Mycobacterium tuberculosis ESX-1 induces eicosanoid mediated neutrophil influx to the lung during Tuberculosis

Abstract

Abstract Tuberculosis disease (TB) is characterized by excessive inflammation and irreversible tissue damage. To determine the bacterial factors responsible for regulating inflammation, different TB susceptible mouse strains were infected with a pool of transposon mutants of M. tuberculosis (Mtb) that revealed transposon insertions into ESX1 locus impaired the ability to cause disease in susceptible mice and elicit inflammatory response comparable to wild type Mtb. However, the underlying mechanisms of ESX1 mediated tissue damage in vivo is obscure. This study aims at elucidating the mechanism by which Mtb ESX1 regulate tissue damaging inflammation in vivo. Mtb ESX-1 secretion function was required for inducing neutrophil infiltration to the lungs, of TB susceptible mice (iNOS−/−, IL1R1−/−, C3HeB/FeJ). Deletion of ESX-1 from virulent Mtb (ΔESX-1) had little impact on T cells, but significantly reduced the neutrophil/T lymphocyte ratio that favored efficient bacterial control. Co-infection of these mice with wild-type and ΔESX-1, rescued the defective neutrophil influx seen in mice infected with the ΔESX-1 alone. Further, the neutrophil influx elicited by wild type Mtb follows the loss of pro-surfactant C expressing type II alveolar epithelial cells that coincided with the generation of lipoxygenase derived eicosanoids in the lungs; indicating involvement of these chemotactic lipid mediators in initiating neutrophil recruitment in an ESX1 dependent fashion. Taken together, this study provides evidence for the involvement of ESX1 in regulating tissue damaging neutrophilic inflammation during TB, expanding the current understanding of the pleiotropic functions of type VII secretion apparatus.