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Neutrophils: Friend or Foe in tuberculosis pathogenesis?
Shabaana A. Khader, PhDASSOCIATE PROFESSOR
DEPARTMENT OF MOLECULAR MICROBIOLOGYWASHINGTON UNIVERSITY IN ST.LOUIS
ST. LOUIS
Neutrophils in TB pathogenesis: Friend or Foe?
Adapted from Craig et al, 2009
Chemokines (CXC, IL-8)Cytokines (IL-1b, TNF),LTB4
Phagocytosis,proteases,ROS, RNSCalprotectin (S100)
Vascular endothelium
Adhesion molecule upregulation
Transmigration
Alveolar Type II
IL-17
Neutrophils are infected with Mtb, and accumulate early in the lungs of Mtb-infected mice
Wolf et al, 2007Kang et al, 2011
Transient depletion of neutrophils impairs T cell activation and IFN production
Kang et al, 2011
Blomgran et al, 2011
Transient depletion of neutrophils impairs Mtb transport to LNs
Blomgran et al, 2011
Blomgran et al, 2011
Transient depletion of neutrophils does not impair overall bacterial control
Kang et al, 2011
Neutrophils play a protective role in early granulomas in zebrafish
Yang et al, 2012Green-neutrophil, Red-M.marinum
Can neutrophils kill mycobacteria
Mycobacteriastrain
Reference
No Mtb H37Rv Dennis, 1991
No Mtb H37Ra/M.bovisBCG
Aston et al, 19
No Mtb HL186T Reyes‐Ruvalcaba, 2007
No Mtb H37Rv Ramos‐Kichik,2009
No Mtb H37Rv Corleis et al, 2012
Yes Mtb H37Rv Jones et al, 1990
Yes Mtb H37Ra Majeed et al, 1998
Yes Mtb Erdman Kisich, 2002
Yes Mtb H37Rv and M.bovis BCG
Maritenau et al, 2007
Yes M.marinum Yang et al, 2012
Can neutrophils kill mycobacteria- jury is still out
Neutrophil-Friend?
ChemokinesCytokines
1. Mtb killing ?2. DC migration/T cell priming3. Early granuloma formation
Vascular endothelium
Neutrophilic responses inmice genetically susceptible to Mtb
Eruslanov et al, 2005
Eum et al, 2010
Neutrophils are the predominant infected phagocyte in airways of ATB patients
An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis
Berry et al, 2010Bloom, et al, 2013Ottenhoff et al, 2012 etc.
S100A8-expressing neutrophils are dominant within human A-TB granulomas
Gopal et al, 2013
S100A8/A9 expressing neutrophils are dominant within A-TB granulomas in a NHP model of TB
Gopal et al, 2013Matilla et al, 2013
Serum S100A8/A9 proteins as biomarkers fordetermining disease severity in human TB
Gopal et al, 2013
Severity of lung inflammation levels in genetically diverse (JDO)Mtb-infected mice correlates with S100A8/A9-expressing neutrophils
Gopal et al, 2013
Neutrophil- Friend or Foe?
ChemokinesCytokines
1. Mtb killing ?2. DC migration/T cell priming3. Early granuloma formation
FRIEND-EARLY STAGES
Vascular endothelium1. Neutrophilic granulomas2. Inflammation and pathology3. Lung injury
FOE- UNRESTRAINED, DISEASE PROGRESSION
IL-17Host and Mtb strain dependent
Adapted from Craig et al, 2009
ChemokinesCytokines
proteases,ROS, RNSCalprotectin (S100)
Can HDT be used to treat neutrophilic inflammation during TB?
Vascular endothelium
Adhesion molecule upregulation
Gopal et al, 2013
Depletion of neutrophil or neutrophil associated products/receptors abrogates inflammation in murine models
Nouailles et al, 2014
Can HDT be used to treat neutrophilic inflammation (along with chemotherapy) during TB?
Drug Company Inhibits Clinical trials
Midesteine Medea Research
Elastase Phase III
Zileuton Critical Therapeutics
LTB4 Phase III(some proinfl.effects)
BAYX1005 Bayer LTB4 Phase II (modest effects)
SCH‐527123 Schering‐Plough
CXCR1/2 antagonist
Phase II (36.5 reduction)
SB‐656933 Glaxo CXCR2 antagonist
Phase I (55‐75 reduction)
BAY‐71‐9678 Bayer Elastase Phase I
FPS‐ZM1 Berislav et al.2013
RAGE experimental
Acknowledgements
Deepak Kaushal (Tulane University)
Moises Selman (U.Mexico)
Joaquin Zuniga (U.Mexico)
Thomas Scriba (SATVI)
Willem Hanekom (SATVI)
Subash Babu (NIH‐TRC)
Tom Vogl (Muenster University)
Dan Zak (Seattle Biomed) Alan Aderem (Seattle Biomed)
Funding NIH ‐NHLBI, NIAID
Children’s Hospital of Pittsburgh
CTSI‐Pittsburgh
Washington University in St. Louis
Collaborators
