leaky barrier (Route 4). Immune cells in the blood and glial cells in the brain respond to infection by releasing inflammatory cytokines, which may damage the BBB and result in greater passive diffusion of the virus. Arrows indicate the direction of signal transmission (A). Arrows indicate the direction of virus movement (B, C, D). Numerals 1-4 indicate different proposed routes of viral transmission. PNC: pneumotaxic center; APC: apneustic center; PRG: pontine respiratory group; pF_L: lateral parafacial nucleus; PiCo: postinspiratory complex; PreBötz: PreBötzinger complex; VRG: ventral respiratory group; DRG: dorsal respiratory group