Severe acute respiratory syndrome (SARS), which is caused by a novel coronavirus (CoV), is a highly communicable disease with the lungs as the major pathological target. Although SARS likely stems from overexuberant host inflammatory responses, the exact mechanism leading to the detrimental outcome in patients remains unknown. Pulmonary macrophages (Mφ), airway epithelium, and dendritic cells (DC) are key cellular elements of the host innate defenses against respiratory infections. While pulmonary Mφ are situated at the luminal epithelial surface, DC reside abundantly underneath the epithelium. Such strategic locations of these cells within the airways make it relevant to investigate their likely impact on SARS pathogenesis subsequent to their interaction with infected lung epithelial cells. To study this, we established highly polarized human lung epithelial Calu-3 cells by using the Transwell culture system. Here we report that supernatants harvested from the apical and basolateral domains of infected Calu-3 cells are potent in modulating the intrinsic functions of Mφ and DC, respectively. They prompted the production of cytokines by both Mφ and DC and selectively induced CD40 and CD86 expression only on DC. However, they compromised the abilities of the DC and Mφ in priming naïve T cells and phagocytosis, respectively. We also identified interleukin-6 (IL-6) and IL-8 as key SARS-CoV-induced epithelial cytokines capable of inhibiting the T-cell-priming ability of DC. Taken together, our results provide insights into the molecular and cellular bases of the host antiviral innate immunity within the lungs that eventually lead to an exacerbated inflammatory cascades and severe tissue damage in SARS patients.
Severe acute respiratory syndrome (SARS) was originally identified as an atypical pneumonia emerging from southern China.This highly contagious respiratory disease, with an 8 to 15% mortality rate, rapidly spread to other countries within Asia and to other continents, causing devastating social, economic, and medical impact worldwide. Individuals severely affected by SARS have had clinical manifestations characterized by fever, dry cough, lymphopenia, various degrees of pancytopenia, arterial hypoxemia, and rapidly progressing changes in chest radiography.Through an intense international effort, the causative agent of SARS has been identified as a novel coronavirus (CoV). The transmission of this deadly virus is thought to be mediated primarily through virus-laden droplets but also via either small-particle aerosol or fecal-oral routes, with the lungs as its main pathological target.
Human coronaviruses (HCoVs) are large RNA viruses that infect the human respiratory tract. The emergence of both Severe Acute Respiratory Syndrome and Middle East Respiratory syndrome CoVs as well as the yearly circulation of four common CoVs highlights the importance of elucidating the different mechanisms employed by these viruses to evade the host immune response, determine their tropism and identify antiviral compounds. Various animal models have been established to investigate HCoV infection, including mice and non-human primates. To establish a link between the research conducted in animal models and humans, an organotypic human airway culture system, that recapitulates the human airway epithelium, has been developed. 

Currently, different cell culture systems are available to recapitulate the human airways, including the Air-Liquid Interface (ALI) human airway epithelium (HAE) model. Tracheobronchial HAE cultures recapitulate the primary entry point of human respiratory viruses while the alveolar model allows for elucidation of mechanisms involved in viral infection and pathogenesis in the alveoli. These organotypic human airway cultures represent a universal platform to study respiratory virus- host interaction by offering more detailed insights compared to cell lines. Additionally, the epidemic potential of this virus family highlights the need for both vaccines and antivirals. No commercial vaccine is available but various effective antivirals have been identified, some with potential for human treatment. These morphological airway cultures are also well suited for the identification of antivirals, evaluation of compound toxicity and viral inhibition.
Background
Respiratory diseases caused by human coronavirus infection are of both medical and socio-economic importance. Currently, they are studied in various model systems, ranging from cell lines to animal models. Originally, the importance of HCoVs in the burden of human disease was underestimated and as a result, no general therapy exists to treat coronavirus induced disease in humans. Furthermore, no commercial vaccine is available leaving the human population vulnerable to emerging coronavirus infections. Both the Severe Acute Respiratory Syndrome and Middle East Respiratory Syndrome coronaviruses have recently crossed the species barrier and entered the human population to cause severe disease. In this review, we summarize the current knowledge on human coronavirus infection emphasizing the usefulness of organotypic human airway cultures as a model system.