Mucosal Associated Invariant T Cell During Viral Pneumonia and Acute Respiratory Distress Syndrome

Overview

Viral pneumonia, including SARS-CoV-2 and influenza A virus (IAV), can culminate in acute respiratory distress syndrome (ARDS), a severe form of respiratory failure with high mortality. Uncontrolled local inflammatory response and impaired tissue repair are hallmarks of ARDS. However, lack of in-depth understanding of the immunopathology lead to limited identification of potential 'endotypes' who may benefit from individualized targeted therapies. Mucosal Associated Invariant T (MAIT) cells represent a peculiar lineage of T cells with a wide panel of effector functions. Thus, they emerge as potential key players and appealing targets in ARDS through their potent abilities to modulate immune response at barrier sites and promote tissue repair. Recent data from the investigators and others indicated that MAIT cells are highly activated in patients with Sars-Cov-2 and IAV ARDS, but the associated activation mechanisms and precise functions remain unknown. In this context, the investigators aim at investigating the implication and potential harnessing of MAIT cells in severe viral pneumonias and associated ARDS by with a dedicated clinical study. First, the investigators will perform a comprehensive and longitudinal phenotyping of immune response during viral pneumonia-induced ARDS, including MAIT cells, in blood -and airway compartment for mechanically ventilated patients. To provide more insight into specificity of virally induced pneumonia and ARDS, longitudinal phenotyping of immune response of patients with bacterial pneumonia, and control patients with unrelated ARDS (severe trauma, pancreatitis or major surgery) will also be performed.

Viral pneumonias, notably those caused by Sars-CoV-2 and influenza, are important threats for humans. Both viral infection and subsequent activation of the immune system result in lung injury. In severe cases, disruption of the lung alveolo-capillary membrane and associated edema impair gas exchanges, requiring admission in intensive care unit (ICU) and respiratory support. Uncontrolled local immune response, non-resolving inflammation and impaired tissue repair may develop in few days and perpetuate respiratory failure, forming the so-called 'Acute Respiratory Distress Syndrome' (ARDS), which culminates with a mortality rate close to 40%. Pathophysiology of ARDS remains poorly understood, which may explain the absence of immunomodulatory treatments despite numerous clinical trials, except for steroids in severe COVID-19. To develop new treatments, the investigators need to dissect the immunopathology of ARDS with new approaches and provide pathophysiological 'endotypes' to lead to future precision-medicine clinical trials1. Here, the investigators will investigate implication and therapeutic use of Mucosal Associated Invariant T (MAIT) cells. MAIT cells recently emerged as key-players in immune responses at barrier sites, including the lungs, where they modulate local immune responses and promote tissue repair. Given their rapid and wide effector potential, MAIT cells are particularly relevant in acute conditions such as ARDS. Interestingly, MAIT cells protect against lethal influenza infection in mouse models. In patients, MAIT cells are activated and their frequency is decreased in blood during severe bacterial and viral infections. In severe COVID-19 patients, the investigators and others showed that MAIT cells from blood and airways were strongly activated. Our preliminary results in other infectious ARDS show high frequency of activated blood MAIT cells, but not in ICU patients admitted for other reason than pneumonia, suggesting that activation does not result from the acute critical condition. While the investigators observed that high activation of MAIT cells in blood was associated with positive clinical outcome, other studies observed a negative association. These discrepancies, probably linked to differences in severity between cohorts, also suggest that MAIT cell play versatile (potentially opposite) functions according to the context in severe viral pneumonias and associated ARDS. Thus, determining how and when these potentially contrasted functions are set and controlled during ARDS is paramount to target MAIT cells for treatment. Hence, the investigators need to i) better characterize MAIT cell phenotype and functions throughout virally-induced ARDS in patients; ii) develop a mechanistic approach to explore MAIT cell functions and therapeutic manipulation in such settings. The study will enroll 150 patients admitted in ICU for influenza and COVID-19 pneumonia, bacterial pneumonia, and control patients with unrelated ARDS (severe trauma, pancreatitis or major surgery). In parallel with comprehensive longitudinal clinical assessment, the investigators will assess MAIT cell frequency and activation marker expression (CD69, CD56, PD-1) in blood and airways. Analysis of the other immune lineages will generate a comprehensive map of the immune response in association with MAIT cell. Among each group, 'prototypical' patients will be selected based on their clinical outcome: rapidly recovering, prolonged ICU stay and death. Blood MAIT cell function and other main myeloid and lymphoid cells will be extensively characterized throughout the disease, by RNA sequencing and secretome analysis. Integrative analysis of these data will define the differentiation patterns of MAIT cells, their dynamic and considered location (blood versus airways). The analysis will also test the hypothesis for which patients with poor outcome and non-resolving ARDS have less tissue-repair oriented MAIT cells.