Unexpected role for IL-17 in protective immunity against hypervirulent Mycobacterium tuberculosis HN878 infection.
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), infects one third of the world's population. Among these infections, clinical isolates belonging to the W-Beijing appear to be emerging, representing about 50% of Mtb isolates in East Asia, and about 13% of all Mtb isolates worldwide. In animal models, infection with W-Beijing strain, Mtb HN878, is considered "hypervirulent" as it results in increased mortality and causes exacerbated immunopathology in infected animals. We had previously shown the Interleukin (IL) -17 pathway is dispensable for primary immunity against infection with the lab adapted Mtb H37Rv strain. However, it is not known whether IL-17 has any role to play in protective immunity against infection with clinical Mtb isolates. We report here that lab adapted Mtb strains, such as H37Rv, or less virulent Mtb clinical isolates, such as Mtb CDC1551, do not require IL-17 for protective immunity against infection while infection with Mtb HN878 requires IL-17 for early protective immunity. Unexpectedly, Mtb HN878 induces robust production of IL-1β through a TLR-2-dependent mechanism, which supports potent IL-17 responses. We also show that the role for IL-17 in mediating protective immunity against Mtb HN878 is through IL-17 Receptor signaling in non-hematopoietic cells, mediating the induction of the chemokine, CXCL-13, which is required for localization of T cells within lung lymphoid follicles. Correct T cell localization within lymphoid follicles in the lung is required for maximal macrophage activation and Mtb control. Since IL-17 has a critical role in vaccine-induced immunity against TB, our results have far reaching implications for the design of vaccines and therapies to prevent and treat emerging Mtb strains. In addition, our data changes the existing paradigm that IL-17 is dispensable for primary immunity against Mtb infection, and instead suggests a differential role for IL-17 in early protective immunity against emerging Mtb strains.
Department of Pediatrics, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Radha
R
Gopal
Department of Pediatrics, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Leticia
L
Monin
Department of Pediatrics, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Samantha
S
Slight
Department of Pediatrics, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Uzodinma
U
Uche
Department of Pediatrics, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Emmeline
E
Blanchard
Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Beth A
BA
Fallert Junecko
Faculty of Biological and Chemical Sciences, Autonomous University of Sinaloa, Culiacan, Sinaloa, Mexico; Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, United States of America.
Rosalio
R
Ramos-Payan
Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, Missouri, United States of America.
Christina L
CL
Stallings
Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Todd A
TA
Reinhart
Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
Jay K
JK
Kolls
Tulane National Primate Center, New Orleans, Louisiana, United States of America.
Deepak
D
Kaushal
Department of Pediatrics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
Uma
U
Nagarajan
Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, United States of America.
Javier
J
Rangel-Moreno
Department of Pediatrics, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America; Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, Missouri, United States of America.
Shabaana A
SA
Khader
D000818:Animals; D002478:Cells, Cultured; D021821:Communicable Diseases, Emerging / Q000235:genetics / Q000276:immunology; D019610:Cytoprotection / Q000235:genetics / Q000276:immunology; D005260:Female; D007113:Immunity, Innate / Q000235:genetics*; D020381:Interleukin-17 / Q000235:genetics / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000502:physiology; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology
C583355:IL1R1 protein, mouse; C098680:Il17a protein, mouse; D020381:Interleukin-17; D053583:Interleukin-1beta; D053573:Receptors, Interleukin-1 Type I; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2