Team Francois TROTTEIN

Lung Infection and Innate Immunity (L3I)

 

Respiratory infections remain major public health and socio-economical hurdles worldwide and it is now established that inflammatory and metabolic disorders enhance their incidence. The identification of susceptibility factors might lead to a better control of pathologies associated with respiratory infections. The laboratory is mainly interested in two clinically relevant pathogens: influenza A virus (flu) and Streptococcus pneumoniae (pneumococcus). Our objectives are:

  • To identify early host antibacterial and antiviral defense mechanisms during influenza and S. pneumoniae infections (theme 1),
  • To define host molecular and cellular factors that predispose to secondary bacterial (pneumococcal) infections during (1) influenza infection,  (2) chronic obstructive pulmonary disease and (3) obesity (theme 2),
  • To develop new strategies to strengthen host defense mechanisms against respiratory pathogens (theme 3).

Theme 1: Innate immune responses to respiratory infections

Innate immunity plays a critical role in host defense against pathogens and regulates the balance between inflammation and tissue repair. The laboratory has a major focus on pulmonary innate immune cells including dendritic cells, non-conventional T lymphocytes, innate lymphoid cells and respiratory epithelial cells.

Natural Killer T (NKT) lymphocytes are non-conventional T lymphocytes that recognize lipid antigens. Our data show a major role for NKT cells in the early steps of influenza and S. pneumoniae infections. During influenza, NKT cells produce interleukin-22 (IL-22) that protects against epithelial damage instigated by the virus. During S. pneumoniae infection, NKT cells participate in bacterial clearance by promoting the effector functions of neutrophils and alveolar macrophages. We have also found that lung innate lymphoid cells produce IL-22 in response to S. pneumoniae infection. More recently, we have identified a new population of pulmonary gd T cells able to produce IL-17 and IL-22 in response S. pneumoniae infection. Our studies now seek to understand the functions of these innate immune cells and the contribution of Th17-type cytokines in host defense and tissue repair processes during influenza and S. pneumoniae infections.

 

Theme 2: Susceptibility factors for secondary respiratory bacterial infections

Acute or chronic lung inflammation, either induced by infectious or chemical agents or associated with metabolic disorders, can predispose to respiratory infections. Influenza infection is often complicated by pneumococcal superinfections. In this context, dysfunction of innate defense mechanisms against bacteria and alteration of epithelial barrier functions are crucial factors. We showed that influenza instigates inhibitory mechanisms (via IL-10) that hamper the innate protective role of NKT cells against S. pneumoniae. This mechanism favours secondary pneumococcal infections. In contrast, IL-22 produced during influenza reinforces the epithelial barrier function, thus limiting bacterial translocation.

Exposure to pollution and cigarette smoke is an important risk factor for chronic obstructive pulmonary disease (COPD), the third cause of mortality in 2020 worldwide. Progression of COPD is marked by episodes of exacerbations mostly caused by bacterial infections. We have developed a mouse model of COPD (long-term exposure to cigarette smoke) and initiated human clinical studies to decipher mechanisms leading to COPD and to secondary bacterial infections. We showed that NKT cells (via early IL-17 production) participate in COPD pathogenesis. Our recent data indicate that enhanced susceptibility to bacterial infections during mouse and human COPD is associated with impaired Th17 cytokine production. These findings might lead to therapeutic and diagnostic perspectives for the control of COPD.

Obesity is characterized by low grade chronic inflammation and predisposes to respiratory infections. We have recently developed experimental models to elucidate the association between obesity, lung inflammation, and viral and bacterial infections.

 

Theme 3: Therapeutic strategies-Development of mucosal immune-stimulators

Immune intervention represents a promising means to prevent or treat infectious respiratory diseases. In this context, we showed that bacterial flagellin (a Toll-like receptor 5 agonist) and a-galactosylceramide (an NKT cell activator) exert prophylactic activities against S. pneumoniae challenge by stimulating innate immunity. Moreover, flagellin and a-galactosylceramide are potent mucosal adjuvants for vaccination. For instance, intranasal administration of flagellin induces strong innate and adaptive immunity by activating airway epithelium and conventional dendritic cells. We are attempting to optimize mucosal immune responses and adjuvant properties of flagellin and a-galactosylceramide, particularly in the context of inflammatory and metabolic disorders. To this end, innovative formulations and delivery systems are being developed.

 

Contacts

Drs Philippe GOSSET/Muriel PICHAVANT ((Activer Javascript pour voir les adresses mails / Enable Javascript to see the email address))

Keywords: BPCO, exacerbation, clinical studies, Th17 cytokines

Drs Jean Claude SIRARD/Christophe CARNOY ((Activer Javascript pour voir les adresses mails / Enable Javascript to see the email address))

Keywords: Flagellin, adjuvants, innate lymphoid cells, S. pneumoniae

Drs François TROTTEIN/Christelle FAVEEUW/Christophe PAGET ((Activer Javascript pour voir les adresses mails / Enable Javascript to see the email address))

Keywords: influenza, bacterial superinfection, innate lymphocytes, immune stimulators.

Dr Isabelle WOLOWCZUK ((Activer Javascript pour voir les adresses mails / Enable Javascript to see the email address))

Keywords: Obesity, metabolic disorders, bioenergy, lung infections

 

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