Introduce
Red blood cells (RBCs) are the most abundant cell type in the
bloodstream and serve
for
transporting oxygen and carbon dioxide via blood circulatory system.
RBCs
are differentiated from multipotent hematopoietic stem cells in the bone
marrow and circulated in the body for about 100-120 days, and then are
recycled by macrophages in spleen and liver (de Back, Kostova, van
Kraaij, van den Berg, & van Bruggen, 2014). Although RBCs lack of
nucleus and organelles, RBCs still have numerous cell surface receptors
for binding chemokines (Darbonne et al., 1991; Fukuma et al., 2003) and
nucleic acids (Hotz et al., 2018). Moreover, the receptors could be
employed by pathogens to adhere or invade in RBCs. For instance,Plasmodium falciparum invaded RBCs by adhering to glycophorin A
(GYPA) (Cowman, Berry, & Baum, 2012) andPlasmodium
vivax attached RBCs via Duffy Ag receptor for chemokines (DARC) (Boddey
& Cowman, 2013; Horuk et al., 1993).
Additionally,
HIV-1 persisted on RBCs through binding to DARC and presented virion to
CD4+ T cells (He et al., 2008). Although several
reports have indicated that certain viruses could bind to RBCs (Beck et
al., 2009; Hess et al., 2002; Sutherland et al., 2016), the underlying
mechanisms have not been confirmed.
The recent outbreak of porcine epidemic diarrhea (PED) is characterized
as vomiting, severe watery diarrhea, dehydration and high mortality in
suckling piglets, resulting in a huge loss in swine industry worldwide.
As the causative agent of PED
porcine
epidemic diarrhea virus (PEDV) is an enveloped, single-stranded, and
positive-sense RNA virus, belonging to the Coronaviridae family (C. Lee,
2015).
Due
to immature immune system, suckling piglets are more susceptible to PEDV
infection,
especially 1-2 days old neonatal piglets.
PEDV
infection causes severe destruction of intestinal villous enterocytes
and villous atrophy in the jejunum and ileum (Jung & Saif, 2015).
Moreover, PEDV can enter the blood and induce viremia in suckling
piglets (Jung et al., 2014; Wang, Hayes, Byrum, & Zhang, 2016),
though
the mechanism has been much less well understood.
Due
to lack of ribosomes or genomes, mature RBSs are inability of gene
transcription and protein synthesis, meaning that RBCs are invulnerable
to viral infection. However, several researches have claimed that RBCs
might be possible vehicles for virus transmission. For instance, RBCs
could bind to HIV-1 virions and enrich virus infectious (Beck et al.,
2009). In addition, a recent study has reported that complete genome
sequence of the DNA of African swine fever virus (ASFV) was determined
from porcine RBCs, suggesting that RBCs might serve as a carrier for
virus transmission (Olesen et al., 2018). Our previous study
demonstrated that PEDV could be captured by dendritic cells (DCs) from
nasal epithelium, transferred to CD3+ T cell and
entered the peripheral blood, causing intestine infection (Li et al.,
2018).
Although
PEDV could be carried into the blood by T cells, is it possible that
RBCs, as the most abundant cell type, serve as another potential vehicle
for PEDV transmission in the blood?
In the present study, the hypothesis
for PEDV transmission in the blood by hijacking RBCs was proposed. To
verify our hypothesis, neonatal RBCs were infected with PEDV.
Subsequently,
an animal challenge through autotransfusion with PEDV-loaded RBCs was
performed to validate whether PEDV could cause intestine infection
through hijacking RBCs in vivo.
A
co-culture model of PEDV-loaded RBCs and CD3+ T cells
was established
to
determine the mechanism of which PEDV entering the intestinal mucosa
from the
blood.
Moreover,
through
intranasal challenge with PEDV in newborn piglets, the PEDV-loaded RBCs
were found in the nasal capillary, consequently, nasal capillary was
speculated to be the possible entry for PEDV binding RBCs. This study
was first time to demonstrate that the coronavirus PEDV could spread
throughout the body and cause intestinal infection by hijacking RBCs in
newborn piglets.
Therefore,
our study provides a novel insight into the role of RBCs in coronavirus
pathogenesis as potential cells for virus
transmission.