title: Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis.
abstract: Parasitic helminth worms, such as Schistosoma mansoni, are endemic in regions with a high prevalence of tuberculosis (TB) among the population. Human studies suggest that helminth coinfections contribute to increased TB susceptibility and increased rates of TB reactivation. Prevailing models suggest that T helper type 2 (Th2) responses induced by helminth infection impair Th1 immune responses and thereby limit Mycobacterium tuberculosis (Mtb) control. Using a pulmonary mouse model of Mtb infection, we demonstrated that S. mansoni coinfection or immunization with S. mansoni egg antigens can reversibly impair Mtb-specific T cell responses without affecting macrophage-mediated Mtb control. Instead, S. mansoni infection resulted in accumulation of high arginase-1-expressing macrophages in the lung, which formed type 2 granulomas and exacerbated inflammation in Mtb-infected mice. Treatment of coinfected animals with an antihelminthic improved Mtb-specific Th1 responses and reduced disease severity. In a genetically diverse mouse population infected with Mtb, enhanced arginase-1 activity was associated with increased lung inflammation. Moreover, in patients with pulmonary TB, lung damage correlated with increased serum activity of arginase-1, which was elevated in TB patients coinfected with helminths. Together, our data indicate that helminth coinfection induces arginase-1-expressing type 2 granulomas, thereby increasing inflammation and TB disease severity. These results also provide insight into the mechanisms by which helminth coinfections drive increased susceptibility, disease progression, and severity in TB.
authors.forename: Leticia
authors.initials: L
authors.lastname: Monin
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Griffiths
authors.forename: Wing Y
authors.initials: WY
authors.lastname: Lam
authors.forename: Radha
authors.initials: R
authors.lastname: Gopal
authors.forename: Dongwan D
authors.initials: DD
authors.lastname: Kang
authors.forename: Mushtaq
authors.initials: M
authors.lastname: Ahmed
authors.forename: Anuradha
authors.initials: A
authors.lastname: Rajamanickam
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cruz-Lagunas
authors.forename: Joaquín
authors.initials: J
authors.lastname: Zúñiga
authors.forename: Subash
authors.initials: S
authors.lastname: Babu
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.forename: Makedonka
authors.initials: M
authors.lastname: Mitreva
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Rosa
authors.forename: Rosalio
authors.initials: R
authors.lastname: Ramos-Payan
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Morrison
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
authors.forename: Javier
authors.initials: J
authors.lastname: Rangel-Moreno
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Pearce
authors.forename: Shabaana A
authors.initials: SA
authors.lastname: Khader
mesh_terms: D000818:Animals; D001119:Arginase / Q000097:blood*; D005260:Female; D006099:Granuloma / Q000201:enzymology / Q000382:microbiology / Q000469:parasitology / Q000473:pathology; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000382:microbiology / Q000469:parasitology / Q000473:pathology; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis; D012550:Schistosoma mansoni; D012555:Schistosomiasis mansoni / Q000097:blood* / Q000382:microbiology / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000097:blood* / Q000469:parasitology / Q000473:pathology
chemical_list: C574619:ARG1 protein, human; C544448:Arg1 protein, mouse; D001119:Arginase