title: Hypervirulent M. tuberculosis W/Beijing strains upregulate type I IFNs and increase expression of negative regulators of the Jak-Stat pathway.
abstract: The role of type I interferons (IFNs) in the host response to bacterial infections is controversial. Here, we examined the role of IFN-alpha/beta in the murine response to infection with Mycobacterium tuberculosis, using wildtype mice, mice with impaired signaling through the type I IFN receptor (IFNAR), and mice treated to reduce levels of type I IFNs. In this study, we used virulent clinical isolates of M. tuberculosis, including HN878, W4, and CDC1551. Our results indicate that higher levels of type I IFNs are induced by the HN878 and W4 strains. Induction of type I IFNs was associated with lower levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin- 12 (IL-12) and reduced T cell activation, and associated with decreased survival of the mice infected with HN878 or W4 relative to infection with CDC1551. Infection of mice with HN878 and W4 was also associated with relatively higher levels of mRNA for a number of negative regulators of the Jak-Stat signaling pathway, such as suppressors of cytokine signaling (SOCS) 1, 4, and 5, CD45, protein inhibitor of activated Stat1 (PIAS1), protein tyrosine phosphatase nonreceptor type 1 (Ptpn1), and protein tyrosine phosphatase nonreceptor type substrate 1 (Ptpns1). Taken together, these results suggest that increased type I IFNs may be deleterious for survival of M. tuberculosis-infected mice in association with reduced Th1 immunity.
authors.affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute, International Center for Public Health, 225 Warren Street, Newark, NJ 07103-3535, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Manca
authors.forename: Liana
authors.initials: L
authors.lastname: Tsenova
authors.forename: Sherry
authors.initials: S
authors.lastname: Freeman
authors.forename: Amy K
authors.initials: AK
authors.lastname: Barczak
authors.forename: Michael
authors.initials: M
authors.lastname: Tovey
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
authors.forename: Clifton
authors.initials: C
authors.lastname: Barry
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D005786:Gene Expression Regulation; D015964:Gene Expression Regulation, Bacterial; D053613:Janus Kinase 1; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000378:metabolism* / Q000472:pathogenicity*; D020411:Oligonucleotide Array Sequence Analysis; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism / Q000382:microbiology; D018417:Th1 Cells; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D014774:Virulence
chemical_list: D002352:Carrier Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C472529:SOCS4 protein, mouse; D050791:STAT Transcription Factors; C491590:Socs1 protein, mouse; C485811:Socs5 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1