REVIEW



Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): a Systemic Infection

Aleksandra Synowiec,a  Artur Szczepan ski,a,b  Emilia Barreto-Duran,a  Laurensius Kevin Lie,a  Krzysztof Pyrca aVirogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland

bMicrobiology Department, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland



SUMMARY …………………………………………………………………………1 INTRODUCTION ……………………………………………………………………1 HOSTFACTORSDETERMININGCELLTROPISM ………………………………………2 THERESPIRATORYTRACT ………………………………………………………….3 THEGASTROINTESTINALTRACT ……………………………………………………8 THECARDIOVASCULARSYSTEM …………………………………………………..10

Vascular Events ………………………………………………………………….11

The Heart ……………………………………………………………………….12 THEIMMUNESYSTEM …………………………………………………………….13 THEKIDNEY ………………………………………………………………………13 THELIVER ………………………………………………………………………..14 THE PANCREAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14 THENEUROLOGICALSYSTEM ……………………………………………………..15

The Eye …………………………………………………………………………16 REPRODUCTIVESYSTEM ………………………………………………………….16 CONCLUSIONSANDKEYTAKEAWAYMESSAGES …………………………………..18 ACKNOWLEDGMENTS …………………………………………………………….18 REFERENCES ……………………………………………………………………..18 AUTHORBIOS …………………………………………………………………….31

SUMMARY To date, seven identified coronaviruses (CoVs) have been found to infect humans; of these, three highly pathogenic variants have emerged in the 21st century. The newest member of this group, severe acute respiratory syndrome co- ronavirus 2 (SARS-CoV-2), was first detected at the end of 2019 in Hubei province, China. Since then, this novel coronavirus has spread worldwide, causing a pan- demic; the respiratory disease caused by the virus is called coronavirus disease 2019 (COVID-19). The clinical presentation ranges from asymptomatic to mild respi- ratory tract infections and influenza-like illness to severe disease with accompany- ing lung injury, multiorgan failure, and death. Although the lungs are believed to be the site at which SARS-CoV-2 replicates, infected patients often report other symptoms, suggesting the involvement of the gastrointestinal tract, heart, cardio- vascular system, kidneys, and other organs; therefore, the following question arises: is COVID-19 a respiratory or systemic disease? This review aims to summarize exist- ing data on the replication of SARS-CoV-2 in different tissues in both patients and ex vivo models.

KEYWORDS COVID-19, SARS-CoV-2, coronavirus, disease, infection, organoids, organs, systemic

INTRODUCTION

Coronaviruses (CoVs), enveloped, nonsegmented, positive-sense single-stranded RNA (ssRNA) viruses that belong to the Coronaviridae family, can infect both humans and animals. To date, seven CoVs have been reported to infect humans, of which four (human CoV-NL63 [HCoV-NL63] [1], HCoV-OC43 [2, 3], HCoV-229E [2, 3], and

Citation Synowiec A, Szczepan ski A, Barreto- Duran E, Lie LK, Pyrc K. 2021. Severe acute

 

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respiratory syndrome coronavirus 2 (SARS- CoV-2): a systemic infection. Clin Microbiol Rev 34:e00133-20. https://doi.org/10.1128/CMR .00133-20.
Copyright © 2021 American Society for Microbiology. All Rights Reserved.
Address correspondence to Krzysztof Pyrc, k.a.pyrc@uj.edu.pl.
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HCoV-HKU1 [4]) circulate worldwide and cause mild, seasonal respiratory tract disease. Importantly, three of seven CoVs emerged in the 21st century and are associated with severe acute respiratory tract infections. Severe acute respiratory syndrome CoV (SARS- CoV) emerged in late 2002 in Guangdong province, China, and spread rapidly to other countries and continents, accounting for ;8,000 confirmed cases and a fatality rate of 9.6% (5, 6). SARS-CoV is a betacoronavirus that originated in horseshoe bats and subse- quently leaked into the population of wild animals, including palm civets, in China; the virus adapted and ultimately was transmitted to humans by direct animal–human con- tact (7). Even though human-to-human transmission of the virus was efficient, the epi- demic burned out in May 2004 due to the seasonal nature of the virus and imposed health care measures; since then, no case of SARS-CoV has been reported. Middle East respiratory syndrome CoV (MERS-CoV) emerged 10 years later and caused outbreaks in Saudi Arabia and South Korea (8, 9). Similar to SARS-CoV, MERS-CoV originated in bats, but dromedary camels were identified as an intermediate host (10). It is still not clear how the virus was transmitted between these animals, and one may speculate that another intermediate host may have been involved (11). While human-to-human trans- mission of MERS-CoV accounts for almost half of cases, it is limited to households or nosocomial outbreaks, and close and prolonged contact is required (12). Despite that, MERS has accounted for ;2400 cases in the last 8 years, with an unsettling fatality rate of 34% (13). These two highly pathogenic coronaviruses caught the attention of researchers and triggered the number of studies on the potential of zoonotic coronavi- ruses to cause pandemics in humans. The discovery of a large pool of SARS-like corona- viruses in bats in Yunnan, China (14), led to the conclusion that we may encounter the SARS virus again. Indeed, 2019 brought us such a novel zoonotic coronavirus, which appears to be a close relative of the 2002 SARS-CoV. Severe acute respiratory syndrome CoV 2 (SARS-CoV-2) emerged in Hubei province, China (15). The virus, initially named “2019-nCoV,” belongs to the SARS-like virus cluster (15, 16) and shares 86% homology on the nucleotide level with the first detected SARS-CoV (17). The disease caused by the virus was named coronavirus disease 2019 (COVID-19). The clinical picture ranges from asymptomatic, through mild respiratory tract infections and influenza-like illness (mainly fever, cough, and fatigue), to severe disease with accompanying lung injury, multiorgan failure, and death (18, 19). Unsurprisingly, the lungs are the main gate of infection; however, SARS-CoV-2 RNA was detected in the kidneys, liver, heart, brain, and blood samples at autopsy (20). This is in agreement with reports showing that COVID-19 patients frequently exhibit other symptoms, suggesting multiorgan involve- ment and a rare but severe complication of SARS-CoV-2 replication, which is a multisys- tem inflammatory syndrome (MIS) in children (MIS-C) and adults (MIS-A) (21–30). This review aims to summarize and pull together existing data about the replication of SARS-CoV-2 in different tissues.

HOST FACTORS DETERMINING CELL TROPISM

Virus entry into a cell is a complex process that requires both viral and cellular fac- tors. The first steps are interaction with an adhesion receptor, binding to the entry re- ceptor, cell internalization/fusion, and transport to the site of replication (cytoplasm or nucleus). Coronavirus particles comprise at least four structural proteins: spike (S), en- velope (E), membrane (M), and nucleocapsid (N). Schematic SARS-CoV-2 structure and protein localization are presented in Fig. 1.

The S protein is responsible for receptor binding and determines the host range and cell tropism (31). This large protein comprises a short C-terminal tail located inside the virion, a transmembrane domain, a rod-like S2 domain responsible for the fusion process, and a large globular S1 domain, within which the receptor-binding domain is located. In advance of interaction with the entry receptor, the virus binds to adhesion receptors; this concentrates the virus on the cell surface. Next, the virus binds to the entry receptor, which initiates a fusion of the viral and cellular membranes. Finally, the

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FIG 1 Schematic structure of the SARS-CoV-2 virion.

viral nucleoprotein enters the cytoplasm. The adhesion and entry receptors used by human coronaviruses (32–42) are presented in Fig. 2.

The in vitro and ex vivo models that are permissive to infection by SARS-CoV-2 are listed in Tables 1 and 2.

The internalization site depends on the availability of the proteases required to trig- ger a transformation of the S protein into the fusogenic state. In vitro models show that human coronaviruses use an endocytic entry pathway in which gradual acidifica- tion of the microenvironment activates endosomal cathepsin B (catB) and cathepsin L (catL), which effectively prime the S protein and initiate entry (43, 44). However, recent studies showed that human coronaviruses bypass this process and use serine pro- teases (transmembrane protease serine 2 [TMPRSS2], kallikrein 13) present on the cell surface (Fig. 2). In such cases, the fusion occurs on the cell surface and endocytosis is not required (45–50). Interestingly, the concentration of cathepsins in the endosomal compartments of primary cells lining the respiratory tract is too low for virus activation. Endocytosis does not allow virus fusion in vivo.

Focusing on SARS-CoV-2, Sungnak et al. (48) evaluated the expression of angioten- sin (Ang)-converting enzyme 2 (ACE2), which is an entry receptor for this virus (40), and of TMPRSS2 (a spike-priming protease) in different cell types. For their study, they used single-cell RNA sequencing (scRNA-seq) data sets from healthy donors generated by the Human Cell Atlas consortium. The authors focused mainly on evaluating the expression of ACE2 in epithelial cell types within the lung and airways. They found that even though the level of ACE2 expression was in general low, it was expressed by numerous epithelial cell types (e.g., alveolar type II [AT2], bronchial secretory, ciliated, and basal), with higher expression levels detected on nasal goblet and ciliated cells (48). Interestingly, although the lungs are considered to be the SARS-CoV-2 target organ, only ;2% of cells in this tissue are ACE2 positive, whereas ACE2-positive cells are found extensively in the small intestine, gallbladder, kidneys, testes, thyroid, adi- pose tissue, heart muscle, vagina, breast, ovary, and pancreas (51, 52). To give some examples, high ACE2 expression was found in ileal epithelial cells (about 30% of cells were found to be ACE2 positive). High expression of this protein was also found in myocardial cells and kidney proximal tubule cells (7.5% and 4% positive, respectively) (52). The widespread tissue distribution of the ACE2 protein explains the multiorgan dysfunction reported in patients. Moreover, it draws attention to the fact that COVID- 19 may be a systemic disease.

THE RESPIRATORY TRACT

The novel human coronavirus mainly affects the respiratory system, causing a respi- ratory disease characterized by cough (mostly dry), dyspnea, fatigue, and, in severe cases, pneumonia or respiratory failure (corroborated by radiographic bilateral ground-

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FIG 2 The entry of human coronaviruses into the host cell. Coronaviruses first interact with an adhesion molecule (e.g., heparan sulfate proteoglycans [HSPGs] for HCoV-NL63 [32], SARS-CoV [33], and [possibly] SARS-CoV-2 [409]; N-acetyl-9-O-acetylneuraminic acid

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glass opacity) (53–55). Damage to the airway tract and lungs was evident during bi- opsy and autopsy studies (53–55). Diffuse alveolar damage (DAD) and airway inflam- mation have been reported both in humans and in nonhuman primates (53, 56–63). The leading cause of mortality for SARS-CoV-2 is respiratory failure from acute respira- tory distress syndrome (ARDS) (64). ARDS can be related to airway remodeling caused by pulmonary fibrosis and systemic inflammation (65, 66). The exact molecular mecha- nism of airway remodeling during the COVID-19 remains unknown and is associated with both viral replication in the tissue and dysregulation of natural pathways such as cytokine production or oxidative stress. Finally, the identification of viral cellular targets may shed some light on potential therapeutic and preventive strategies that may be used in COVID-19 patients with ARDS in the future.

While it is known that the respiratory tract is an entry point for SARS-CoV-2, it is vital to identify the cells that are the primary targets of the infection. First, in vitro analyses carried out by Hoffmann et al. demonstrated that SARS-CoV-2 pseudoviruses entered human cell lines derived from the airways, including Calu3, A549, BEAS-2B, and H1299 cells (49), with Calu3 cells being the most permissive (49). While efficient SARS-CoV-2 replication in the Calu3 cell line was also demonstrated by others (54, 67–71), A549 cells were not found to be permissive unless they overexpressed ACE2 (54, 70, 72–75).

Data mining allowed the identification of cell types that may be permissive to infec- tion in vivo (48, 52, 73, 76–78). The cells present in the human respiratory tract are shown in Fig. 3. In general, lung and bronchial tissues show low expression of ACE2 (73, 79); alveolar type II cells (AT2) show higher expression of ACE2 and TMPRSS2 (48, 49, 52, 77, 80–82). Hikmet et al. reported expression of ACE2 in more than 150 cell types from different tissues (immunohistochemical analysis) (73), but in that study, the level of expression of ACE2 in the respiratory system was limited. Aguiar et al. showed similar results using microarrays and scRNA-seq data set analysis (79). Sungnak et al. reported high expression of both ACE2 and TMPRSS2 in nasal goblet and ciliated cells (48). They corroborated these results by performing an independent scRNA-seq study of nasal brushings and studies using an in vivo nasal human airway epithelium (HAE) model. In accordance with those results, Lukassen et al. evaluated healthy human lung tissues (biopsy specimens) and bronchial HAE air-liquid interphase (ALI) cultures (HBEC); they reported that “transient secretory cells” showed expression of ACE2 and TMPRSS2 (81). These cells were reported to be cells transiting from a club or goblet phenotype to a differentiated ciliated phenotype (81). Tindle et al. demonstrated the expression of ACE2 in club cells using immunofluorescence staining of human lung sections from infected and noninfected patients (66). Zhang et al. analyzed airway epi- thelia using bulk RNA sequencing, scRNA-seq, and microarrays. They found that ACE2 is expressed in basal, club, goblet, and ciliated cells of the small airway, large airway, and trachea (83). Valyaeva et al. proposed that levels of expression of ACE2 and other SARS-CoV-2 entry factors might be underestimated when using 39 scRNA-seq data sets rather than full-length scRNA-seq data. They showed that ACE2 levels in basal cells were almost 10 times higher when evaluated using full-length scRNA-seq data, which is in accordance with results of ex vivo lung experiments showing basal cell infection (425).

Different approaches have been used to identify the cells that constitute the real targets for the virus; studies have examined primary human airway cells, tissue explants, and tissue cultures (49, 80, 84–87). Zhang et al. and Tindle et al. reported high expression of the viral N protein in alveolar epithelial cells within immunostained

FIG 2 Legend (Continued)
[Neu5Ac] for HCoV-HKU1 and HCoV-OC43 [34]; or carcinoembryonic antigen-related cell adhesion molecule 5 [CEACAM5] for MERS- CoV [35]). Next, the virus interacts with the entry receptor (aminopeptidase N [APN] for HCoV-229E [36]; dipeptidyl peptidase 4 [DPP4] for MERS-CoV [37]; 9-O-acetylated sialic acid for HCoV-OC43 [39]; or angiotensin-converting enzyme 2 [ACE2] for HCoV-NL63, SARS-CoV, and SARS-CoV-2 [40]). Recently, neuropilin 1 (NRP1) was reported to enhance the SARS-COV-2 entry (41, 42). To enter the cell, the S protein requires proteolytic priming, which may occur on the cell surface (TMPRSS2, TMPRSS4, kallikrein 13) or after endosomal entry (cathepsin B [catB] and cathepsin L [catL]) (43–50, 410–414).

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TABLE 1 Cell lines that support the replication of SARS-CoV-2

CPEa Additional information (reference[s])
1/2 Robust replication, no cell death detected, also

susceptible to SARS-CoV, one group reports

visible cytopathic effect (131)
1/2 Robust replication, no cell death detected, also

susceptible to SARS-CoV, some groups report

visible cytopathic effect (71, 415)
2 Robust replication, highly permissive (higher virus

titer than a parental line), no cell death detected 2 Robust replication

1 Robust replication. Also susceptible to SARS-CoV 2 Robust (80) or modest (416) replication; also

susceptible to SARS-CoV
2 Robust (80) or modest (416) replication; also

susceptible to SARS-CoV 2 Modest replication

1 Cessation of beating after 72 h of infection

2 Alpha, beta, and delta cells; alpha and beta cells were permissive for VSV-based SARS-CoV-2

pseudoviruses
2 The entry of pseudoparticles harboring spike protein

2 The entry of pseudoparticles harboring spike protein

1 Robust replication, cell rounding, detachment, degeneration, and syncytium formation; also

susceptible to SARS-CoV
1 Robust replication, cell rounding, detachment,

degeneration, and syncytium formation; also

susceptible to SARS-CoV
2 Robust replication; also susceptible to SARS-CoV

2 Also susceptible to SARS-CoV
2 Also susceptible to SARS-CoV
1/2 Robust replication; also susceptible to SARS-CoV 2 Modest replication

lung tissue biopsy specimens from a SARS-CoV-2-infected patient, suggesting that these cells may be effectively infected (53, 66). Hui et al. used ex vivo cultures of human bronchus and lung to show that AT1 cells, ciliated cells, club cells, and goblet cells, but not basal cells, are susceptible to SARS-CoV-2 infection (85). They also showed that the level of SARS-CoV-2 replication was higher than that of SARS-CoV in ex vivo bronchial cultures. Zhou et al. also demonstrated higher infectivity and replication of SARS-CoV- 2 than SARS-CoV in the airway organoids and confirmed the observation using subge- nomic mRNA analysis, transmission electron microscopy (TEM), and immunofluores- cence staining (88). Likewise, Chu et al. demonstrated replication and cell tropism of SARS-CoV-2 and SARS-CoV using ex vivo lung explants (80). The authors used plaque assay, quantitative reverse transcription-PCR (RT-qPCR), and confocal microscopy to show that SARS-CoV-2 infected and replicated more efficiently in human lung tissues than SARS-CoV. These findings are in agreement with results of studies performed with the Calu3 cell line (80, 85). The human airway epithelium (HAE) cultures are ALI models, which are used commonly to study human respiratory tract diseases due to their re- semblance to in vivo airway tissue (89–91). The ALI methodology promotes epithelial cell differentiation into different cell types (e.g., basal, ciliated, club, and goblet cells); besides, it allows the production of mucus and beating cilia, thereby providing a more reliable model of virus infection and cell tropism than traditional cell culture models (92–96). The first study to use HAE as a model for SARS-CoV-2 was presented by

Cell line

Caco-2

Calu3

C2BBe1 (Caco-2 subclone)

T84 CL14 Huh7

293T

U251 hiPSC-MC

hPSC

BEAS-2B H1299 Vero E6

FRhK4

LLC-MK2

Origin Species

Colorectal adenocarcinoma Human

Lung adenocarcinoma Human

Colorectal adenocarcinoma Human

Colorectal adenocarcinoma Human Colorectal adenocarcinoma Human Hepatocellular carcinoma Human

Embryonic kidney epithelia Human

Glioblastoma Human Induced pluripotent stem Human

cell-derived

cardiomyocytes
hPSC-derived pancreatic Human

endocrine cells

Nontumorigenic bronchial Human epithelium

Non-small-cell lung Human carcinoma

Kidney African monkey

Kidney Rhesus monkey

Kidney Rhesus monkey

Reference

54, 80, 130, 131

67–71, 80, 130, 331, 415–419

130

128 131 80, 416

80

80 242

309

49

49, 415

69, 70, 80, 416, 418, 420

80

80

80
80
80, 130 130

Kidney Cat Kidney Rabbit Kidney Pig Intestine Pig

CRFK
RK-13
PK-15
IPEC-J2
aCPE, cytopathic effect. 1, positive; 2, negative; 1/2, ambiguous result.

green



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TABLE 2 Ex vivo models used to study SARS-CoV-2 infection

Model

Human airway epithelium (HAE) cultures, ALI cultures

Primary human airway epithelial cells Primary cell-derived lung organoids hPSC-derived lung and macrophage

coculture system
hPSC-derived lung organoids Human lung organoids with mixed

proximodistal epithelia
Human embryonic stem cell (hESC)-

derived organoid 3D alveolar organoids Lung-on-chip

hESC-derived SEAM eye organoids

Human intestinal organoids (HIOs) hPSC-derived colon organoids

(hPSC-COs)
Human gastric organoids (HGOs)

Human tonsil organoids
Human blood vessel organoids Human kidney organoids
Human liver ductal organoids Human bronchial organoids (HBOs)

Human brain organoids

hPSC-derived choroid plexus organoids

Bat intestinal organoids

Additional information

Also susceptible to SARS-CoV; the virus infects primarily ciliated cells; cessation of cilium beating

Also susceptible to SARS-CoV
Also susceptible to SARS-CoV; SARS-CoV-2 infection of ciliated and basal cells M2 and M1 macrophages have inhibitory effects on SARS-CoV-2 infection

Mainly composed of AT2 and AT1 cells
Composed of both proximal and distal airway epithelia

Differentiated human airway organoids from hESC

Distal lung epithelial cells with or without lung fibroblasts
Cultures are composed of human airway epithelial and endothelial cells;

macrophages were also present in some experiments
Organoids are composed of four distinct zones of ocular tissues, including retinal

pigment epithelium (RPE), neural retina, ciliary body, lens, and cornea; highly

active SARS-CoV-2 replication in the corneal limbus
The virus replicates in enterocytes, cytopathic effect; also susceptible to SARS-CoV hPSC-derived organoids, composed of enterocytes, goblet cells, transit-amplifying

(TA) cells, enteroendocrine (EE) cells, and LGR51 or BMI11 stem cells; viral RNA

was detected in all five cell populations
Organoids derived from human fetal and pediatric tissue; standard and reversed-

polarity organoids included; robust viral replication in pediatric-derived

organoids but not fetal ones
Obtained from tonsil tissues, secretion of the progeny viral particles
iPSC-derived organoids, infectious viral progeny production
iPSC-derived organoids, infectious viral progeny production
Robust replication in cholangiocytes
Generated from commercially available cryopreserved human bronchial epithelial

cells
iPSC-derived organoids; SARS-CoV-2 enters into neuronal cells and targets cortical

region, but replication is probably abortive; neuronal cell death Simulated the blood-cerebrospinal fluid barrier; productive SARS-CoV-2

replication was observed, with SARS-CoV-2 preferentially infecting the choroid

plexus epithelium Progressive cytopathic effect

References

15, 67–69, 81, 98, 102–105, 421, 422

49 88 62

108 66

107

100, 107, 110–112 423, 424

347

123, 126, 136 108

137

246

98

98

298

84

317, 318 318, 335

126



Milewska et al. (97). The quantitative results indicated that the virus infects ciliated cells and is released on the apical side of the culture, not the basolateral side; this means that viral infection is effective in the airway lumen (97). Subsequent reports by others confirmed these observations (15, 98–101). Zhu et al. reported that ciliated, club, and goblet cells were infected in their HAE model and that the cytopathic effect (CPE) was observed (101). Ravindra et al. showed that the virus primarily infects ciliated cells and that during infection other cells (basal and club) can become infected (97, 102). They used scRNA-seq to show that goblet cells, neuroendocrine cells, tuft cells, and mono- cytes are rarely infected (102). TEM revealed that infection of human airway epithelial models of nasal and bronchial origin induced remodeling of the cellular ultrastructure of the ciliated, goblet, and (to a lesser extent) basal cells (102, 103). Following the results obtained reported by Ravindra et al., Mulay et al. used immunostaining to dem- onstrate that SARS-CoV-2 predominantly infected ciliated cells and a small portion of goblet cells in their HAE model (100). The HAE model has also been efficiently used by different research groups to evaluate different SARS-CoV-2 inhibitors (67–69, 72, 100, 104–106), suggesting that it is also a suitable model for this approach. Pei et al. showed that human embryonic stem cell (hESC)-derived organoids reflected the natural micro- environment. In this model, more than 90% of ciliated cells, less than 10% of club cells, and no basal or goblet cells were infected with SARS-CoV-2 (107). Tindle et al. devel- oped an adult stem cell-derived human lung organoid model composed of both proxi- mal and distal airway epithelia. They showed that the proximal airway epithelium is

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FIG 3 Cell types and their localization within the human respiratory tract.

more permissive to SARS-CoV-2 than the distal alveolar tissue (66). Han et al. demon- strated SARS-CoV-2 pseudovirus entry and SARS-CoV-2 infection in a human pluripo- tent stem cell (hPSC)-derived lung organoid model composed mainly of AT2 cells, AT1 cells, stroma cells, neuroendocrine cells, and airway epithelial cells (108). Similarly, Huang et al. proved the infection of iAT2 (AT2 cells derived from induced pluripotent stem cell [iPSC]) organoids in ALI culture (109) and Youk et al. the infection of the alve- olar stem cell-derived organoids (110). The results obtained by others (100, 107, 111, 112) are consistent with these observations.

THE GASTROINTESTINAL TRACT

Although coronaviral infections in humans are associated mainly with respiratory tract disease, accompanying symptoms in the gastrointestinal (GI) tract have been reported (113–119). According to one study, during a SARS-CoV outbreak in March 2003 in Hong Kong, 19.6% of infected patients developed nausea, diarrhea, and/or vomiting (113). Another study reported that 38% of patients experienced diarrhea during their illness (114). Interestingly, some patients (5.8%) with fever and diarrhea did not develop a respiratory disease (114). Consequently, viral replication in the small and large intestine of patients with SARS-CoV was confirmed (114). Infection by the second highly pathogenic coronavirus, MERS-CoV, was also associated with GI symptoms. Descriptive studies from 2012 to 2013 reported that a quarter of MERS-positive patients had accompanying GI symptoms, including diarrhea and vomiting (119). Importantly, not only highly pathogenic coronaviruses but also sea- sonal human coronaviruses are associated with GI infections. As an example, 33% of HCoV-NL63-positive patients and 57% of HCoV-OC43-positive patients in France developed digestive problems such as abdominal pain, diarrhea, and vomiting (116, 118). These data clearly show that the fecal-oral route of coronavirus transmis- sion is an important research area that needs further investigation during the COVID-19 pandemic.

After the emergence of SARS-CoV-2, it was observed that COVID-19 patients often suffered from GI tract disease symptoms (120, 121) and that up to 53% of patients

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FIG 4 Cell types and their localization in the human intestine.

infected with SARS-CoV-2 tested positive for viral RNA in stool specimens (117, 122, 123). Moreover, viral RNA can be detected in fecal samples for up to 5 weeks after re- spiratory samples become virus negative. In contrast, in some patients, an occurrence of GI tract symptoms does not correlate with the detection of viral RNA in fecal sam- ples (124). Some may speculate that such symptoms may be related to alterations in the gut microbiota and/or dysbiosis during COVID-19 (125). These findings make it uncertain whether SARS-CoV-2 replicates in the GI tract. Immunostaining of viral pro- teins in gastrointestinal tissue samples collected from affected patients shed some light on this by providing evidence for viral replication within these tissues, suggesting that the fecal-oral route is indeed a relevant transmission route (117). Moreover, some groups have reported successful isolation of infectious virus from stool samples (126, 127).

Efforts to model GI infection in vitro led to identification of four colon carcinoma cell lines (human intestinal epithelial cells [IECs]) that are permissive to SARS-CoV-2 infection: Caco-2 (49, 128) (also susceptible to the SARS-CoV infection) (129); C2BBe1, the Caco-2 brush border-expressing subclone (130); CL14 (131); and T84 (128). However, most niche-mimicking models and models of the GI tract are based on the use of human intestinal organoids (HIOs), which are currently the most advanced tool available. HIOs are differentiated, nontransformed, and physiologically active cultures, containing multiple intestinal epithelial cell types such as enterocytes, goblet cells, tuft cells, enteroendocrine cells (EECs), and Paneth cells (132). Cell types present in intes- tines are shown in Fig. 4. Importantly, a recent study showed that HIOs allow replica- tion of MERS-CoV (133), along with other viruses that could not be cultured using the standard cell lines (134, 135). HIOs, which can be grown in three-dimensional (3D) or 2D monolayers, support replication of SARS-CoV-2 and SARS-CoV in the ileum, duode- num, and colon-derived organoids (126, 128, 136). Importantly, the intestines are not the only affected part of the digestive system; viral nucleocapsid protein was visualized in gastric tissue derived from COVID-19 patients (117). Unsurprisingly, human gastric organoids (HGOs) derived from pediatric patients supported SARS-CoV-2 replication (137). Of note, human organoids are not the only organoids permissive to novel coro- navirus; bat intestinal organoids also support SARS-CoV-2 infection, which is in agree- ment with the virus origin predictions (126, 138).

Generally, ACE2 is an entry receptor for the virus, and TMPRSS2 is the spike priming protease. Intriguingly, the level of ACE2 expression in intestinal tissues is much higher

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than that seen in the lungs (139). To be more precise, ACE2 is abundantly expressed in stomach epithelial cells and in enterocytes from the small intestine, including the duo- denum, jejunum, and ileum, and it is poorly expressed in colonocytes (140). Unsurprisingly, human colonoids are affected to a lesser extent than organoids deriv- ing from the small intestine (128, 136). Consequently, SARS-CoV and SARS-CoV-2 infect only enterocytes and not goblet cells, EECs, tuft cells, or Paneth cells (123, 136). Mature enterocytes express higher ACE2 levels than immature ones, but the levels of replica- tion are comparable. This may indicate that a low level of ACE2 expression is sufficient for the virus to enter the cell (123, 136) or that there is an additional restriction factor present in mature enterocytes. What is interesting is that ACE2 expression increases during gastric (141) and colorectal (142) cancer development. Increased expression of ACE2 is also observed in patients with inflammatory bowel disease (IBD) (143, 144). Although ACE2 is not the only factor required during the infection, one might think that cancer or/and IBD patients might experience more-severe gastrointestinal symp- toms. Nevertheless, it is still an understudied research area that needs to be addressed. Human intestinal enteroid monolayer models confirmed that SARS-CoV-2 efficiently infects and replicates in the enterocytes and that the virus is released from the apical side (123). Except for ACE2, there are additional “players” during virus entry, and in intestines, the spike protein, similarly to other organs, is primed by TMPRSS2 (49) and possibly also by TMPRSS4 (123). As in the case of the respiratory tract, the role of cathe- psins in in vivo and ex vivo activity seems to be limited.

Nevertheless, one can imagine that bowel inflammation can lead to the “leaky gut” syndrome. This may result in systemic distribution of the virus and infection of other organs, for example, the lungs or heart. No reports have shown that the infectious virus can be found in blood, but viral RNA was found in 15% of plasma samples from COVID-19 patients in one study (139). Further, the systemic distribution of the virus confirms that SARS-CoV-2 may be spread either by blood or by blood cells. A similar study was carried out for MERS-CoV, when humanized dipeptidyl peptidase 4 (DPP4) mice were intragastrically administered with the virus; in addition to GI disease, ani- mals developed lung and brain infections (133). If the situation is similar in COVID-19 patients, the results may support clinical reports suggesting that gastrointestinal tract disease precedes respiratory tract symptoms (145). While infectious viral progeny are produced by gut organoids (136) and infectious SARS-CoV-2 can be isolated from stool samples (126, 127), the importance of the fecal-oral transmission route for SARS-CoV-2 remains unclear. Although the GI tract seems to be a replication site, it is worth men- tioning that in order to employ this route, the virus needs to cross the GI tract and remain infectious. This is questionable, as the recombinant SARS-CoV-2 mNeonGreen reporter virus was previously shown to be susceptible to inactivation by human gastric fluids (123). A similar phenomenon was reported for MERS-CoV, wherein the virus appeared to be tolerant of gastric and intestinal fluids produced during the fed state but not during fasting (133). Taking the data altogether, it remains unclear whether the GI tract can serve as the primary site of infection. Further investigations and devel- opment of appropriate animal models are needed.

THE CARDIOVASCULAR SYSTEM

The cardiovascular system was also thought to be a target for SARS-CoV-2 infection. Cardiovascular sequelae have been reported for other highly pathogenic human coro- naviruses. In SARS-CoV patients, these are usually mild and self-limiting (146), but MERS-CoV is associated with acute myocarditis and heart failure (147). It is well recog- nized that patients with preexisting cardiovascular diseases are more likely to suffer COVID-19 complications and to require admission to an intensive care unit (ICU) (148–154). Furthermore, myocardial injury and heart failure are considered to be sequelae of COVID-19 (51, 152, 153, 155). Nevertheless, one may say that cardiovascu- lar clinical manifestations may be solely the result of thrombosis.

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Vascular Events

FIG 5 Cell types and their localization in the cardiovascular system.

Endothelial cells are another cell population in the lungs but also in the cardiovascular system; importantly, they express ACE2 receptors and TMPRSS2 protease, as well as some other molecules that may mediate infection (e.g., CD147) (140, 156–160). The presence of SARS-CoV-2 virions was confirmed within endothelial cells; moreover, endotheliitis and ele- vated levels of circulating endothelial cells were observed (156, 157, 161–163). Cell types present in the cardiovascular system are shown in Fig. 5. The infection results in the pro- duction of virulent progeny viruses, which was confirmed using human capillary organoids (98).

Interestingly, severe illness is rare in children (164); however, several Kawasaki-like disease cases have been reported, first in Bergamo province in Italy and in England and later in other regions (22–24, 26, 165–175). Kawasaki disease is an acute pediatric vasculitis of unknown origin and is associated with coronary artery aneurysms. It is believed to be an aberrant response of the immune system and it was previously thought to be triggered by human coronaviruses (26, 164, 166). Diagnosed children are generally older than is usual for Kawasaki syndrome and present with more-severe disease; some require circulatory and respiratory assistance, with coronary artery aneurysms appearing to be frequent complications. Based on these cases, a definition of MIS-C, also called pediatric multisystem inflammatory syndrome (PMIS/PIMS), was formulated (21–23, 26, 27, 164, 166–168, 176). Similar symptoms were later observed in adolescents and adults, leading to the recognition of multisystem inflammatory syn- drome in adults (MIS-A). In contrast to other severe cases of COVID-19, patients with MIS-C or MIS-A have minimal respiratory symptoms and often test negative in PCR tests for SARS-CoV-2, suggesting that the symptoms constitute pathological sequelae of the infection (25, 177–184).

The renin-angiotensin system (RAS) is believed to play a central role in the pathoge- nesis of COVID-19, and medications that modulate the RAS pathway have been pro- posed as potential therapeutics (185). Under physiological conditions, a decrease in

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renal blood flow stimulates the secretion of renin and generation of angiotensin I (AngI). The angiotensin-converting enzyme (ACE) then converts AngI to angiotensin II (AngII), which mediates effects such as vasoconstriction; sodium and fluid retention in a kidney; fibrosis; inflammation; and vascular permeability. It also leads to accelerated thrombosis by activating the coagulation cascade and flux of neutrophils and macro- phages to the affected tissues. In contrast, ACE2 generates angiotensin fragments (Ang1 to Ang9 and Ang1 to Ang7) which have vasodilatory, anti-inflammatory, antipro- liferative, antifibrotic, and cardioprotective properties (186–190). SARS-CoV-2 infection facilitates loss of the ACE2 catalytic effect, downregulates its expression, and promotes shedding from the cell surface, leading to accumulation of AngII and, through this, to endothelial dysfunction, inflammation, and thrombosis (187, 188, 191–193). While ACE inhibitors (ACEIs) and receptor blockers (ARBs) might be beneficial, the advisability of their usage is debatable (185, 194–197).

Furthermore, coagulopathy and resulting thromboembolic events were observed in COVID-19 patients. Importantly, these conditions were recognized as a cause of death in up to one-third of cases (158, 198–203). In consequence, the International Society on Thrombosis and Hemostasis recommends prophylactic doses of low-molecular- weight heparin (LMWH) for all patients who require hospital admission (202–204), which results in significantly lower mortality (205, 206). Interestingly, this result is a consequence not only of anticoagulative activity of LMWH but also of its anti-inflam- matory activity and LMWH-mediated inhibition of viral adhesion to the cells (205–209). The exact mechanism underlying coagulopathy is unknown; however, recent reports suggest a role of RAS axis dysregulation, inflammation and complement activation, for- mation of neutrophil extracellular traps (NETs), prolonged immobilization of patients, and activation of endothelial cells and platelets (161, 210–218). Endothelial cells are in constant contact with blood and endothelial glycocalyx, providing anticoagulant prop- erties and preventing platelet activation and aggregation. Endothelial damage may easily alter this situation and contribute to the development of disseminated intravas- cular coagulation. Additionally, while formation of NETs is part of the body’s defense against pathogens, dysregulation of this process during COVID-19 may also result in endothelial damage and blood vessel occlusion. Consequently, SARS-CoV-2 may con- tribute to the hypercoagulation observed in patients and multiorgan failure in more- severe cases (158, 159, 161, 199, 216, 217, 219–226). Among the other SARS-CoV-2 manifestations most likely related to endothelial damage are chilblain-like skin lesions, also known as “COVID toes.” While, based on PCR data, evidence of infection is not consistently found, viral particles and proteins were previously observed in endothelial cells from skin biopsy specimens (227–229).

The Heart

There are several hypotheses about the mechanism of underlying cardiac injury during the course of COVID-19; these include direct injury mediated by SARS-CoV-2 virus invasion, pulmonary infection, induced severe cases of hypoxia resulting in damage to myocardial cells, cardiotoxicity of antiviral drugs, and indirect damage mediated by excessive inflam- matory responses. Such indirect damage is especially relevant in patients with preexisting conditions, as inflammation may be associated with rupture of the coronary atheroscler- otic plaques. Furthermore, endothelial cell damage and loss of the cardioprotection pro- vided by Ang1 to Ang7 may also lead to myocardial injury (150, 155, 230–238). Several reports document elevated levels of serum troponin, creatinine kinase, and lactate dehy- drogenase in individuals with COVID-19 (51, 150–152, 155, 230, 239–241). A higher con- centration of troponins, reflecting cardiac injury, is present in 5% to 27.8% of hospitalized patients and is associated with significantly worse prognosis and increased risk of mortality (151, 152, 155, 230, 242, 243). High expression of ACE2 in the heart suggests that direct injury is possible (152, 231, 244); indeed, pericytes are thought to be the target cardiac cells for SARS-CoV-2 due to high ACE2 expression (220, 240). Viral particles have been detected in cardiac tissue (157, 245), and viral replication was shown in human induced

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pluripotent stem cell (iPSC)-derived cardiomyocytes which led to visible cytopathic effects and a decrease in contractility (242).

THE IMMUNE SYSTEM

At the moment, not much data concerning the effects of SARS-CoV-2 on the immune system are available. Palatine tonsils are among the first lines of defense, and SARS-CoV-2 was reported to infect and replicate in 3D tonsil organoids, reflecting the in vivo tonsil epithelium (246). Further, other organs responsible for the immune responses were investigated, and cell degeneration or necrosis was also observed in the spleen (220, 247, 248). Additionally, Diao et al. (249) showed that lymphocytopenia is common among COVID-19 patients, and that finding was confirmed by other stud- ies. It was suggested that components of the immune system might be infected by SARS-CoV-2 and that poor prognoses might be related to loss of specific T-cell subsets (250–254). It was also demonstrated that the virus infects alveolar macrophages (255), as well as ACE2-positive and CD68-positive macrophages, and induces interleukin-6 (IL-6) secretion, which is in some cases associated with a fatal outcome (139, 220, 256–261). A similar effect was observed for SARS-CoV and MERS-CoV, and while most laboratories report poor, incomplete, or abortive replication, these viruses seem to prime macrophages and dendritic cells to release proinflammatory cytokines, leading to systemic hyperinflammation (“cytokine storm”) (252, 262–267). What is more, SARS- CoV-2 was frequently detected in monocytes and B cells and, to a lesser extent, in T cells of COVID-19 patients. The permissiveness of these cells was further confirmed using peripheral blood mononuclear cells (PBMCs) from healthy donors (254, 260). The permissiveness of T-lymphocytes is noteworthy, considering the low level of ACE2 expression; however, there is a need for further study to confirm this phenomenon, as it remains debatable (254, 268). These results are similar to those reported for MERS- CoV, which infects T cells and induces their apoptosis; surprisingly, T cells are resistant to infection by SARS-CoV (269). The entry of SARS-CoV-2 into lymphocytes is unex- pected because MERS-CoV infection correlates with surface levels of DPP4 (269); how- ever, ACE2 expression in T cells is almost nonexistent (268). An alternative route of entry might be a CD147 receptor-dependent route, as this molecule is expressed widely by T lymphocytes or DPP4 as the interaction between Spike S1 domain and DPP4 was predicted. However, those data were not validated experimentally and should be interpreted with caution (270–277). While the complement system repre- sents the first response of the immune system to infection, there is growing evidence that virus-induced activation of this system plays a role in COVID-19 pathogenesis. There are still many unknowns, but postmortem analysis of COVID-19 patients with ARDS revealed deposits of complement components, including membrane attack com- plex (C5b-9), C3, C4, and mannose-binding lectin (MBL)-associated serine protease 2 (MASP2) (278–280). Results of animal studies showed that C3- and C4-deficient mice exhibited lower levels of respiratory dysfunction and body weight loss than wild-type mice. Further, C3 activation was already noted in the lungs 1 day after the infection (280–282). Interestingly, a humanized anti-C5 antibody (eculizumab) was shown to improve patients’ parameters (283, 284).

THE KIDNEY

Acute renal injury was first considered to be an extrapulmonary clinical presenta- tion of SARS-CoV-2 infection (285, 286). Renal involvement was first suggested in reports describing the isolation of infectious viral particles from patients’ urine (287, 288). Chu et al. demonstrated that SARS-CoV-2 replicates in multiple kidney cell lines (54). Among these, the virus productively replicates in CRFK (feline), PK-15 (porcine), RK-13 (rabbit), and LLCMK2 (monkey) cells (54). They also observed SARS-CoV-2 replica- tion in 293T human embryonic kidney cells (54). However, they observed CPE forma- tion only in nonhuman primate kidney cell lines Vero E6 and FRhK-4, where infected cells visibly rounded together and detached from the monolayer (54). Another recent

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study by Monteil et al. demonstrated robust SARS-CoV-2 replication in a human kidney organoid model (98). Several RNA-seq studies identified multiple cell types in the kid- ney that showed extensive ACE2 expression. These included podocytes, glomerular pa- rietal epithelial cells, basal epithelial cells, and tubular epithelial cells (52, 77, 98). Heightened expression of TMPRSS2 and cathepsin L (two suspected facilitators of SARS-CoV-2 infection) was reported in multiple cell types in the kidney (20). Indeed, postmortem electron microscopic analyses of kidney tissues revealed the presence of viral particles in proximal tubules accompanied by abnormal formations of the double- membraned vesicles (289–291). Further immunohistochemical analyses by Diao et al. revealed the presence of macrophage and CD81 T-lymphocyte infiltrates, as well as significant deposition of C5b-9 complement components (290), which is indicative of cytokine release syndrome (292). Further studies are required to establish the pathol- ogy, understand the interplay between host immunity and the infected kidney tissue, and understand the intercellular dissemination of SARS-CoV-2 in this organ.

THE LIVER

Liver injury has been reported in some patients with severe SARS-CoV-2; the avail- able data show that 2% to 11% of COVID-19 patients had liver comorbidities (293). This suggests that this organ is a potential secondary infection site for SARS-CoV-2 (18, 294). Importantly, liver impairment has been previously reported in patients infected with SARS-CoV or MERS-CoV (295, 296). Indicatively, significant elevation of serum ala- nine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) levels has been reported in patients with severe SARS-CoV-2 cases (257, 293, 297), as well as abnormal bilirubin levels (18).

Recently, replication of SARS-CoV-2 in the human hepatocellular carcinoma cell line Huh7 was reported (54). Moreover, two separate studies on the RNA-sequence libraries of human tissues identified the cholangiocyte as a potential target for SARS-CoV-2 infection due to high levels of ACE2 expression (52, 77). This was confirmed by Zhao and colleagues using a human liver ductal organoid model in which they observed ro- bust SARS-CoV-2 replication (298). Dysregulated expression of tight junction protein claudin-1 and two bile acid transporters (apical sodium-dependent bile acid trans- porter [ASBT] and cystic fibrosis transmembrane conductance regulator [CFTR]) was also observed, indicating defective tight junction formation and bile transport in chol- angiocytes due to the SARS-CoV-2 infection (298). It remains unclear whether liver injury in severe cases of SARS-CoV-2 is due to viral infection or excessive immune responses. Analysis of cholangiocyte intercellular interaction networks indicates possi- ble interactions between these cells and Kupffer cells via an interaction between CD74 and macrophage migration inhibitory factor (MIF) (77), which triggers a proinflamma- tory response in various organs (299–301). Another point of contention lies in how pre- existing liver conditions increase the risk of severe SARS-CoV-2 infection; this is because ACE2 expression is upregulated significantly in a cirrhotic liver (302, 303). Conversely, Biquard et al. examined patients with metabolic-associated fatty liver dis- ease and reported no significant change in expression levels of ACE2 or TMPRSS2 in the liver (304). Enhanced infection models are therefore needed to evaluate the activity of resident inflammatory cells in the liver during SARS-CoV-2 infection, along with the relationship between changes in expression of SARS-CoV-2 receptors and lipid metab- olism in the liver.

THE PANCREAS

The pancreas is also a potential target for SARS-CoV-2. Pancreatitis was reported in ferrets infected with a feline coronavirus (305, 306). In the case of SARS-CoV-2, clinical reports have described acute hyperglycemia and transient diabetes in COVID-19 patients without a history of type 2 diabetes, which may indicate pancreatic injury (258). Of note, Liu et al. observed increased levels of amylase and lipase in the sera of patients with severe SARS-CoV-2, and some of those patients also presented focal

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pancreatic enlargement and dilatation of the pancreatic duct under computed tomog- raphy scanning (307). Furthermore, ACE2 is highly expressed by both pancreatic islets and exocrine glands (307, 308). These observations suggest that SARS-CoV-2 may tran- siently infect the pancreatic islets and disrupt glucose metabolism (258). Indeed, Yang et al. demonstrated the permissiveness of human pancreatic alpha and beta cells to SARS-CoV-2, using induced hPSC-derived pancreatic islets and vesicular stomatitis virus (VSV)-based SARS-CoV-2 pseudoviruses (309). Further studies are required to deter- mine the clinical relevance of these observations and possibly also to assess the impact of the infection on patients’ metabolism.

THE NEUROLOGICAL SYSTEM

The involvement of human coronaviruses in a neurological disease was suggested a long time ago. For example, an immunocompromised child with OC43 coronavirus developed fatal progressive encephalitis (310). The neurotropic potential of OC43 and 229E coronaviruses was demonstrated through experimental infection of several microglial, oligodendrocytic, and astrocytic cell lines (311–313). Neurological symp- toms, including headache, confusion, and impaired consciousness, have also been reported in some patients with COVID-19 (314–316). Modest SARS-CoV-2 replication was observed in U251 human glioblastoma cells, which may indicate the neurotropic potential of this virus (54). Very recently, some groups utilized a human brain organoid model to study the pathophysiology of SARS-CoV-2 (317, 318). Although they observed inefficient SARS-CoV-2 replication in this model, they showed that SARS-CoV-2 targets the soma of cortical neurons and is associated with Tau missortment in the axons and soma (317). They also observed colocalization of SARS-CoV-2 particles with Tau phos- phorylated at threonine-231, which is associated with neuronal apoptosis and is indica- tive of the early stage of neurodegeneration (317, 319, 320).

Different routes of coronavirus neuroinvasion have been proposed. Intranasal inoc- ulation of transgenic mice with SARS-CoV expressing human ACE2 results in neuronal dissemination into the brain through the olfactory bulb (321, 322). In the human brain, ACE2 is expressed predominantly in neurons, astrocytes, and oligodendrocytes of the middle temporal gyrus and posterior singular cortex, as well as by endothelial and arte- rial smooth muscle cells (140, 323, 324). Unlike in mice, ACE2 and TMPRSS2 are not expressed in the human olfactory sensory and bulb neurons (325). However, they are expressed in the supporting cells, olfactory basal cells, and perivascular cells (325). These observations not only indicate the possibility of intranasal entry of SARS-CoV-2 into a human brain but could also explain the onset of hyposmia and hypogeusia reported at the early stage of SARS-CoV-2 infection (156, 326). It is worth remembering that the observed neurological symptoms in SARS-CoV-2 patients may also be associ- ated with improper blood coagulation (327–329), resulting in thrombosis of blood ves- sels and ischemic tissue damage. This is indicated by reports describing patients with severe SARS-CoV-2 cases who suffer seizures and impaired consciousness, which are accompanied by ischemic stroke (330, 331). Alternatively, SARS-CoV has also been detected in circulating monocytes (332) and has been shown to induce activation of microglia (321, 333). Furthermore, both monocytic and lymphocytic infiltrates were observed in the brain tissue of a deceased SARS-CoV patient, indicating possible neu- roinflammation during SARS-CoV infection (334). It remains unclear if SARS-CoV-2 can similarly manipulate host innate immune responses to induce inflammatory damage to the blood-brain barrier in order to disseminate into the central nervous system. However, using choroid plexus organoid models, Pellegrini et al. and Fadi et al. demon- strated that SARS-CoV-2 can disrupt the blood-cerebrospinal fluid barrier. They found that SARS-CoV-2 preferentially infected mature choroid plexus epithelium, which abun- dantly expressed ACE2. This resulted in the disruption of tight junction integrity and subsequent leakage of cerebrospinal fluid (318, 335). Nevertheless, further studies using neuronal tissue and blood-brain barrier models are required to investigate SARS- CoV-2 dissemination and pathology in the neurological system.

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The Eye

Eyes were suggested to be potential entry points for SARS-CoV-2 and secondary infection sites. Clinical signs of SARS-CoV-2 infection in the eyes ranged from mild (e.g., chemosis, epiphora, and conjunctival hyperemia) to visual impairment, ophthalmopa- resis, and retinitis (336–338). In multiple cases, viral RNA was detected in ocular dis- charges of SARS-CoV-2 patients both with and without conjunctivitis. The onset of con- junctivitis in some cases precluded the respiratory symptoms (339, 340), and it is hypothesized that SARS-CoV-2 may be transferred from the eyes to the respiratory sys- tem through the nasolacrimal duct connecting the eyes and the nasal cavity (341). Conversely, an onset of ophthalmic clinical signs had also been reported at later stages of COVID-19 (342). Among the components of the human ocular system, expression of SARS-CoV-2 receptor ACE2 had been observed in the conjunctival epithelium, retina, and aqueous humor (343–346). More recently, Makovoz et al. used eye organoids rep- resenting hESC-derived self-formed ectodermal autonomous multizone of ocular cells (SEAM) to study SARS-CoV-2 ocular infection (347). This study identified distinct sub- sets of ACE2-expressing corneal cells, furin-expressing corneal cells, and a presumptive subset of TMPRSS2-expressing corneal cells by bulk RNA sequencing (347). Subsequent infection of eye organoids revealed low levels of SARS-CoV-2 replication in a central cornea and efficient replication in the corneal limbus—the site of corneal and conjunc- tival stem cells (347, 348). Moreover, type I and III interferon responses appeared to be suppressed during SARS-CoV-2 infection of eye organoids, but the NF-κB-mediated inflammatory response was upregulated (347). The replication trend of SARS-CoV-2 observed in the eye organoid was similar to what was observed in intestinal organoids by Lamers et al. (136), highlighting the preference of SARS-CoV-2 for actively proliferat- ing cells. Taking the data together, further studies are required to understand the role of the ocular tissues on SARS-CoV-2 spread.

REPRODUCTIVE SYSTEM

Among the organs affected during COVID-19, reproductive organs have been reported rarely (349, 350). Only a limited number of studies on this topic have been carried out. Bioinformatic analyses and data mining suggest that the testes show a high level of expression of the ACE2 protein (82, 85, 351–354), with the spermatogonia, seminiferous ducts (Sertoli cells), and Leydig cells showing the highest levels (353, 355–362). While the majority of publications postulate that the testes express ACE2, infection of the male reproductive organs by SARS-CoV-2 is not obvious (363, 364). Bian et al. reported the presence of SARS-CoV-2 in testes tissue of deceased COVID-19 patients. This was demonstrated using PCR, immunohistochemistry, and TEM (63). A similar study was carried out by Yang et al., but in this case, 11 of 12 samples tested negative for SARS-COV-2 (365). Li and colleagues evaluated the presence of SARS-CoV- 2 in semen samples from 23 COVID-19 patients in the acute or recovery stage and found 6 of 38 samples positive (366). Song et al. reported that SARS-CoV-2 was not present in semen samples obtained from 12 patients during the recovery phase or in a testicular biopsy specimen from a patient who died during the acute phase (367). In agreement with this, Pan et al. showed that SARS-CoV-2 was not detected in the semen of 34 adult Chinese males recovering from COVID-19 (368), Guo et al. showed that SARS-CoV-2 was not detected in 23 samples collected from patients in the acute and recovery infection phases (369), and Nora et al. did not detect SARS-CoV-2 in 18 semen samples from recovered patients or in two samples from patients with active COVID-19 infection (370). Besides, the virus was not detected in prostatic secretions from 23 COVID-19 patients (371). It is worth noting that Ma et al. and Xu et al. analyzed sex-related hormones levels in 119 and 39 men infected with SARS-CoV-2, respectively. Ma et al. reported some alterations in the hormone levels, whereas Xu et al. did not observe such changes (372, 373).

Except for some transcriptomic studies that evaluated the susceptibility to infection of the female reproductive system (85, 352, 353, 361, 374), data on this subject are

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FIG 6 Organs affected by COVID-19. The solid and dotted lines indicate direct and indirect viral replication, respectively.

limited (19, 375). Jing et al. reported ubiquitous expression of ACE2 in the ovary, uterus, vagina, and placenta (376). Goad et al., using single-cell sequencing of uterus, myometrium, ovary, fallopian tube, and breast epithelium, found that none of these tissues had high expression of ACE2 and none of them showed coexpression with TMPRSS2 (377). Qiu et al. tested vaginal fluid from 10 women with severe COVID-19 disease, but all the samples were negative for the virus (378). Similar results were obtained in other studies that evaluated vaginal fluid samples and breast milk samples from pregnant patients (379–382). Studies of pregnant women with COVID-19 showed that placenta, amniotic fluid, and/or cord blood analysis results were also negative for SARS-CoV-2 (160, 382–387). However, Fenizia et al. analyzed the presence of the viral RNA in nasopharyngeal swabs from the mothers and the newborns; vaginal swabs; maternal and umbilical cord plasma, placenta, and umbilical cord biopsy specimens; amniotic fluids; and milk. SARS-CoV-2 RNA was found in one blood sample from an umbilical cord, two placenta samples, one vaginal mucosa sample, and one milk sam- ple (388). Additionally, three studies identified an infection in the placenta by qPCR, histological examination, and electron microscopy (389–392). It is difficult at this stage to ultimately determine the long-term effect of the infection in pregnant women for the women and their newborns (393–399). Some studies have shown the absence of vertical transmission or complication in the pregnancy or neonates (383, 386, 387, 395, 400, 401), and there are other studies that have reported vertical transmission of the vi- rus (388, 402–404).

Taking into account all of the cited studies, it is evident that the subject should be further evaluated to determine the effect of SARS-CoV-2 on male and female reproduc- tive systems. There is no evidence of sexual transmission of SARS-CoV-2, but the conse- quences regarding male fertility as well as female fertility and perinatal outcomes are not evident at the moment. Nevertheless, it should be a topic of further study and dis- cussion (396, 405–408).

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CONCLUSIONS AND KEY TAKEAWAY MESSAGES

SARS-CoV-2 is a recently emerged virus that has caused a pandemic that has para- lyzed the world. Our understanding of the threat is still limited, and aside from the mortality rate, the long-term consequences of the infection must be discussed widely, particularly when different epidemic management strategies are considered. While the main COVID-19 outcome involves lungs, other organs are also reported to be affected (Fig. 6). During the COVID-19 pandemic, we have witnessed an incredible boost in the research on coronaviruses. In our opinion, some of the most important work encompasses the employment of human organoids, which are three-dimensional, miniaturized, and sim- plified versions of natural organs. The organoids may be used to mirror in vivo tissue orga- nization and complexity, and the relevance of these models has been proven well, as the results obtained using organoids were in several cases confirmed in the clinic. Importantly, the possible sites of infection impact the person-to-person transmission that shapes the pandemic. Some of the observations, however, still require confirmation in vivo, but even the slight possibility of permanent damage to neural or reproductive tissue, cardiac tissue, or blood vessels in children needs to be verified; this is because adoption of the herd im- munity concept may result in a permanent detrimental effect on society that extends beyond that of the pandemic itself.

ACKNOWLEDGMENTS

This work was supported by the funds provided by the Ministry of Science and Higher Education for research on SARS-CoV-2 (K.P.), by grants from the National Science Center (grants UMO-2017/27/B/NZ6/02488 to K.P.), and by EU-Horizon2020 ITN OrganoVir grant 812673.

We declare no conflict of interest. The funders had no role in the preparation of the manuscript.

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Aleksandra Synowiec is a Ph.D. Student at
Malopolska Centre of Biotechnology,
Jagiellonian University, Krakow, Poland. She
completed her master’s degree in molecular
biotechnology at the Faculty of Biochemistry,
Biophysics and Biotechnology, Jagiellonian
University, Krakow, Poland, in 2019. Her area
of interest is molecular biology of viral entry
as well as antiviral research, with a focus on
human coronaviruses and human norovirus.
She has been awarded several awards and
scholarships such as L’Oréal-UNESCO For Women in Science Award or Ministry of Science and Higher Education Scholarship for scientific achievements.

Takeda M, Kinoshita N, Ohmagari N, Gohda J, Semba K, Matsuda Z, Kawaguchi Y, Kawaoka Y, Inoue J-i. 2020. The anticoagulant nafamostat potently inhibits SARS-CoV-2 infection in vitro: an existing drug with multiple possible therapeutic effects. bioRxiv https://doi.org/10.1101/ 2020.04.22.054981.

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421. Milewska A, Kula-Pacurar A, Wadas J, Suder A, Szczepanski A, Dabrowska A, Owczarek K, Marcello A, Ochman M, Stacel T, Rajfur Z, Sanak M, Labaj P, Branicki W, Pyrc K. 2020. Replication of severe acute respiratory syn- drome coronavirus 2 in human respiratory epithelium. J Virol 94:e00957- 20. https://doi.org/10.1128/JVI.00957-20.

422. Milewska A, Chi Y, Szczepanski A, Barreto-Duran E, Liu K, Liu D, Guo X, Ge Y, Li J, Cui L, Ochman M, Urlik M, Rodziewicz-Motowidlo S, Zhu F, Szczubialka K, Nowakowska M, Pyrc K. 2020. HTCC as a highly effective polymeric inhibitor of SARS-CoV-2 and MERS-CoV. bioRxiv https://doi .org/10.1101/2020.03.29.014183.

423. Thacker VV, Sharma K, Dhar N, Mancini G-F, Sordet-Dessimoz J, Mckinney JD. 2020. Rapid endothelialitis and vascular inflammation characterise SARS-CoV-2 infection in a human lung-on-chip model. bioRxiv https://doi .org/10.1101/2020.08.10.243220.

424. Si L, Bai H, Rodas M, Cao W, Oh CY, Jiang A, Nurani A, Zhu DY, Goyal G, Gilpin SE, Prantil-Baun R, Ingber DE. 2020. Human organs-on-chips as tools for repurposing approved drugs as potential influenza and COVID19 therapeutics in viral pandemics. bioRxiv https://doi.org/10 .1101/2020.04.13.039917.

425. Valyaeva AA, Zharikova AA, Kasianov AS, Vassetzky YS, Sheval EV. 2020. Expression of SARS-CoV-2 entry factors in lung epithelial stem cells and its potential implications for COVID-19. Sci Rep 10:17772. https://doi .org/10.1038/s41598-020-74598-5.

Artur Szczepan ski is a Ph.D. Student at
Faculty of Biochemistry, Biophysics and
Biotechnology, Jagiellonian University,
Krakow, Poland. He is finishing his thesis on the
early stages of Canine Respiratory Coronavirus
entry to the cell. He completed his master’s
degree in biotechnology at the Faculty of
Biochemistry, Biophysics and Biotechnology,
Jagiellonian University, Krakow, Poland, in 2013.
His area of interest includes molecular virology
of viral entry with a focus on human and animal
coronaviruses, antiviral research, and advanced methods of imaging.

  

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Synowiec et al.

Clinical Microbiology Reviews



Emilia Barreto-Duran studied Biology at Los
Andes University, Bogota, Colombia, and did
her master’s in Cell Biology at the Pontificia
Universidad Javeriana, also in Bogota. Her
master’s thesis was aimed at developing an
organotypic spheroid model for the study of
the human bone marrow microenvironment.
She is currently a Marie Skłodowska-Curie
Fellow within the OrganoVIR Training Net-
work (MSCA-ITN) at the Jagiellonian Univer-
sity in Krakow, Poland. Emilia is part of Professor’sKrzysztofPyr cresearchgroup,ViroGenticslaboratory,inThe Malopolska Centre of Biotechnology. The objective of her Ph.D. research project is the development of a complex coculture model that resembles the human airway epithelium microenvironment for the study of coronavi- rus pathogenesis.

Laurensius Kevin Lie is a Ph.D. student at
Malopolska Center of Biotechnology, Jagiel-
lonian University, Krakow, Poland. He is an
early-stage researcher enrolled in the Marie
Skłodowska-Curie Action – Integrated Train-
ing Network program OrganoVIR, which
focuses on the study of viruses using orga-
noid technology. He completed his master’s
degree in biomedical science at the Catholic
University of Leuven, Belgium, in 2015. He
had previously worked as a research and
teaching staff in the Laboratory of Hygienic Sciences of Kobe Pharmaceutical University in Japan in 2016. His area of interest is in molecu- lar virology of virus dissemination, with a particular focus on understanding cross-tissue and cross-species dissemination of corona-viruses using organoids.

Krzysztof Pyrc, Ph.D. is a full professor and a
leader of the Virogenetics team at Malopolska
Centre of Biotechnology, Jagiellonian Univer-
sity, Krakow, Poland. Ph.D. in 2007 at the
University of Amsterdam, the Netherlands,
habilitation in 2013 at the University of Lodz,
Poland, and title of professor by the president
of Poland in 2019. Laureate of several national
and international awards and research grants.
Official governmental advisor during the
COVID-19 pandemic, author of almost 100 sci-
entific publications in journals as Nature Medicine, Science Translational Medicine, PNAS, ACS Applied Materials & Interfaces, Journal of Virology, and others. Scientific interests: virology with particular focus on coronavi- ruses and flaviviruses.

 

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