The pathogenesis and virulence of enterovirus-D68 infection

Figures & data

Table 1. Cellular receptors for EV-D68 and their expression on different cells types of the respiratory tract, CNS and lymphoid system SAs: Sialic acids; CNS: central nervous system; DCs: dendritic cells; NA: not available; *: in vitro study

Receptors	Tissue
	Respiratory tract	CNS	Lymphoid
α2,3-linked SAs	goblet cells; club cells; type II pneumocytes; alveolar macrophages (23, 24)	neurons; astrocytes; glial cells (93)	monocytes; macrophages (94, 95)
α2,6-linked SAs	ciliated epithelial cells; goblet cells; type I pneumocytes (23, 24)	neurons; glial cells; astrocytes; oligodendrocytes (93, 96)	monocytes; macrophages; B cells (94-96)
ICAM-5	NA	dendrites/soma of neurons of the telencephalon (33, 97)	NA
Heparan sulfate	basal side of human respiratory epithelial cells* (28)	neurons*; astrocytes (28, 30)	monocytes; macrophages; immature DCs; mature DCs; B cells (98, 99)

Figure 1. Hypothetical model of pathogenesis of EV-D68 infection based on findings from EV-D68 infected patients and experimental in vivo and in vitro studies. (a) EV-D68 infection in the respiratory tract: Inhaled virus particles firstly replicate in the upper respiratory tract and might spread to the lower respiratory tract. (b) EV-D68 infection outside the respiratory tract: Systemic dissemination of virus into the bloodstream and/or draining lymph nodes, resulting in viremia and infection of extra-respiratory tissues including the gastrointestinal tract, skin and heart. (c) EV-D68 infection in the CNS: EV-D68 may invade the CNS through infection of the muscles and subsequent spread via the neuromuscular junction to motor neurons in the anterior horn of the spinal cord using retrograde axonal transport. Other possible invasion mechanisms into the CNS are via the blood-brain barrier, blood-CSF barrier or cranial nerves. Purple dot represents EV-D68. Purple arrow represents the flow of EV-D68 systemic dissemination in the circulation

Table 2. The detection of EV-D68 in diagnostic samples including whole blood, serum or plasma, stool and CSF samples in reported cases. CSF: cerebrospinal fluid; NA: not available. *: More than 1 sample were collected from a patient

Studies	Total EV-D68-positive sample tested	Number of EV-D68-positive samples out of total EV-D68-positive sample tested
		Respiratory tract	Whole blood	Serum or plasma	Stool	CSF
Imamura et al. [51]	30	30/30	NA	28/30	NA	NA
Greninger et al. [16]	12	12/12	1/12	NA	1/12	0/12
Esposito et al. [6]	1	1/1	NA	NA	NA	0/1
Chong et al [50].	11*	7/11	1/11	1/11	2/11	1/11
Giombini et al. [2]	1*	1/1	0/1	NA	0/1	1/1
Cabrerizo et al. [100]	3*	3/3	0/3	NA	3/3	0/3
Sejvar et al. [77]	11	11/11	NA	NA	0/11	1/11
Pfeiffer et al. [80]	2	2/2	NA	0/2	0/2	0/2
Van Haren et al. [68]	9	9/9	NA	1/9	NA	NA
Kusabe et al [39].	1	NA	NA	1/1	NA	0/1
Hu et al. [101]	9*	9/9	0/9	0/9	0/9	0/9
ElBadry et al. [102]	1	NA	NA	1/1	NA	NA

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