Project 2: Metabolic regulation of host response and repair mechanisms to influenza A viral pneumonia

Project summary
Viral pneumonia is currently among the most common causes of death in the world. Viral pneumonia impairs
tissue repair leading to both in-hospital death and prolonged hospital-acquired disability. Understanding and
targeting mechanisms that impair tissue repair after viral pneumonia therefore offers promise to both improve
survival and prevent multiple organ morbidity after hospital discharge. In this Project and PPG, we hypothesize
that ongoing inflammation after the influenza A virus (IAV) is cleared precludes proper lung repair. The cytosolic
NOD-like receptor protein-3 (NLRP3)-dependent inflammasome complex initiates production of mature forms of
the inflammatory cytokines IL-1 and IL18, inducing recruitment of effector cells to the site of infection that are
essential to clearance of the influenza A virus. In addition, inflammasome activation within the monocyte derived
alveolar macrophages participates in the ongoing inflammation observed in patients after influenza A virus
clearance. Mitochondria have been proposed to be key regulators of NRLP3 dependent inflammasome
activation. Our preliminary data demonstrate that inhibition of mitochondrial complex I or III as well as
administration of sodium lactate, which does not alter the pH, attenuates inflammasome activation. Furthermore,
our preliminary data indicate that monocyte-derived alveolar macrophages upon influenza infection display an
increase in mitochondrial pyruvate carrier (MPC) mRNA, which diminishes pyruvate conversion into lactate by
lactate dehydrogenase A (LDHA). We will test whether inflammasome dependent inflammation post-viral
clearance in mice requires mitochondrial complexes I and III as well as lactate production in monocyte-derived
alveolar macrophages using conditional knockout mice. Collectively these hypotheses will be tested in three
interrelated Specific Aims: (1) Is mitochondrial complex I generated ROS required for influenza A induced
NLRP3-dependent inflammasome activation in monocyte-derived alveolar macrophages? (2) Is mitochondrial
complex III produced ROS necessary for influenza A induced NLRP3-dependent inflammasome activation in
monocyte-derived alveolar macrophages? (3) Does in vivo lactate production decrease NLRP3-dependent
inflammasome activation following influenza A virus infection in monocyte-derived alveolar macrophages.

Grant Number: 5P01HL154998-05
NIH Institute/Center: NIH
Principal Investigator: NAVDEEP CHANDEL