Page 177 - IJB-10-2

International Journal of Bioprinting Coronavirus-infected bioprinted intestine

induced intestinal inflammation using the pathogenic infected with SARS-CoV-2. Subsequent studies using
31
bacterium Helicobacter pylori in human intestinal intestinal organoids have contributed additional insights
organoids. Additionally, since the infection behavior of into SARS-CoV-2 infection. Combined experiments using
24
intestinal pathogens is often determined by the polarity of cell lines and intestinal organoids revealed that type I and
intestinal cells, the ability of intestinal organoids to exhibit III interferons play a role in controlling SARS-CoV-2
clear cell polarization is highly useful in discerning these infection in human intestinal epithelial cells. Moreover,
32
differences, particularly in terms of apical or basolateral transmembrane serine protease 2 (TMPRSS2) has
infection sites. 22,25 been identified as a mediator of virus entry in intestinal
In some cases, experiments involving organoids may organoids. 33,34 Furthermore, the application of single-cell
require microinjection, which presents certain limitations RNA-sequencing (scRNA-seq) analysis to SARS-CoV-
such as extensive labor, difficulties in controlling injection 2-infected intestinal organoids revealed the induction
doses, and low-throughput. To overcome these challenges, of pro-inflammatory pathways and interferon-mediated
26
35
alternative techniques have been developed, such as apical- signaling. These findings shed light on the host response
out organoids and organoid-derived monolayers (Figure to viral infection within the intestinal organoids and
2B). Apical-out organoids are formed by dissolving the provide valuable insights into the mechanisms underlying
35
surrounding matrix of the organoids, which is then SARS-CoV-2 pathogenesis in the intestine (Figure 2C–E).
resuspended in a culture medium and transferred to While numerous studies have focused on modeling
low-attachment surface culture platforms, resulting in intestinal SARS-CoV-2 infections using intestinal
the formation of apical-out intestinal organoids, where organoids, there is a lack of organoid models for other
the apical microvilli face outward. Organoid-derived human coronavirus strains. SARS-CoV and MERS-
27
monolayers, on the other hand, involve the enzymatic CoV infections have been modeled with human
dissociation of 3D organoids into fragments or single cells, intestinal organoids. 30,36 However, only a few organoid
which are then seeded on traditional two-dimensional models have been reported for other strains, and most
(2D) platforms like flat plastic surfaces or transwells. of the studies have utilized human airway organoids
These monolayers of organoid-derived cells allow easier to recapitulate infection. 37-40 As seen during the SARS,
access to the apical side of cells and enable straightforward MERS, and COVID-19 pandemics, the lack of pan-
microscopic analysis due to their flat 2D cell layer. These coronavirus antivirals significantly contributes to the
26
techniques have been effectively used to study pathogen– vulnerability of public health systems. To address this, it
human intestine interactions. 28 is crucial to develop organoid models that can simulate
infections in other organs, such as the intestine, with
3.2. Intestinal organoids for human different coronavirus strains. For instance, Calistri et al.
coronavirus infection demonstrated that MEDS433, a human dihydroorotate
Intestinal organoids have also been instrumental in studying dehydrogenase inhibitor, could inhibit the replication of
viral infections, providing new insights into behaviors SARS-CoV-2 and other strains, such as HCoV-229E, using
of various viruses. For example, human intestinal kidney organoids. Similarly, employing other strains in
22
41
organoids revealed that respiratory adenovirus serotypes organoid models may provide new insights into intestinal
predominantly infect intestinal goblet cells, contrasting with HCoV infection.
human enteric adenovirus strains that infect enterocytes.
29
Thus, by infecting intestinal organoids with human 4. Intestine-on-chip for studying human
coronaviruses, researchers can investigate the mechanisms coronavirus infection
of viral entry, replication, and pathogenesis specifically in
the gut. This approach allows for the examination of the 4.1. Intestine-on-chip
viral life cycle and the identification of potential targets for Organ-on-chip platforms, also known as
intervention or therapeutics that can disrupt gut infection. microphysiological systems, are innovative tools that aim
to replicate the structure and function of human organs in
In the early stages of the COVID-19 pandemic, our 42,43
understanding of SARS-CoV-2 infection in the human a controlled laboratory environment. These platforms
integrate microfluidics and cell culture techniques to create
intestine was limited. Later on, studies using human dynamic, miniaturized models of organs, allowing for
intestinal organoids demonstrated that both SARS-CoV detailed studies of organ-level physiology and interactions
and SARS-CoV-2 could readily infect enterocytes within with various stimuli (Figure 3A).
the organoids, leading to the production of infectious
viral particles. These findings were further supported Intestine-on-chip platforms are a specific type of
30
by studies using bat and human intestinal organoids organ-on-chip system designed to replicate the structure

Volume 10 Issue 2 (2024) 169 doi: 10.36922/ijb.1704