title: Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population.
abstract: Type I IFN has been demonstrated to have major regulatory effects on the outcome of bacterial infections. To assess the effects of exogenously induced type I IFN on the outcome of Mycobacterium tuberculosis infection, we treated pathogen-exposed mice intranasally with polyinosinic-polycytidylic acid condensed with poly-l-lysine and carboxymethylcellulose (Poly-ICLC), an agent designed to stimulate prolonged, high-level production of type I IFN. Drug-treated, M. tuberculosis-infected WT mice, but not mice lacking IFN-alphabeta receptor 1 (IFNalphabetaR; also known as IFNAR1), displayed marked elevations in lung bacillary loads, accompanied by widespread pulmonary necrosis without detectable impairment of Th1 effector function. Importantly, lungs from Poly-ICLC-treated M. tuberculosis-infected mice exhibited a striking increase in CD11b+F4/80+Gr1int cells that displayed decreased MHC II expression and enhanced bacterial levels relative to the same subset of cells purified from infected, untreated controls. Moreover, both the Poly-ICLC-triggered pulmonary recruitment of the CD11b+F4/80+Gr1int population and the accompanying exacerbation of infection correlated with type I IFN-induced upregulation of the chemokine-encoding gene Ccl2 and were dependent on host expression of the chemokine receptor CCR2. The above findings suggest that Poly-ICLC treatment can detrimentally affect the outcome of M. tuberculosis infection, by promoting the accumulation of a permissive myeloid population in the lung. In addition, these data suggest that agents that stimulate type I IFN should be used with caution in patients exposed to this pathogen.
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA. lisantonelli@cpqrr.fiocruz.br
authors.forename: Lis R V
authors.initials: LR
authors.lastname: Antonelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Gigliotti Rothfuchs
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gonçalves
authors.forename: Ester
authors.initials: E
authors.lastname: Roffê
authors.forename: Allen W
authors.initials: AW
authors.lastname: Cheever
authors.forename: Andre
authors.initials: A
authors.lastname: Bafica
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.forename: Carl G
authors.initials: CG
authors.lastname: Feng
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis; D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D007370:Interferon Type I / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D008168:Lung / Q000382:microbiology*; D008264:Macrophages / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology*; D011070:Poly I-C / Q000627:therapeutic use*; D011107:Polylysine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D054390:Receptors, CCR2 / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D039481:CD11b Antigen; C515335:Ccr2 protein, mouse; D007370:Interferon Type I; D054390:Receptors, CCR2; D011107:Polylysine; D016899:Interferon-beta; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C
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