Role of SARS-CoV-2-infected pulmonary cells and antibody response in COVID-19 outcomes: From pathophysiology to testing candidate drugs in mucosal cell models – MUCOLUNG
The emerging SARS (Severe Acute Respiratory Syndrome)-CoV (Corona virus)-2 is a novel airborne coronavirus threatening public health that is currently spreading worldwide causing the severe respiratory syndrome known as COVID-19 1, for which no treatment is yet available. One of the relevant questions regarding the current COVID-19 pandemic is the wide spectrum of disease severity ranging from mild to severe, especially in a subgroup of patients that might develop a cytokine storm syndrome accompanied by a hyperinflammation syndrome 2. The lung is one of the major target of virus infection and severe COVID-19 has been associated with a massive influx of myeloid cells that might, as lung epithelial cells, be targeted by the virus.
While the cell receptor and entry mechanisms of SARS-CoV-2 have been recently described in cell lines3, which cell type(s) in the lung are targeted by the virus as well as virus replication and spread mechanisms remain to be determined. In contrast to lung biopsies, the bronchoalveolar lavage (BAL) that contains all cell types composing the lung are easy to sample and routinely collected in patients for diagnostic purposes. BAL from COVID-19 individuals therefore represents a reliable biological material to address the cell specificity of SARS-CoV-2 infection and its dynamic.
The immunoglobulin (Ig)/antibody (Ab) response raised through either contemporary or earlier infection is a key determinant in controlling virus replication in infected individuals. Among other Ig classes, IgAs represent the first line of defense against microbial mucosal invasion and are the predominant Ig class in lung secretion, whereas IgG subclasses have been detected in patients with high levels of inflammatory disorders and could potentially contribute to the severity of COVID-19.
We believe that our expertise can contribute to approach a critical question on COVID-19, namely how to inhibit the exacerbated inflammatory reaction responsible for the acute respiratory syndrome in COVID-19 patients. Achieving this would promote full recovery of respiratory capacities and shortening hospitalization period on intensive care units. We hypothesize that pulmonary myeloid cells such as macrophages and megakaryocytes host SARS-CoV-2 and orchestrate an inflammatory cytokine storm that promotes lethal acute respiratory syndrome.
Objectives and Strategy:
In this collaborative project, complementary tasks will be developed. We will:
1- Use SARS-CoV-2-infected patient BAL samples to address the pathophysiology of the COVID-19 induced disease in the lung by investigating both in vivo and ex vivo the interaction between the virus and its target cells and the specificity of the mucosal humoral immune responses to the virus as compared to the systemic one.
2- Establish an association between SARS-CoV-2-infected cell lineages and antibody responses with COVID-19 severity in vivo
3- Develop mucosal lung cell models, with which candidate drugs will be evaluated for their activities against SARS-CoV-2 lung cell infection and COVID-19-induced hyperinflammation.
This collaborative project developing complementary research axes will involve MD partners having direct access to COVID-19 patient samples and researcher teams that have complementary expertise in virus host interaction, especially at mucosal level and the viral immune response. Furthermore partners are long lasting collaborators, and their common research has resulted in the publication of highly-recognized scientific articles in the field over the years.
Altogether, these results will provide a better understanding of the factors controlling the virulence of SARS-CoV-2 and will help to establish the protective nature of the humoral immune response. Our cell models will contribute to the development of drug candidates.
Madame Morgane Bomsel (Institut Cohin)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INSERM Institut Cohin
Help of the ANR 142,560 euros
Beginning and duration of the scientific project: March 2020 - 18 Months