key: cord-0704569-iomao9a7 authors: Liu, Jia; Zheng, Xin; Tong, Qiaoxia; Li, Wei; Wang, Baoju; Sutter, Kathrin; Trilling, Mirko; Lu, Mengji; Dittmer, Ulf; Yang, Dongliang title: Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS‐CoV, MERS‐CoV, and 2019‐nCoV date: 2020-02-21 journal: J Med Virol DOI: 10.1002/jmv.25709 sha: d788066e8d97146037fbde0d0636611d725f91d3 doc_id: 704569 cord_uid: iomao9a7 First reported from Wuhan, The People's Republic of China, on 31 December 2019, the ongoing outbreak of a novel coronavirus (2019‐nCoV) causes great global concerns. Based on the advice of the International Health Regulations Emergency Committee and the fact that to date 24 other countries also reported cases, the WHO Director‐General declared that the outbreak of 2019‐nCoV constitutes a Public Health Emergency of International Concern on 30 January 2020. Together with the other two highly pathogenic coronaviruses, the severe acute respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV), 2019‐nCov and other yet to be identified coronaviruses pose a global threat to public health. In this mini‐review, we provide a brief introduction to the pathology and pathogenesis of SARS‐CoV and MERS‐CoV and extrapolate this knowledge to the newly identified 2019‐nCoV. The available pathology data for SARS-CoV infections were mainly obtained from autopsies. The predominant visceral macroscopic changes in fatal SARS-CoV cases have been edematous lungs with increased gross weights and multiple areas of congestion, enlargement of lymph nodes in the pulmonary hila and the abdominal cavity, as well as a diminished spleen size and reduced spleen weights. 7, 8 Morphological changes were bronchial epithelial denudation, loss of cilia, and squamous metaplasia. 7 The histological feature in the early phase of pulmonary SARS-CoV infections is commonly associated with acute diffuse alveolar damage, while later phases of the disease demonstrate a combination of diffuse alveolar damage and acute fibrinous and organizing pneumonia. 9 Large numbers of SARS-CoV particles and genomic sequences were detected within circulating lymphocytes, monocytes, and lymphoid tissues, as well as in epithelial cells of the respiratory tract, the intestinal mucosa, the epithelium of renal distal tubules, neurons in the brain, and tissue-resident macrophages residing in different organs. 10 Co-localization of SARS-CoV RNA and cellular cytokeratins within the lung was evident by immunofluorescent in situ hybridization, suggesting that pneumocytes become infected. 11 Accordingly, electron microscopic examinations also showed SARS-CoV virions and nucleocapsid inclusions in pneumocytes. 12 Additionally, SARS-CoV may occasionally be identified in the alveolar macrophages of the lung. 12 The mechanisms underlying more severe pathogenicity of SARS-CoV are so far not fully understood. Extensive lung damage in SARS-CoV-infected patients appears to be associated with high initial virus titers, 13 increased monocyte, macrophage, and neutrophil infiltration in the lungs, 7 and elevated levels of serum proinflammatory cytokines and chemokines. 14 High serum levels of proinflammatory cytokines (IL-1, IL-6, IL-12, Interferon γ [IFN-γ], and transforming growth factor-β) and chemokines (CCL2, CXCL9, CXCL10, and IL-8) were found in patients with SARS with severe disease compared to individuals with uncomplicated SARS. 14, [16] [17] [18] In addition, the early induction of CXCL10 and IL-2, as well as the subsequent hyperproduction of IL-6 with a coinciding lack of IL-10 production are thought to contribute to the immuno-pathological processes involved in lung injury during SARS-CoV infection. 17 Additionally, robust and persistent expression of IFN-α, -γ and IFN-stimulated genes (ISGs) accompanied early SARS sequelae. 19 It has also been shown that SARS-CoV infections result in a delayed expression of type I IFN. 20 The delayed-type I IFN signaling, which was accompanied with robust virus replication, was found to promote the accumulation of pathogenic inflammatory monocyte/ macrophages, resulting in elevated lung cytokine/chemokine levels, vascular leakage, and impaired virus-specific T cell responses. 21 The understanding of pathophysiological changes caused by MERS-CoV infections relies on limited numbers of autopsy and biopsy cases. Few studies indicate that the pathological features of MERS-CoV infection include exudative diffuse alveolar damage with hyaline membranes, pulmonary edema, type II pneumocyte hyperplasia, interstitial pneumonia (which was predominantly lymphocytic), and multinucleate syncytial cells. 22, 23 Bronchial submucosal gland necrosis was also observed. 22 These bronchial lesions comprise the pathologic basis for the respiratory failure and radiologic abnormalities of MERS-CoV infection. 24 Target cells of the MERS-CoV infection in the lung include pneumocytes, multinucleated epithelial cells, and bronchial submucosal gland cells. 22 All of these cells express a multifunctional cell surface protein, called dipeptidyl peptidase 4 (DPP4; also known as CD26), constituting the primary entry receptor of MERS-CoV. 25 Ultrastructurally, viral particles were found in the pneumocytes, pulmonary macrophages, macrophages infiltrating the skeletal muscles, and renal proximal tubular epithelial cells. 23 Consistent with the ultrastructural findings in the kidney, renal biopsies demonstrated acute tubulointerstitial nephritis and acute tubular sclerosis with proteinaceous cast formation. 26 DPP4, the entry receptor of MERS-CoV, is widely expressed on epithelial cells in the kidney, alveoli, small intestine, liver, prostate, and on activated leukocytes, 27 suggesting that the range of MERS-CoV tissue tropism is broader than that of any other coronavirus. 28 Accordingly, MERS-CoV was found to be able to infect many human immune cells, including dendritic cells, 29 33 The genetic sequence analysis revealed that the 2019-nCoV belongs to the β-coronavirus genus, with a 79.0% nucleotide identity to SARS-CoV and 51.8% identity to MERS-CoV. 34 Furthermore, it has been reported that nCoV-2019 is 96% identical across the entire genome to a bat coronavirus. 35 Inoculation of the 2019-nCoV onto surface layers of human airway epithelial cells in vitro causes cytopathic effects and cessation of the cilium beating of the cells. 5 The 2019-nCoV infection was of clustering onset that is more likely to affect older males with comorbidities and can result in severe and even fatal respiratory diseases. 36, 37 The major clinical symptoms resulting from 2019-nCoV infection at the prodromal phase include fever, dry cough, myalgia, fatigue, and diarrhea. 38 Many patients also developed dyspnea and lymphopenia. Complications of 2019-nCoV infections included acute respiratory distress syndrome, RNAaemia, acute cardiac injury, and secondary (super-)infections. 38 All reported cases, including asymptomatic patients, had abnormal findings concerning the chest computed tomography (CT) as indicated by bilateral ground-glass opacity. 6, 38 The prototypical findings of chest CT images of seriously ill patients requiring intensive care unit (ICU) admission were bilateral multiple lobular and subsegmental areas of consolidation. 38 MIP1A, and TNF-α than non-ICU patients. 38 These results suggest that immunopathology may also play a relevant role in the development of disease severity. The comprehensive lessons learned from the SARS-CoV and MERS-CoV outbreaks provide, despite their inherent tragedy, valuable experiences and insights into how to fight the 2019-nCoV epidemic. Drugs which inhibit viral dissemination and disrupt viral replication may reduce the coronavirus-induced direct cytopathic effects, and treatments which restrain host inflammatory responses (eg, by antibodies or compounds neutralizing cytokines or their cognate receptors, such as anti-IL-6, anti-IL-6R, or anti-IL-1β), ideally in the respiratory tract only, may reduce virus-triggered immunepathologies. We infer that a combination of such treatments would be the most suitable therapeutic strategy for more severe human coronavirus infections. However, we must bear in mind that currently, no specific antiviral treatment is available for SARS, MERS, and 2019-nCoV, and therefore further research into the pathogenesis of human coronavirus infection is imperative for identifying appropriate therapeutic targets. We thank all the doctors, nurses, disease control workers, and re- Report of clustering pneumonia of unknown etiology in Wuhan City Coronaviruses: genome structure, replication, and pathogenesis Bats are natural reservoirs of SARS-like coronaviruses Emerging diseases. researchers scramble to understand camel connection to MERS A novel coronavirus from patients with pneumonia in China A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster Lung pathology of fatal severe acute respiratory syndrome The clinical pathology of severe acute respiratory syndrome (SARS): a report from China Emerging respiratory infections: The infectious disease pathology of SARS, MERS, pandemic influenza, and Legionella Multiple organ infection and the pathogenesis of SARS Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an insitu hybridization study of fatal cases Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome Elucidating the molecular physiopathology of acute respiratory distress syndrome in severe acute respiratory syndrome patients An interferon-gamma-related cytokine storm in SARS patients Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome Analysis of serum cytokines in patients with severe acute respiratory syndrome Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome Pathogenic influenza viruses and coronaviruses utilize similar and contrasting approaches to control interferon-stimulated gene responses Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice Clinicopathologic, immunohistochemical, and ultrastructural findings of a fatal case of Middle East respiratory syndrome coronavirus infection in the United Arab Emirates Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infectionclinicopathological and ultrastructural study Value of autopsy emphasized in the case report of a single patient with Middle East respiratory syndrome Dipeptidyl peptidase 4 distribution in the human respiratory tract: implications for the Middle East respiratory syndrome A case report of a middle east respiratory syndrome survivor with kidney biopsy results Differential expression of the Middle East respiratory syndrome coronavirus receptor in the upper respiratory tracts of humans and dromedary camels From SARS to MERS, thrusting coronaviruses into the spotlight Productive replication of Middle East respiratory syndrome coronavirus in monocyte-derived dendritic cells modulates innate immune response Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis Middle East respiratory syndrome coronavirus efficiently infects human primary T lymphocytes and activates the extrinsic and intrinsic apoptosis pathways MERS coronavirus induces apoptosis in kidney and lung by upregulating Smad7 and FGF2 A novel coronavirus outbreak of global health concern Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study A pneumonia outbreak associated with a new coronavirus of probable bat origin Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS-CoV, MERS-CoV, and 2019-nCoV The authors declare that there are no conflict of interests. http://orcid.org/0000-0002-8262-4997